Điều Trị Bỏng Toàn Diện (Bản Expert Consult)

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350
In addition to insulin protocols, reassessing patients’
caloric needs and reducing intake as their clinical
status changes is an important step in managing
hyperglycemia. A number of other adjuncts can
contribute to effective blood sugar maintenance,
including controlling infections, increasing patient
activity, and restricting oral intake of sweets. Oral
hypoglycemic agents and anabolic agents may
ultimately prove to have major benefit in this effort.181
•
Other metabolic complications A number of other
common metabolic complications are summarized in
Table 29.4. Both deficiencies and excesses of serum
electrolytes are common, and often associated with
fluid balance. Significant deficiencies of vitamins or
essential fatty acids are very rare, and usually found
only in patients treated exclusively with TPN for long
periods.
Complications of enteral nutrition
In addition to the metabolic complications listed in Table
29.4, a number of other complications can occur, specifically
with the use of enteral nutrition. Mechanical complications
include misplaced feeding tubes, gastric distension, nausea,
and aspiration. All tube placements should be verified prior
to use, and clinicians must monitor gastrointestinal function
frequently. Surgically placed gastrostomy or jejunostomy
tubes eliminate problems with tube migration but are associ­
ated with (generally low) risks of dislodgement, leakage, and
bowel perforation. Some units have added blue dye to tube
feeds in an effort to detect aspiration more efficiently.
However, the low specificity and sensitivity of this method
of detecting aspiration, coupled with reports of dye-
associated mortality, have led the FDA to recommend elimi­
nating blue dye for this purpose.182
Bowel necrosis and perforation
Several reports have documented bowel necrosis and perfo­
ration as a rare complication in the critically ill, including
burn patients.183–185 It is likely that continued administration
of tube feeding in the face of decreased bowel motility causes
distension, interfering with intestinal blood supply. Bacterial
overgrowth of stagnant tube feedings and administration of
narcotics and antidiarrheal agents also contribute to this
complication.99 Fever, leukocytosis, tachycardia, and abdom­
inal distension may precede frank peritonitis. Abdominal CT
scanning can confirm perforation, which mandates laparot­
omy and usually intestinal resection. Mortality rates approxi­
mate 50%.184
Diarrhea
Tube feedings are frequently blamed for diarrhea, which can
range from a minor problem to a major source of patient
discomfort, fluid and electrolyte imbalance, and morbidity.
Often the cause is multifactorial.186 The high glucose loads
of hypertonic tube feedings may contribute to diarrhea,
although diluting feedings has generally not proved helpful
in treatment. Enteral medications, including antacids, phos­
phates, antibiotics, and others, also contribute to diarrhea.
Infectious causes include cytomegalovirus infection187 and
•
Hyperglycemia Hyperglycemia is extremely common
following critical illness. Approximately 10–20% of
patients admitted to ICUs have pre-existing diabetes.
Far more important, however, is that up to 90% of all
ICU patients develop elevated blood glucose values
during their hospital stay.175 In burn patients, insulin’s
effects are overwhelmed by catabolic hormones,
causing relative insulin resistance and hyperglycemia
which can be both profound and sustained – the
‘diabetes of injury.’ Prolonged elevations in blood sugar
are clearly associated with immune deficiency and
increased susceptibility to infection; this may also be
true for acute hyperglycemia;175 and, as infection
exaggerates glucose intolerance, infection and
hyperglycemia often potentiate each other.
Recent evidence has emphasized the value of
maintaining glucose levels as close to normal as
possible. In a landmark study, surgical ICU patients
randomized to a regimen of ‘intensive’ glucose control
(maintaining glucose levels at 80–110 mg/dL),
compared to more traditional control (180–200 mg/
dL) had substantial reductions in multiple organ
failure, infection, renal failure, length of stay, and
mortality.176 Additional evidence suggests that insulin
may itself be beneficial by reducing circulating levels of
C-reactive protein and other proinflammatory
compounds,177,178 which may explain some of the
benefits shown in these studies.
These findings have contributed to widely accepted
recommendations for very rigorous glucose control in
ICU populations.179 However, other recent large studies
have found that intensive insulin therapy may be
associated with increased mortality and an
unacceptably high incidence of hypoglycemia.180 Thus,
the optimal target level for blood sugar has not been
defined. Current recommendations are for ‘moderately
strict’ glucose control (target levels 110–150 mg/dL)
which appears to offer many of the benefits of intensive
therapy while minimizing risks.4
In response to these recommendations, many units
have adopted comprehensive protocols for intensive
monitoring and treatment of blood sugar values.
Effective glucose control often requires substantial
insulin doses, meticulous monitoring, and significant
nursing time. Hyperglycemia is both more common
and more severe with TPN than with EN, and this
alone constitutes a powerful argument for avoiding
parenteral nutrition. However, hypoglycemia can also
occur frequently, particularly if insulin regimens are not
followed carefully. At the University of Utah we have
developed a uniform protocol for glucose control
which is standardized throughout all adult ICUs; this
prevents many potential errors in insulin
administration when nurses ‘float’ or house staff
‘cross-cover’ unfamiliar patients. Our protocol begins
with use of a ‘sliding scale’ for subcutaneous
administration of insulin in patients who are
hyperglycemic. If this fails to reduce blood sugar, a
regimen of continuous IV insulin (‘insulin drip’) is
begun. These protocols are illustrated in Figure 29.4
Similar protocols have been developed in many burn
care facilities.

Nutritional support of the burned patient
351
Start Insulin Protocol
Any BG >250
Start Insulin Drip Protocol
(next page)
3 Consecutive BG >120
BG continues to be >120 or pt
transferring out of critical care unit
OR
BG between 60–120 x 48 hours
Consider:
1. Home insulin regimen
2. Oral diabetic medications
3. Long acting insulin
4. D/C protocol and order another sliding scale
5. Continue the insulin drip
Hypoglycemia Protocol:
If BG <60 mg/dL, give 1
amp (50 mL) D50 IV and
repeat every 30 minutes until
BG >60. Then resume the
protocol as instructed above.
IV Regular insulin
sliding scale
*Hypoglycemia
protocol & call HO
0
4 units
7 units
10 units
13 units
Start Drip Protocol
Glucose level
(mg/dL)
<60
60–120
121–150
151–180
181–210
211–250
>250
Initial Hyperglycemia Management Guidelines
Burn Intensive Care
University of Utah
A
Figure 29.4  Hypoglycemia Management
Guidelines, Burn Intensive Care Unit, University of
Utah. (a), Addressograph.
Clostridium difficile.188 A prospective study found an associa­
tion between the concentration of fat in tube feedings and
the incidence of diarrhea;189 diarrhea was reduced in a group
of children fed a low-fat ‘immune-enhancing diet.’82 Because
the gut’s tolerance of tube feedings is limited, diarrhea is
increased with overfeeding and can often be controlled by
reducing infusion rate.
A variety of compounds have been suggested for treatment
of diarrhea, including opiates (Imodium, Lomotil, Paregoric,
etc.), bulk agents (Metamucil), fiber-containing tube feed­
ings, and others. Fiber may help prevent bacterial overgrowth
and stasis,190 but use of these compounds has also been
blamed for intestinal stasis and bowel necrosis.191 In addition,
fiber-containing feedings sometimes clog small-diameter
tubes. In our experience, attempts to control diarrhea
with medications are frequently either ineffective or lead to
constipation and distension. Infectious diarrhea may be
worsened by slowing intestinal transit. Most diarrhea is
self-limited and does not require pharmacologic therapy.
Options for management include altering the tube formula,
stopping enteral medications, reducing the infusion rate,
or simply waiting a day or two. It may be necessary to with­
hold feedings temporarily to permit refractory diarrhea to
resolve.192
Complications of parenteral nutrition
Many complications of TPN are both more common and
potentially more severe than those of enteral nutrition.
Technical complications of line placement for TPN can
be life-threatening, including pneumothorax, hemothorax,
pericardial tamponade, hydrothorax, catheter misplacement,
hemorrhage, or air embolism. Serious infections including
catheter sepsis, septic thrombophlebitis, and endocarditis
are well-recognized and dreaded complications of central
lines. These infections are more common when catheters are
placed through cutaneous burn wounds,193 when they are
used for TPN, and if they are used for multiple purposes
(blood draws, hemodynamic monitoring, maintenance
fluids, etc.). Patients should be evaluated daily for the
ongoing necessity for central venous catheters, and lines
should be removed as soon as possible.

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352
or excess can develop. A number of other common compli­
cations of any nutritional regimen can be either more fre­
quent or more severe when associated with TPN use as
opposed to enteral nutrition. Such complications are out­
lined in Table 29.4.194
Metabolic complications of TPN can be both severe and
difficult to treat. Because TPN often represents the only fluid
and electrolyte therapy given to patients, the body’s ability
to compensate for deficiencies/excesses is severely limited,
and almost any disorder of electrolyte or vitamin deficiency
B
Insulin drip protocol
Important note:
All patients receiving
IV insulin drip therapy
must have a
continuous source of
glucose (continuous
tube feeds OR TPN
unless ordered by MD)
Step 1: initiate insulin infusion
• Standard insulin drip: Regular insulin 100 units/100 mL of NS
• Give IV bolus as indicated and initiate insulin drip based on the following table:
Initiation of insulin drip protocol only
Blood glucose
Regular insulin
bolus
Regular insulin
dose
121–140
141–169
170–249
250–299
300–399
400–500
>500
<60
60–79
80–120
121–140
141–170
171–250
>250
0 units
6 units
8 units
10 units
10 units
10 units
10 units
1 unit/h
1 unit/h
2 units/h
3 units/h
4 units/h
5 units/h
6 units/h
Blood glucose
Infusion rate adjustment
Hold drip. Give 1/2 amp D50. Recheck
Q30min, repeat 1/2 amp D50 until BG >60
Hold drip. Check BG in 1 hour. If BG >80,
restart at 1/2 rate prior to holding drip
No change
↑ rate by 0.2 unit/h
↑ rate by 1 unit/h
Give 8 units regular insulin bolus and
↑ rate by 1 unit/h
Give 10 units regular insulin bolus and
↑ rate by 1 unit/h
Note: If blood glucose <60 on glucometer send
sample to the lab for measurement per policy
Step 2: monitoring
• Check BG Q1h timed such that BG are checked 1 hour after drip
initiation or rate change.
• If 3 consecutive BG within 80–120 with no change in therapy,
reduce checks to Q2h.
• Then, if 3 consecutive BG within 80–120 with no change in
therapy and insulin rate is ≤2 units/h, reduce checks to Q4h.
Step 3: ongoing infusion
• Make adjustments based on the following table:
Step 5: discontinuation
• After insulin drip is discontinued, check BG Q2h.
• Begin appropriate insulin sliding scale and/or oral diabetic
agents (i.e. home regimen).
• If BG decreases by ≥100 mg/dL from previous level, ↓ rate by
1/2 and recheck in 1 hour.
• If BG ≤150 mg/dL and subsequent level decreases by
≥30 mg/dL, ↓ rate by 1/2.
• If patient’s enteral or parenteral nutrition is discontinued,
hold insulin drip and check BG Q2h and restart sliding scale
on previous page.
Step 4: important nursing information
(b), Insulin drip protocol.
Figure 29.4

Nutritional support of the burned patient
353
 
Access the complete reference list online at

Conclusion
Although nutritional support following a major burn con­
tinues to evolve, several aspects are clear. Enteral nutrition
with high calorie and protein solutions is generally benefi­
cial, although there is no ‘one-size-fits-all’ solution: needs
vary with each individual and change throughout the course
of care. A thorough protocol involving all team members
that includes ongoing and systematic assessment can tailor
support to changing needs, and provide optimal care to
every patient.
Further reading
Cave MC, Hurt RT, Frazier TH, et al. Obesity, inflammation, and the
potential application of pharmaconutrition. Nutr Clin Pract. 2008
Feb;23(1):16-34.
Comment: Excellent article summarizing current knowledge of
physiology and support of the obese, critically ill patient.
Dickerson RN, Gervasio JM, Riley ML, et al. Accuracy of predictive
methods to estimate resting energy expenditure of thermally
injured patients. JPEN. 2002 Jan-Feb;26(1):17-29.
Comment: This careful review compared measured energy expenditure
in 24 adult burn patients with predicted values from 46 published
formulas. Authors found that NONE of these formulas were within 15%
of actual measurements; formulas published before 1980 tended to
over-estimate energy requirements significantly. This review underscores
the difficulties of using predictive formulas for individual patients.
Hart DW, Wolf SE, Chinkes DL, et al. Determinants of skeletal
muscle catabolism after severe burn. Ann Surg. 2000 Oct;232(4):
455-465.
Comment: This sophisticated study using stable isotope kinetics
demonstrated that increased muscle wasting is seen in heavier
patients, more muscular patients, and those in whom surgery is
delayed.
Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the
provision and assessment of nutrition support therapy in the adult
critically ill patient: Society of Critical Care Medicine and
American Society for Parenteral and Enteral Nutrition: Executive
Summary. Crit Care Med. 2009;37(5):1757-1761.
Comment: This authoritative clinical guideline summarizes current
recommendations for nutritional support of critically ill patients, and
includes burn patients, though specific data for burns is lacking in many
areas. Specific recommendations include early enteral nutrition,
indications for PN, dosing and monitoring of EN, selection of EN
formulas for specific conditions, and adjunctive therapy. Authors
specifically recommend hypocaloric nutrition for obese patients, and use
of immune-enhancing diets for burn patients, both of which remain
unproven and controversial.
Windle EM. Glutamine supplementation in critical illness: evidence,
recommendations, and implications for clinical practice in burn
care. J Burn Care Res. 2006 Nov-Dec;27(6):764-772.
Comment: Of all the components of ‘immune-enhancing’ diets, the
greatest evidence can be found in support of glutamine supplementation
for burn patients. This article reviews the evidence for use of this
component.

Nutritional support of the burned patient
353.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
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134. Gottschlich MM, Mayes T, Khoury JC, et al. Significance of
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135. Hobson KG, Havel PJ, McMurtry AL, et al. Circulating leptin and
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136. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose
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138. Cave MC, Hurt RT, Frazier TH, et al. Obesity, inflammation, and
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140. Jeevanandam M, Young DH, Schiller WR. Obesity and the
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141. Ireton-Jones C. Comparison of the metabolic response to burn
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143. Duncan GE. The ‘fit but fat’ concept revisited: population-based
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144. Berger MM, Chiolero RL. Hypocaloric feeding: pros and cons.
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148. Burge JC, Goon A, Choban PS, et al. Efficacy of hypocaloric
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149. Choban PS, Burge JC, Scales D, et al. Hypoenergetic nutrition
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150. Dickerson RN, Rosato EF, Mullen JL. Net protein anabolism with
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151. McCowen KC, Friel C, Sternberg J, et al. Hypocaloric total
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152. Dickerson RN. Hypocaloric feeding of obese patients in the
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Mar;8(2):189-196.
153. Shopbell J, Hopkins B, Shronts E. Nutrition screening and
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154. Gump F, Kinney J. Energy balance and weight loss in burned
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155. Zdolsek HJ, Lindahl OA, Angquist KA, et al. Non-invasive
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156. Hart DW, Wolf SE, Herndon DN, et al. Energy expenditure and
caloric balance after burn: Increased feeding leads to fat rather
than lean mass accretion. Ann Surg. 2002;235(1):152-161.
157. Streat S, Beddoe A, Hill G. Aggressive nutritional support does
not prevent protein loss despite fat gain in septic intensive care
patients. J Trauma. 1987;27:262-266.
158. Graves C, Saffle J, Morris S. Comparison of urine urea nitrogen
collection times in critically ill patients. Nutr Clin Pract. 2005
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159. Konstantinides FN, Radmer WJ, Becker WK, et al. Inaccuracy of
nitrogen balance determinations in thermal injury with
calculated total urinary nitrogen. J Burn Care Rehabil. 1992
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160. Konstantinides F, Radmer W, Becker W, et al. Inaccuracy of
nitrogen balance determinations in thermal injury with
calculated total urinary nitrogen. J Burn Care Rehabil.
1992;13:254-260.
161. LeBlanc A, Gogia P, Schneider V, et al. Calf muscle area and
strength changes after five weeks of horizontal bed rest. Am J
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162. Rettmer R, Williamson J, Labbe R, et al. Laboratory monitoring
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163. Greenhalgh DG, Housinger TA, Kagan RJ, et al. Maintenance of
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164. Sheridan RL, Prelack K, Cunningham JJ. Physiologic
hypoalbuminemia is well tolerated by severely burned children.
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165. Cynober L, Prugnaud O, Lioret H, et al. Serum transtyretin levels
in patients with burn injury. Surgery. 1991;109:640-644.
166. Manelli J, Abdetii C, Botti G, et al. A reference standard for
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167. Meakins J, Pietsch J, Bubekik O. Delayed hypersensitivity:
indicator of acquired failure of host defenses in sepsis and
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168. Pietsch J, Meakins J. Delayed hypersensitivity response:
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170. Bachrach LK. Dual energy X-ray absorptiometry (DEXA)
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171. Williamson J. Actual burn nutrition care practices: a national
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172. Askanazi J, Rosenbaum S, Hyman A, et al. Respiratory changes
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173. Lowry S, Brennan M. Abnormal liver function during parenteral
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174. Iapichino G, Radrizzani D. Parenteral Nutrition. In: Webb A,
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179. Lewis KS, Kane-Gill SL, Bobek MB, et al. Intensive insulin
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183. Kowal-Vern A, McGill V, Gamelli R. Ischemic necrotic bowel
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Modulation of the hypermetabolic
response after burn injury
Gerd G. Gauglitz, Celeste C. Finnerty, David N. Herndon,
Felicia N. Williams, Marc G. Jeschke
Introduction
Treatment of the sequelae induced by a severe burn injury
presents a substantial medical management challenge. More
than 1 million burns occur in the USA annually. Even though
the majority of these patients have minor injuries, nearly
20% of patients with thermal injuries are admitted for treat­
ment at specialized burn centers each year.1 Advances in
clinical knowledge and treatment strategies have resulted in
a major decline in burn-associated deaths over the last two
decades; these advances include defining the hypermetabolic
response, refining reconstructive techniques, supporting
inhalation injury in an aggressive manner, and improving
infection control.2,3
Despite these improvements in clinical care, severe burn
injuries can still lead to multi-system organ failure, with
associated morbidity and mortality.4 The dramatic metabolic
changes underlying severe burn injury clearly contribute to
unfavorable outcomes in severely burned patients.4,5
Metabolic alterations following severe
burn injury
Characterization of the response to severe burn injuries
covering over 40% of the total body surface area (TBSA) has
shown the association of severe hypermetabolism and
inflammatory and stress responses with development of a
hyperdynamic circulation, altered body temperature regula­
tion, glycolysis, proteolysis, lipolysis, and inefficient sub­
strate cycling.6–8 The severity, duration, and magnitude of the
metabolic changes are uniquely different in burn patients
than in other critically ill patients.4 Enhanced secretion of
catecholamines, glucocorticoids, glucagon, and dopamine is
closely associated with the formation of the acute hyper­
metabolic response and the associated catabolic state.6,9–16
However, the underlying mechanisms of this complex
response to burn injury remain unclear. Based on current
knowledge, a variety of cytokines (including tumor necrosis
factor (TNF), platelet-activating factor (PAF), interleukin
(IL)-1, and IL-6), endotoxin, nitric oxide, reactive oxygen
species, and complement cascades participate in this multi­
factorial response to burn injury.17 These modulators act
to increase metabolic rate and alter glucose metabolism
post-burn.18
The metabolic derangements after burn injury occur in
two distinct patterns that are time-dependent.19 Within 48 h
post-burn, decreases in oxygen consumption, cardiac output,
metabolic rate, and glucose tolerance are considered the
“ebb phase.”19,20 Amplification of these metabolic changes
within the first 5 days post-burn to a plateau characterizes
the second phase. This so-called “flow phase” is typically
characterized by the development of a hyperdynamic circula­
tion alongside the hypermetabolic state.
Multiorgan dysfunction results from the extreme activa­
tion of the acute phase response post-burn. Immediately
post-burn, patients typically have low cardiac outputs char­
acteristic of early shock.21 However, 72–96 h post-burn, at
the onset of shock, cardiac outputs are >150% of those in
non-burned, healthy volunteers.22 Heart rates in burn
patients approach 160% of those in non-burned, healthy
patients.23 After severe burn injury, cardiac work is signifi­
cantly elevated, and this lasts well into the rehabilitation
phase.4,24 Myocardial oxygen consumption values far surpass
values seen in trained long-distance runners, and these
values remain elevated far into the rehabilitative phase.25 A
profound hepatomegaly also develops after burn injury. We
have shown that the liver may increase by 225% within 2
weeks of injury and remains enlarged at discharge by 200%.22
The release of insulin during this time period is increased
in response to glucose load when compared with con­
trols,24,26 and glucose levels remain significantly elevated,
signifying an insulin-resistant state.26,27 Although it was
believed that these metabolic derangements resolved as the
wound healed, we and others have demonstrated that the
duration of this hypermetabolic response may exceed 1 year
after burn trauma.6,9,16,28 Post-burn hypermetabolic altera­
tions may last for up to 36 months and include elevations
in cortisol, cytokines, and catecholamines; increased resting
energy expenditures; hindered glucose metabolism; and
decreased insulin sensitivity.
In healthy human beings, a postprandial increase in serum
glucose levels stimulates insulin secretion from pancreatic
β-cells, which in turn decreases hepatic gluconeogenesis and
supports peripheral uptake of glucose into adipose tissue
and skeletal muscle.29,30 Acutely after burn injury, profound
derangements in energy substrate metabolism occur. The
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00030-8
CHAPTER 30 
Access the complete reference list online at

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30
356
monocyte chemotactic protein (MCP)-1 act directly on the
insulin signal transduction pathway through insulin recep­
tor substrates, resulting in both post-burn hyperglycemia
insulin resistance43–45 and lean muscle catabolism during the
acute and convalescent phases post-burn.46,47
During starvation, energy is supplied by lipolysis and
ketosis. Marked lean body mass (LBM) wasting occurs
because the burn patient preferentially uses skeletal muscle
as the major source of fuel.4,48 Nitrogen balance studies
(whole body and cross leg) show persistent muscle break­
down for up to 9 months post-burn.49 Importantly, as the
skeletal muscle accounts for the majority of insulin-
stimulated, whole-body glucose uptake, significant LBM loss
may contribute to post-burn insulin resistance.50 Flakoll and
co-workers51 studied the relationship between muscle protein
catabolism and hyperglycemia, demonstrating that a signifi­
cant increase in proteolysis rates was not accompanied by
changes in leucine oxidation or non-oxidative disposal. They
also demonstrated that increased plasma glucose levels sti­
mulate whole-body proteolysis during hyperinsulinemia.51
Catabolic losses in LBM correlate with increased morbidity
and mortality: marked delays in wound healing and signifi­
cant increases in infection rates accompany a loss of 10% of
LBM;52 wound healing is impaired following a 20% loss in
LBM; severe infections are associated with losses of 30%
of LBM; losses of 40% or more ultimately lead to death.
Acutely, the net LBM losses from muscle wasting lead to
prolonged mechanical ventilation, inhibition of cough
reflexes, and a delay in mobilization, markedly contributing
anabolic properties of insulin are inhibited by stress media­
tors (cortisol and catecholamines) to increase delivery of
glucose to vital organs.31 In thermally injured patients, the
availability of gluconeogenic substrates is increased by lipo­
lysis of adipose tissue32 and proteolysis of skeletal muscle.33
This, in turn, augments hepatic glucose production (Fig.
30.1).29,30,34,35 The normal feedback mechanisms are dis­
torted as part of the response to burn. Elevated blood glucose
levels fail to suppress hepatic glucose release,36 while the
inhibitory effects of insulin on hepatic glucose secretion
exacerbate hyperglycemia after severe burn injury.37 This is
further complicated by catecholamine-mediated glycogeno­
lysis in the liver and sympathetic stimulation of glycogen
breakdown.30 Catecholamines impair glucose disposal and
cause peripheral insulin resistance by altering the insulin
signaling pathway and by changing GLUT-4 translocation in
adipose and muscle tissue (Fig. 30.1).29,38 In fact, in muscle
biopsied at 1 week post-burn, insulin receptor signaling via
Akt was diminished.37 A physiologic link exists between
impaired mitochondrial oxidative function in the liver versus
the muscle, resulting in altered lipolysis and impaired insulin
signaling post-burn. This affects the inhibitory actions of
insulin on glucose production in the liver and alters glucose
uptake into skeletal muscle.26,32,36,37
Glucagon plays a major role during the acute phase post-
burn as well. Like epinephrine, glucagon increases the pro­
duction of glucose by glycogenolysis and gluconeogenesis.39
These actions are further intensified by secretion of various
proinflammatory cytokines.40–42 Specifically, IL-6, TNF, and
Figure 30.1  The effects of metabolic dysfunction after severe burn injury.34
Burn wound
↑↑20-fold Catecholamines
Serum
↑↑Glucagon
↑↑Cortisol ↑↑Insulin
Bone
↓↓Calcium
↓↓Magnesium
Fat
↑↑Oxygen consumption
Heart
↑↑Cardiac output ↑↑Heart rate
↑↑Nitrogen wasting
↑Fractures
↓Bone mineral content
↓Bone mineral density
↑↑Fatty acids
↑↑Glycerol
↑↑Lactate
Glutamine
Kidney
Ammonia
Liver
Urea Ammonia
Glucose
Glycolysis Lactate
Pyruvate
Lipid complexes
Alanine Glutamine
Muscle
Glucose
Glycolysis Lactate
Pyruvate
Glucose
Intestine
Alanine Ammonia
Glutamine

Modulation of the hypermetabolic response after burn injury
357
Nutritional support
Patients suffering from severe burns who are treated solely
with vigorous oral supplementation may lose one-quarter of
their pre-admission weight within the first several weeks.66
Therefore, adequate nutrition is a critical issue for severely
burned patients. A high-calorie nutritional intake is associ­
ated with diminished muscle metabolism after burn.67
However, high-calorie feeding has recently been associated
with enhanced mortality rates.68 Instead of overfeeding, ade­
quate caloric enteral intake is currently recommended.4,58
Various formulations have been established to adequately
meet the energy requirements of each individual burn
patient.69–71 The Curreri formula (25 kcal/kg per day plus
40 kcal/% TBSA burned per day) is normally used to calcu­
late the caloric requirements in adult burn patients.72 The
marked post-burn changes in lipid, carbohydrate, and
protein metabolism determine the caloric needs of each
respective patient. The optimal dietary composition includes
1–2 g/kg per day of protein, supporting the synthetic needs
of the patient, thus counteracting the proteolysis occurring
in muscle tissue.48 Many intensive care units (ICUs) deliver
a substantial percentage of calories as fat because essential
fatty acid deficiency frequently accompanies long-term
nutritional supplementation.73 This approach reduces
carbohydrate requirements and burn-induced glucose intol­
erance, and therefore, dietary compositions of 30–50% fat
are now the standard of care when treating critically ill
patients.48 Unfortunately, enhanced fat administration in
burn patients is associated with hepatic steatosis, hypox­
emia, hyperlipidemia, higher infection rates, and higher
postoperative mortality rates.74–76 Hepatic triglyceride levels
are enhanced, thereby limiting the utility of exogenous lipids
as a post-burn energy source.32,73,77,78 Recent data obtained
by our group demonstrated that patients receiving Vivonex®
T.E.N., a low-fat/high carbohydrate diet, had a significantly
lower incidence of hepatic steatosis than milk-fed burn
patients. We also demonstrated improved survival, signifi­
cantly lower incidences of sepsis, reduced length of ICU stay
per % TBSA, and markedly decreased average ICU stay. We
thus advocate nutritional regimens for burn patients that
include reduced proportions of fat.
Environmental support
Burn patients may lose a significant portion of body water
(approximately 4000 mL/m2 burned/day) by way of evapo­
rative or other losses from extensive burn wounds.79 Skin
and core temperatures are increased by 2°C above normal
to abate the resultant hypermetabolic and catabolic responses
by generating a portion of energy needed to offset the
losses in heat accompanying the water loss. Increasing the
ambient temperature to 33°C may result in a decrease to 1.4
times the resting energy expenditure instead of 2.0 times
the resting energy expenditure. This environmental modula­
tion is a key primary treatment goal that is too often
under-utilized.80
Exercise and adjunctive measures
Burn-wound contracture remains a morbid consequence of
severe burns. It is well established that physical therapy is
to increased mortality in these patients.53 Chronically, these
net losses reduce strength and the possibility for full reha­
bilitation. Our patients experience an average nitrogen loss
of 20–25 g/m2 TBSA/day, a rate at which lethal cachexia
becomes imminent in less than 1 month if left untreated.
Continued post-burn loss may persist for up to 9 months.
Persistent protein catabolism probably accounts for the
growth delay that frequently occurs in our pediatric burn
patients.54
Emphasis has therefore been placed on developing
both non-pharmacologic and pharmacologic therapeutic
approaches that may attenuate or reverse the hypermetabolic
response post-burn.
Non-pharmacologic approaches
that ameliorate the post-burn
hypermetabolic response
Early wound closure
In recent years, burn wound management has changed, and
the most significant advances in burn care have been the
early excision of necrotic tissue and burn wound closure.
This has significantly diminished basal energy requirements
and in turn, improved mortality rates.55–59 Early closure of
the burn wound is also associated with diminished inci­
dence of excessive scars and joint contractures and is respon­
sible for faster rehabilitation of these patients.55,58
Currently, powered dermatomes or hand skingraft knives
are used to excise most burn wounds. Excisions via electro­
cautery or knife are usually used in areas where optimal
function or cosmesis are important. Preservation of viable
dermis may be possible in partial thickness wounds.
However, excision of all necrotic and infected tissue is para­
mount in full-thickness burn wounds.60 Tangential, full-
thickness, and fascial excision techniques are typically used.
During tangential excision, the deep dermal partial thickness
burn is repeatedly shaved using a knife (Goulian, Watson,
or Braithwaite) or a dermatome (set to a depth of 5–10/1000
inch). Necrotic or infected tissue is shaved until punctate
dermal wound bed bleeding signifies the uncovering of the
viable dermal wound bed.60 Full-thickness excision and
serial passes are made to excise the full-thickness wound
using a Watson or powered dermatome (set at 15–30/100
inch). In this case, the complete excision is indicated by
reaching an actively bleeding wound bed.60 Fascial excision
is the surgical removal of subcutaneous fat until the fascia is
reached. It is used for burns that extend deep into the muscle
or when invasive fungal infections are present. However, this
technique generally leaves a permanent contour defect.60
During these operations, blood loss is a critical issue, as
approximately 5% of the total blood volume is lost with the
excision of every 1% of the body surface.61,62 Blood loss is a
major determinant of morbidity and mortality,63 and a
variety of techniques need to be used to control bleeding,
including the local application of fibrin or thrombin sprays,
epinephrine-soaked pads (1 : 40 000), topically administered
epinephrine (1 : 10 000–1 : 20 000) or electrocautery of blood
vessels.64 Additional use of tourniquets for pre-excisional
tumescence with epinephrine and saline may also help limit
blood loss.65

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30
358
at 0.1 mg/kg twice daily reduced length of the acute hospi­
talization, sustained LBM, and improved liver protein
synthesis.103 In conclusion, administration of oxandrolone
decreased the sequelae of the burn-induced hypermetabolic
response and alterations in LBM and bone mineral content.104
Exercise, however, remains an essential tool for developing
strength.105
Propranolol
Beta-adrenergic blockade with propranolol may represent
the most efficacious anticatabolic therapy for severe burns.
As shown in several studies, the administration of pro­
pranolol (titrated to decrease heart rate by 15–20%) dimin­
ishes cardiac work25 and reduces hepatic steatosis, a typical
phenomenon in this particular patient population resulting
from increased peripheral lipolysis and alterations in sub­
strate handling. It is thought that reductions of hepatic fat
may occur via decreased palmitate delivery, coupled with
reduced hepatic uptake and diminished peripheral lipoly­
sis.76,106 Also, administration of propranolol leads to reduced
skeletal muscle catabolism and increased LBM post-burn, as
demonstrated using stable isotope studies and body compo­
sition studies.23,107 Propranolol exerts its effects in the post-
burn environment of heightened protein breakdown and
diminished peripheral lipolysis, enhancing protein synthesis
and improving post-burn morbidity.108
Overcoming burn-associated insulin resistance
Claude Bernard was the first clinician to describe the devel­
opment of hyperglycemia following hemorrhagic shock in
1877. Today it is well accepted that acute diseases and
injuries, including burn trauma, induce “critical illness dia­
betes.”109 Indeed, Gornik and colleagues reported that the
risk of developing impaired glucose metabolism or type-2
diabetes increased when acute critical illness was compli­
cated by hyperglycemia.110 Previously, the duration of the
post-burn hypermetabolic response was believed to be
limited; we now know that it persists for at least a full year
following injury.22,49 In a large prospective clinical trial, we
recently demonstrated that, in 194 severely burned children,
insulin sensitivity was impaired for at least 3 years post-burn.
Interestingly, hemoglobin A1c values were normal during the
entire post-burn period studied. Even the insulinogenic
index, an index for β-cell function, showed normal values in
the patient population. The levels of insulin and C-peptide,
on the other hand, remained elevated throughout the
study.111
Insulin
Insulin is one of the best-characterized hormones. While
glucagon, catecholamines, glucocorticoids, and thyroid hor­
mones all increase blood glucose levels, insulin is the only
hormone lowering blood glucose concentrations in the
human organism. Insulin mediates metabolic effects and
pathways in several important organs, including muscle and
fat. It also suppresses gluconeogenesis in the liver, dimin­
ishes proteolysis, and increases fatty acid synthesis.112 The
latter effects indicate that insulin may have great utility for
paramount to preclude burn wound contractures. Progres­
sive resistance exercises maintain or even increase LBM,
facilitate the formation of muscle proteins by incorporating
amino acids, enhance muscle strength, and increase walking
distances by 50%.81 In burned children, progressive resist­
ance exercise can be performed safely without any exercise-
related hyperpyrexia. Judicious use of sedation, narcotics
support, and supportive psychotherapy are obligatory to
reduce long-term morbidity post-burn.82
Pharmacologic approaches to attenuate
the metabolic alterations post-burn
Recently, particular drugs that modulate aspects of the hyper­
metabolic response have been studied to determine the effi­
cacy of these agents in severely burned patients.
Recombinant human growth hormone (rhGH)
As demonstrated by our group, during the acute hospitaliza­
tion period, daily intramuscular injection of rhGH (0.2 mg/
kg) positively alters the acute phase response in the liver,83,84
improves muscle protein kinetics, maintains muscular
growth,85,86 improves resting energy expenditure, decreases
cardiac output,87 and decreases donor site healing by approx­
imately 1.5 days.88 RhGH mediates its effects through its
secondary mediator IGF-I.89 In patients receiving rhGH,
serum IGF-I and IGF-binding protein (IGFBP)-3 increase by
100% over levels seen in healthy controls.90,91 Nevertheless,
as demonstrated in a recent study by Takala and colleagues,
in 532 non-burned critically ill patients, increased rhGH
(0.10 ± 0.02 mg/kg) correlated with increased morbidity and
mortality rates91 and was associated with hyperglycemia and
insulin resistance.92,93 This may be reflective of an age-specific
effect, however, as in severely burned children, mortality
rates were not affected by either short- or long-term rhGH
administration.87,94
Insulin-like growth factor (IGF)
Since the positive effects of rhGH on the post-burn hyper­
metabolic response are predominantly mediated by the sec­
ondary mediator IGF-I, it is not surprising that, in these same
patient populations, administration of equimolar amounts
of recombinant human IGF-1 with its binding protein,
IGFBP-3, successfully enhanced protein metabolism,95,96
attenuated muscle catabolism, restored gut mucosal integ­
rity,96 enhanced immune function, and returned serum con­
centrations of constitutive proteins to non-burned levels.96–99
However, Van den Berghe et al.100 could not demonstrate any
efficacy in non-burned critically ill patients when using
IGF-1 alone.
Anabolic agents: oxandrolone
The use of oxandrolone, an analog of testosterone possessing
only 5% of its virilizing androgenic effects, also enhances
anabolism of muscle protein by improving the efficiency of
protein synthesis.101 Oxandrolone decreases loss of body
weight and improves healing of the donor site wound.102 In
a large clinical trial by our group, oxandrolone administered

Modulation of the hypermetabolic response after burn injury
359
(hepatic or renal failure) or tissue hypoxia and should be
handled with caution in sub­acute burn patients. Neverthe­
less, metformin is still not considered a first-line approach
in subacute burn patients. More experience and follow-up
studies are necessary for the evaluation of metformin as a
new therapeutic intervention.
Novel therapeutic options
Other antidiabetic drugs being investigated for the treatment
of post-burn hyperglycemia include glucagon-like-peptide-1
(GLP-1); peroxisome proliferator-activated receptor-γ (PPAR-
γ) agonists, also known as glitazones; or a combination of
various anti-diabetic drugs. Cree et al. observed that the
application of fenofibrate, a PPAR-γ agonist, significantly
decreased plasma glucose levels and augmented tyrosine
phosphorylation of the insulin receptor and insulin receptor
substrate-1 in skeletal muscle tissue when compared to the
placebo treatment, indicating enhanced insulin receptor
signaling.37
Summary and conclusion
The physiologically exhaustive hypermetabolic derange­
ments post-burn, which are associated with prolonged
derangements in glucose metabolism and insulin sensitivity,
significantly contribute to adverse outcomes in this patient
population. Advances in non-pharmacologic and pharmaco­
logic therapies have significantly improved the clinical
outcome of these patients (Table 30.1). However, therapeutic
strategies to abate the persistent hypermetabolism and
hyperglycemia remain challenging. Early burn wound exci­
sion and grafting has been one of the greatest improvements
in the last two decades, improving both morbidity and mor­
tality. Currently, beta-adrenergic blockade using propranolol
appears to be the most efficacious anticatabolic therapy in
burns (Fig. 30.2). RhGH, IGF-1, and oxandrolone (Table
30.1) have also been successfully used in the attenuation of
abrogating burn-induced hyperglycemia. This was confirmed
by administering insulin to severely burned children. Donor
site healing time was reduced, muscle protein synthesis
increased, and muscle wasting reduced.113–119 In a recent
study, insulin was also found to wield anti-inflammatory
effects.117 Thus, administration of insulin post-burn may
reduce the inflammatory state induced by burn-induced
hyperglycemia by re-establishing euglycemia.120 In a land­
mark trial, Van den Berghe et al. demonstrated that mortal­
ity, infection rates, and acute renal failure were diminished
following continuous intensive insulin treatment to main­
tain lower blood glucose levels (80 and 110 mg/dL) in criti­
cally ill surgical patients.121 They also found that intensive
insulin therapy significantly reduced the time on mechanical
ventilation. The length of stay (in the ICU and hospital) was
reduced with intensive insulin therapy.122 Long-term reha­
bilitation was improved, as was the successful reintegration
of these patients into their lives during the first year.122,123
Unfortunately, high doses of insulin may increase the risk
of hypoglycemic events in critically ill patients.121 Brunkhorst
and colleagues investigated the use of intensive insulin treat­
ment in septic patients. In this study, intensive insulin
therapy needed to be interrupted because of elevated rates
of severe hypoglycemia with glucose levels below 40 mg/
dL.124 The continued use of a hyperinsulemic euglycemic
clamp was studied during the ICU stay in a separate multi­
center study. A critical increase in the incidence of serious
hypoglycemic events was reported.125 The general recom­
mendations, however, of studies to determine the ideal
glucose range in critically ill patients suggest that glucose
levels under 140 or 150 mg/dL should be efficacious.126,127
Nevertheless, it is particularly challenging to maintain con­
tinuous hyperinsulinemic, euglycemic clamp in the severely
burned patient population due to the continuous enteral
feeding of large caloric loads to maintain euglycemia. Also,
since burn patients frequently require weekly operations and
daily dressing changes, enteral nutrition must occasionally
be stopped, which may contribute to disruption of gastroin­
testinal motility and an increased risk of hypoglycemia.4
Thus, an alternative strategy for attenuating hyperglycemia
post-burn has been the exploration of other glucose-
lowering drugs, such as metformin, that do not provoke
hypoglycemic events as often as insulin.
Metformin
The biguanide drug, metformin, inhibits gluconeogenesis,
enhances peripheral insulin sensitivity, and has recently
been recommended as an alternative means to correct hyper­
glycemia in severely injured patients.128 It directly targets the
two main metabolic processes that underlie injury-induced
hyperglycemia.129–131 Hypoglycemic events have rarely been
associated with the use of metformin.132 Gore et al. observed,
in a small burn study, that the application of metformin is
associated with diminished glucose levels, decreased endog­
enous glucose production, and enhanced glucose clear­
ance.128 The same group also demonstrated enhanced
fractional synthetic rates of muscle protein and increases in
net muscle protein balance in patients receiving met­
formin.131 However, use of metformin may be associated
with lactic acidosis.132,133 Thus, metformin is contraindicated
in diseases associated with an impaired lactate elimination
Figure 30.2  Relative efficacy of the different anabolic agents to improve
muscle protein synthesis compared to standard of care alone. Changes in
net protein balance of muscle protein synthesis and breakdown induced by
burn injury were measured by stable isotope studies using d5-phenyalanine
infusion studies.6,109,134,135,164–167 *Denotes significance of p<0.05. Graphs are
averages ± SEM. Gray bars represent patients with burns ≥40% TBSA that
received no anabolic agents. Blue bars represent patients with burns ≥40%
TBSA that were randomized to receive the drugs.34
µmol/min/100cc leg
Oxand and prop
-0.100
-0.075
-0.050
-0.025
0.000
0.025
0.050
0.075
0.100
rHGH and prop
Ketoconazole
Propranolol
Oxandrolone
Low insulin
High insulin
IGF-1
rHGH
*
*
*
*
*
*
*

Total Burn Care
30
360
Table 30.1  Summary of the main effects of various pharmacologic interventions to alter the hypermetabolic response to burn injury
Drug
Inflammatory
response
Stress
hormones
Body
composition
Net protein
balance
Insulin
resistance
Hyperdynamic
circulation
rhGH
Improved
No difference
Improved
No difference
Hyperglycemia
No difference
IGF-I
Improved
No difference
Improved
Improved
Improved
No difference
Oxandrolone
Improved
No difference
Improved
Improved
No difference
No difference
Insulin
Improved
No difference
Improved
Improved
Improved
No difference
Fenofibrate
No difference
No difference
No difference
No difference
Improved
No difference
GLP-1
Unknown
Unknown
Unknown
Unknown
Improved
(indirect)
Unknown
Propranolol
Improved
Improved
Improved
Improved
Improved
Improved
Ketoconazole
Unknown
Improved
Unknown
Unknown
Unknown
Unknown
rhGH + propranolol
Improved
Improved
Improved
Improved
Improved
Improved
Oxandrolone + propranolol
Improved
(preliminary)
Improved
(preliminary)
Improved
(preliminary)
Improved
(preliminary)
Improved
(preliminary)
Improved
(preliminary)
The data summarized in the table are extrapolated from references 134–163. Previously published in: Williams FN, Herndon DN, Jeschke MG. The hypermetabolic response to
burn injury and interventions to modify this response. Clin Plast Surg. 2009;36:583–596.109
 
Access the complete reference list online at

the hypermetabolic, catabolic response. While maintaining
blood glucose at levels below 110 mg/dL using intensive
insulin therapy has been demonstrated to diminish mortal­
ity and morbidity rates in critically ill patients, the frequently
associated hypoglycemic events have created additional
strategies, such as administration of metformin and PPAR-γ
agonists in the thermally injured patient. Nonetheless,
further work is needed to elucidate the ideal glucose ranges
and safety of the aforementioned therapies in this unique
patient population.
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.
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.
Jeschke MG, Chinkes DL, Finnerty CC, et al. Pathophysiologic
response to severe burn injury. Ann Surg. 2008;248:387-401.
Jeschke MG, Mlcak RP, Finnerty CC, et al. Burn size determines
the inflammatory and hypermetabolic response. Crit Care.
2007;11:R90.
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin
therapy in the critically ill patients. N Engl J Med. 2001;345:
1359-1367.
Williams FN, Herndon DN, Jeschke MG. The hypermetabolic response
to burn injury and interventions to modify this response. Clin Plast
Surg. 2009;36:583-596.

Modulation of the hypermetabolic response after burn injury
360.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
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95. Moller S, Jensen M, Svensson P, et al. Insulin-like growth factor
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98. Jeschke MG, Herndon DN, Barrow RE. Insulin-like growth factor
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99. Cioffi WG, Gore DC, Rue LW 3rd, et al. Insulin-like growth
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102. Demling RH, Orgill DP. The anticatabolic and wound healing
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104. Murphy KD, Thomas S, Mlcak RP, et al. Effects of long-term
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2004;136:219-224.
105. Suman OE, Thomas SJ, Wilkins JP, et al. Effect of exogenous
growth hormone and exercise on lean mass and muscle function
in children with burns. J Appl Physiol. 2003;94:2273-2281.
106. 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;223:777-787; discussion
787-789.
107. Gore DC, Honeycutt D, Jahoor F, et al. Propranolol diminishes
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108. Pereira CT, Jeschke MG, Herndon DN. Beta-blockade in burns.
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109. Williams FN, Herndon DN, Jeschke MG. The hypermetabolic
response to burn injury and interventions to modify this
response. Clin Plast Surg. 2009;36:583-596.
110. Gornik I, Vujaklija-Brajkovic A, Renar IP, et al. A prospective
observational study of the relationship of critical illness
associated hyperglycaemia in medical ICU patients and
subsequent development of type 2 diabetes. Crit Care.
2010;14:R130.
111. 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.
112. Pidcoke HF, Wade CE, Wolf SE. Insulin and the burned patient.
Crit Care Med. 2007;35:S524-S530.
113. Ferrando AA, Chinkes DL, Wolf SE, et al. A submaximal dose of
insulin promotes net skeletal muscle protein synthesis in
patients with severe burns. Ann Surg. 1999;229:11-18.
114. Pierre EJ, Barrow RE, Hawkins HK, et al. Effects of insulin on
wound healing. J Trauma. 1998;44:342-345.
115. Thomas SJ, Morimoto K, Herndon DN, et al. The effect of
prolonged euglycemic hyperinsulinemia on lean body mass after
severe burn. Surgery. 2002;132:341-347.
116. Zhang XJ, Chinkes DL, Wolf SE, et al. Insulin but not growth
hormone stimulates protein anabolism in skin wound and
muscle. Am J Physiol. 1999;276:E712-E20.
117. Jeschke MG, Klein D, Herndon DN. Insulin treatment improves
the systemic inflammatory reaction to severe trauma. Ann Surg.
2004;239:553-560.
118. 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.
119. 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.
120. Dandona P, Chaudhuri A, Mohanty P, et al. Anti-inflammatory
effects of insulin. Curr Opin Clin Nutr Metab Care. 2007;10:511-
517.
121. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin
therapy in the critically ill patient. N Engl J Med. 2001;345:1359-
1367.
122. Ellger B, Debaveye Y, Vanhorebeek I, et al. Survival benefits of
intensive insulin therapy in critical illness: impact of
maintaining normoglycemia versus glycemia-independent
actions of insulin. Diabetes. 2006;55:1096-1105.
123. Ingels C, Debaveye Y, Milants I, et al. Strict blood glucose
control with insulin during intensive care after cardiac surgery:
impact on 4-years survival, dependency on medical care, and
quality-of-life. Eur Heart J. 2006;27:2716-2724.
124. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy
and pentastarch resuscitation in severe sepsis. N Engl J Med.
2008;358:125-139.
125. Langouche L, Vanhorebeek I, Van den Berghe G. Therapy insight:
the effect of tight glycemic control in acute illness. Nat Clin Pract
Endocrinol Metab. 2007;3:270-278.
126. Finney SJ, Zekveld C, Elia A, et al. Glucose control and mortality
in critically ill patients. JAMA. 2003;290:2041-2047.
127. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis
Campaign: international guidelines for management of
severe sepsis and septic shock: 2008. Crit Care Med.
2008;36:296-327.
128. Gore DC, Wolf SE, Herndon DN, et al. Metformin blunts
stress-induced hyperglycemia after thermal injury. J Trauma.
2003;54:555-561.
129. DeFronzo RA, Goodman AM. Efficacy of metformin in patients
with non-insulin-dependent diabetes mellitus. The Multicenter
Metformin Study Group. N Engl J Med. 1995;333:541-549.
130. Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of
metformin in non-insulin-dependent diabetes mellitus. N Engl J
Med. 1995;333:550-554.
131. Gore DC, Herndon DN, Wolfe RR. Comparison of peripheral
metabolic effects of insulin and metformin following severe
burn injury. J Trauma. 2005;59:316-323.
132. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574-
579.
133. Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanide-
treated diabetics: a review of 330 cases. Diabetologia. 1978;14:75-
87.
134. Ferrando AA, Chinkes DL, Wolf SE, et al. A submaximal dose of
insulin promotes net skeletal muscle protein synthesis in
patients with severe burns. Ann Surg. 1999;229:11-18.
135. Debroy MA, Wolf SE, Zhang XJ, et al. Anabolic effects of
insulin-like growth factor in combination with insulin-like
growth factor binding protein-3 in severely burned adults.
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136. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism
by beta-blockade after severe burns. New Engl J Med.
2001;345:1223-1229.
137. Chang DW, DeSanti L, Demling RH. Anticatabolic and anabolic
strategies in critical illness: A review of current treatment
modalities. Shock. 1998;10:155-160.
138. Herndon D. Mediators of metabolism. J Trauma. 1981;21:701-
705.
139. Heszele MFC, Price SR. Insulin-like growth factor I: The yin and
yang of muscle atrophy. Endocrinology. 2004;145:4803-4805.
140. Herndon DN, Barrow RE, Kunkel KR, et al. Effects of
recombinant human growth-hormone on donor-site healing in
severely burned children. Ann Surg. 1990;212:424-431.
141. Barret JP, Dziewulski P, Jeschke MG, et al. Effects of recombinant
human growth hormone on the development of burn scarring.
Plast Reconstr Surg. 1999;104:726-729.
142. Jeschke MG, Herndon DN, Wolf SE, et al. Recombinant human
growth hormone alters acute phase reactant proteins, cytokine
expression, and liver morphology in burned rats. J Surg Res.
1999;83:122-129.
143. Ramirez RJ, Wolf SE, Barrow RE, et al. Growth hormone
treatment in pediatric burns. A safe therapeutic approach. Ann
Surg. 1998;228:439-446.
144. Takagi K, Suzuki F, Barrow RE, et al. Recombinant human
growth hormone modulates Th1 and Th2 cytokine response in
burned mice. Ann Surg. 1998;228:106-111.
145. Takagi K, Suzuki F, Barrow RE, et al. Growth hormone improves
immune function and survival in burned mice infected with
Herpes simplex virus type? J Surg Res. 1997;69:166-170.
146. Low JFA, Barrow RE, Mittendorfer B, et al. The effect of
short-term growth hormone treatment on growth and energy
expenditure in burned children. Burns. 2001;27:447-452.
147. Low JFA, Herndon DN, Barrow RE. Effect of growth hormone on
growth delay in burned children: a 3-year follow-up study.
Lancet. 1999;354:1789.
148. Moller S, Jensen M, Svensson P, et al. Insulin-Like Growth
Factor-I (Igf-1) in Burn Patients. Burns. 1991;17:279-281.
149. Jeschke MG, Herndon DN, Barrow RE. Insulinlike growth factor
I in combination with insulinlike growth factor binding protein
3 affects the hepatic acute phase response and hepatic
morphology in thermally injured rats. Ann Surg. 2000;231:408-
416.
150. Spies M, Wolf SE, Barrow RE, et al. Modulation of types I and II
acute phase reactants with insulin-like growth factor-1/binding
protein-3 complex in severely burned children. Crit Care Med.
2002;30:83-88.
151. Hart DW, Wolf SE, Ramzy PI, et al. Anabolic effects of
oxandrolone after severe burn. Ann Surg. 2001;233:556-564.
152. Jeschke MG, Finnerty CC, Suman OE, et al. The effect of
Oxandrolone on the endocrinologic, inflammatory, and
hypermetabolic responses during the acute phase postburn. Ann
Surg. 2007;246:351-362.
153. Demling RH, DeSanti L. Oxandrolone, an anabolic steroid,
significantly increases the rate of weight gain in the recovery
phase after major burns. J Trauma. 1997;43:47-51.
154. 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.
155. 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.
156. Minnich A, Tian N, Byan L, et al. A potent PPAR alpha agonist
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157. Schnabel D, Grasemann C, Staab D, et al. A multicenter,
randomized, double-blind, placebo-controlled trial to evaluate
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158. Herndon DN, Barrow RE, Rutan TC, et al. Effect of propranolol
administration on hemodynamic and metabolic responses of
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159. Engelhardt D, Dorr G, Jaspers C, et al. Ketoconazole blocks
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160. Engelhardt D, Mann K, Hormann R, et al. Ketoconazole inhibits
cortisol secretion of an adrenal adenoma in vivo and in vitro.
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161. Loose DS, Stover EP, Feldman D. Ketoconazole binds to
glucocorticoid receptors and exhibits glucocorticoid antagonist
activity in cultured-cells. J Clin Invest. 1983;72:404-408.
162. Hart DW, Wolf SE, Chinkes DL, et al. beta-blockade and growth
hormone after burn. Ann Surg. 2002;236:450-457.
163. 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.
164. Jeschke MG, Chinkes DL, Finnerty CC, et al. Pathophysiologic
response to severe burn injury. Ann Surg. 2008;248:
387-400.
165. Jeschke MG, Mlcak RP, Finnerty CC, et al. Burn size determines
the inflammatory and hypermetabolic response. Crit Care.
2007;11:R90.
166. Hart DW, Wolf SE, Chinkes DL, et al. Determinants of skeletal
muscle catabolism after severe burn. Annals of Surgery.
2000;232:455-463.
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catabolism after severe burn: Effects of IGF-1/IGFBP-3 treatment.
Ann Surg. 1999;229:713-722.

The cure of many diseases remains unknown.
(Socrates, circa 400 bc)
Introduction
Despite its common occurrence in critically ill burn patients,
our understanding of the multisystem organ failure syn­
drome remains fragmented and incomplete. The cascade of
organ dysfunctions which typify the multisystem organ
failure syndrome is driven by an unregulated inflammatory
state, often, but not always, associated with uncontrolled
infection.1 Other potential ‘engines’ driving this cascade of
organ dysfunctions are an impaired gastrointestinal barrier,2,3
the open burn wound,4 and inadequate delivery of oxygen
to peripheral tissues.5 The line between organ dysfunction
and failure is admittedly unclear, but a set of organ-specific
definitions of failure is helpful and has been developed
(Box 31.1).6 Approximately 15% of patients admitted to
surgical intensive care units have multisystem organ failure,7
and perhaps 8% of burn patients ultimately develop the
syndrome.8
The sequence of failures often follows a predictable
course, although the cascade can be modified by various
treatments, such as the prophylactic use of proton-pump
inhibitors or H2-receptor blockers. In burn patients, two
cascades have been described.8 An early clinical sequence is
characterized by resuscitation failure, adult respiratory dis­
tress syndrome, hemodynamic failure, renal failure, liver
failure, gut failure, and infection, and a later cascade typi­
fied by pulmonary failure, hemodynamic instability, renal
failure, gut failure, and liver failure. Frequently, vasomotor
failure and death is seen at the end of both cascades. Mor­
tality increases with increasing numbers of failed organ
systems. When three organs have failed, mortality has been
reported as 100%, although survival is sometimes seen in
patients with even more failed organ systems.9 An under­
standing of the progression of the syndrome aids in prog­
nostication and facilitates decisions regarding termination
of futile efforts.10,11 The management of specific organ fail­
ures will be presented in the next chapter. The purpose of
this chapter is to discuss the etiology and prevention of
the syndrome.
Etiology
The etiology of multisystem organ failure remains a mystery
under intense investigation. All patients seem to share char­
acteristics associated with an uncontrolled inflammatory
state, and there are several proposed ‘engines’ which drive
this uncontrolled inflammation, including sepsis, the open
burn wound, the gut, and hypoperfusion.
Sepsis is clearly the most common initiator of the syn­
drome, and was recognized early on as the primary cause.1
One single overwhelming infection is not required, as small
repetitive infections may initiate the cascade,12 perhaps by
priming immune cells, making them react more intensely
to each subsequent stimulus.12 It was recognized later that
many patients with multisystem organ failure did not have
infection,13 and this led the search for other ‘engines’. Endo­
toxin liberated from the walls of Gram-negative bacteria is a
major, but not the only, intermediary,14 as Gram-positive
bacteria cause similar aberrations in oxygen transport and
hemodynamics,15 via similar cascades of mediators.16
In burn patients the wound may also be a source of the
inflammatory mediators leading to multiple organ failure.
Certainly, an infected wound will do this, but wound sepsis
is decreasing in incidence with the advent of early burn
wound excision17 and most infectious deaths in burn patients
today are caused by pneumonia rather than wound sepsis.18
Complete wound closure, without donor sites, decreases
oxygen consumption19 and presumably ameliorates the
inflammatory response to the open wound. Incomplete
wound closure does not have this effect.20 Increased levels
of circulating mediators such as interleukin-6 (IL-6), IL-8,
and tumor necrosis factor (TNF) have been shown to origi­
nate from the burn wound21 and contribute to the hyper­
metabolic and inflammatory state seen in burn patients.
Interleukin-8 has been demonstrated to be upregulated in
the lung after burn injury21 and the stimulus for this upregu­
lation, which is associated with pulmonary dysfunction, may
come from the wound.21
Failure of the gut barrier can contribute to the develop­
ment of multisystem organ failure.22 Normal barrier function
prevents the movement of bacteria and their products from
the gut lumen into the portal and lymphatic circulations.
Bacterial densities range from near 0 in the stomach, to
104–105 in the distal small bowel, to 1011–1012/g of stool in
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00031-X
Etiology and prevention of
multisystem organ failure
Robert L. Sheridan, Ronald G. Tompkins
CHAPTER 31 
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IN THIS CHAPTER
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Total Burn Care
31
362
circulations. Hemorrhagic shock,25 endotoxin administra­
tion,26 burns,27 and burn wound sepsis28 have each been
shown to result in increased translocation of bacteria from
the gut. Gut permeability to macromolecules, such as endo­
toxin, has been shown to increase with increasing burn
wound size using polyethylene glycol 3350 as a tracer.29
Smaller molecules, with lactulose as the tracer, have also
been shown to pass more readily through the gastrointesti­
nal membrane after injury.30 The exact mechanism by which
bacteria and their products pass through the gastrointestinal
barrier is not clear. Both intra- and transcellular processes
may be involved.31,32 The consequences of loss of the gas­
trointestinal barrier are profound. Translocating whole bac­
teria can be a direct source of sepsis or can activate Kupffer
cells2,3 and promulgate an inflammatory response in con­
junction with bacterial products such as endotoxin.
Cellular dysfunction, caused by inadequate oxidative
metabolism secondary to hypoperfusion, is another
potential ‘engine’ resulting in multisystem organ failure. In
ischemia-reperfusion models, oxygen radicals are generated,
resulting in peroxidation of cell membrane lipids and accu­
mulation of activated neutrophils,33 with progressive cellular
and whole-organ dysfunction. It has been proposed that
critically ill patients suffer from supply-dependent oxygen
consumption because of defects in cellular oxygen extraction
and utilization.34,35 This results in inadequate aerobic meta­
bolism unless supranormal levels of oxygen are supplied.36
The reality of this proposal is still actively debated.37,38 Cer­
tainly, a grossly inadequate amount of oxygen available to
cells dependent on aerobic metabolism can lead to cellular
dysfunction, and this may be followed by organ failures.5
Maintaining oxygen delivery at least at normal, and possibly
supranormal, levels should help maintain cellular homeo­
stasis and minimize the risk of multiple organ failure.39
Although the requirement for a supranormal level of tissue
oxygenation in critical illness is controversial and our ability
to predict organ-specific oxygen delivery and consumption
from whole-body data is poor,40 careful attention to whole-
body hemodynamics is an integral part of the management
of any critically ill patient.
Common ground: mediators
Sepsis, open burn wounds, impaired gut barrier function,
and hypoperfusion are all associated with multiorgan failure.
The similarity in the response to these differing events
implies that there is some common ground. These processes
all probably impact on individual organs via a number of
mediators, whose complex interactions are still very poorly
understood,41 but are being unraveled by investigators using
blocking antibodies, soluble receptors, and receptor antago­
nists.42 At this point, these mediators, including endotoxin,
arachidonic acid metabolites, cytokines, platelet activating
factor, activated neutrophils and adherence molecules, nitric
oxide, complement, and oxygen free radicals will be reviewed
briefly.
Endotoxin, a lipopolysaccharide component of Gram-
negative bacterial cell walls, induces many of the symptoms
associated with sepsis, including fever, hypotension, the
release of acute phase proteins, and the production of
multiple cytokines including TNF and IL-1.43 Endotoxin also
the normal colon.23 That the normal gut can carry this
bacterial load, without the frequent occurrence of Gram-
negative infection, is a tribute to normal barrier function.
Although not seen immediately after trauma,24 several insults
have been shown to result in increased translocation of
bacteria and their products into the portal and lymphatic
Box 31.1  Organ-specific definitions of failure (OSF)
If the patient had one or more of the following during a 24-hour
period (regardless of the values), OSF existed on that day.
Cardiovascular failure (presence of one or more of
the following):
•
Heart rate ≤54 beats/min
•
Mean arterial blood pressure ≤49 mmHg
•
Occurrence of ventricular tachycardia and/or ventricular fibrillation
•
Serum pH ≤7.24 with a PaCO2 of ≤49 mmHg
Respiratory failure (presence of one or more of
the following):
•
Respiratory rate ≤5 beats/min or ≥40 beats/min
•
PaCO2 ≥50 mmHg
•
AaDO2 ≥350 mmHg (AaDO2 = 713 FIO2 − PaCO2 − PaO2)
•
Dependent on ventilator on the fourth day of OSF, e.g. not
applicable for the initial 72 h of OSF
Renal failure (presence of one or more of
the following):a
•
Urine output ≤479 mL/24 h or ≤159 mL/8 h
•
Serum BUN ≥100 mg/dL
•
Serum creatinine ≥3.5 mg/dL
Hematological failure (presence of one or more of
the following):
•
WBC ≤1000 cells/mm3
•
Platelets ≤20 000 cells/mm3
•
Hematocrit ≤20%
Neurological failure
•
Glasgow Coma Score ≤6 (in absence of sedation at any one point
in day)
•
Glasgow Coma Score: sum of best eye opening, best verbal, and
best motor responses.
Scoring of responses are as follows: (points)
Eye
Open: spontaneously (4); to verbal command (3); to pain (2); no
response (1).
Motor
Obeys verbal command (6); response to painful stimuli: localizes pain
(5); flexion-withdrawal (4); decorticate rigidity (3); decerebrate rigidity
(2); no response (1); movement without any control (4).
Verbal
Oriented and converses (5); disoriented and converses (4);
inappropriate words (3); incomprehensible sounds (2); no response
(1). If intubated, use clinical judgment for verbal responses as follows:
patient generally unresponsive (1); patient’s ability to converse in
question (3); patient appears able to converse (5).
aExcluding patients on chronic dialysis before hospital admission. Reproduced from
Knaus et al. 1985,6 with permission.

Etiology and prevention of multisystem organ failure
363
5-lipoxygenase, leukotrienes (LT) C4, D4, and E4 (the sulfi­
dopeptide group) and LTB4.52 Leukotrienes are generated in
response to multiple stimuli by several cell types, including
neutrophils, macrophages, and monocytes.53 Vessel walls are
also capable of generating leukotrienes.54 Leukotrienes C4,
D4, and E4 have variable actions on vascular tone depending
on the presence or absence of other mediators such as
cyclooxygenase product.55 In addition to their variable effects
in redirecting blood flow, LTC4, LTD4, and LTE4 also increase
vascular permeability,56 and have been described as being
elevated immediately prior to the development of pulmo­
nary failure.57 The major effect of LTB4 is an enhancement of
neutrophil chemotaxis.58 Thus, leukotrienes as a group may
be involved in the edema formation and pulmonary and
systemic vascular changes that are seen in the multisystem
organ failure syndrome.
Cytokines are regulatory proteins that are secreted by
immune cells and have multiple paracrine and endocrine
effects. There are six major classes,59 including interleukins,
TNF, interferons, colony-stimulating factors, chemotactic
factors, and growth factors. Those which have been most
extensively characterized are IL-1, IL-6, and TNF.
Interleukin-1 and IL-6 are elevated in septic states, and
high levels are associated with a fatal outcome60 and predict
systemic infection.61 Interleukin-1β causes hypotension
and decreased systemic vascular resistance, which may
be synergistic with the effects of TNF.62 Even better character­
ized is TNF, the administration of which causes hypoten­
sion, cardiac depression, and pulmonary dysfunction in
animals.63–65 When administered to humans, TNF causes
fever, hypotension, decreased systemic vascular resistance,
increased protein turnover, elevation of stress hormone
levels,66,67 and activation of the coagulation cascade.68
Platelet activating factor is a nonprotein phospholipid that
is secreted by many cells including platelets, endothelial
cells, and inflammatory cells,69 and is a major mediator of
the pulmonary70 and hemodynamic71 effects of endotoxin.
The major effects of platelet activating factor are vasodila­
tion, cardiac depression, and enhancement of capillary leak.
Its complex interactions with other mediators are still poorly
understood.
Although tissue injury can occur in the absence of neu­
trophils,72 the inflammatory process results in local accumu­
lation of activated inflammatory cells which release various
local toxins such as oxygen radicals, proteases, eicosanoids,
platelet activating factor, and other substances. When unreg­
ulated, such accumulations of activated cells can cause tissue
injury.73 The initial attachment of neutrophils to the vascular
endothelium at an inflammatory site is facilitated by the
interaction of adherence molecules on the neutrophil and
endothelial cell surfaces.74
These neutrophil adherence receptors are induced by
numerous stimuli but, interestingly, are reduced after major
thermal and nonthermal injury,75 perhaps explaining in part
the increased incidence of infection in such patients. The
importance of this adherence mechanism can be seen in
patients who are deficient in one of the integrin class
of neutrophil adherence receptors, CD-18, who suffer
from frequent bacterial infections.76 The biology of the
transmembrane polypeptides that govern these complex
cell-to-cell interactions is an active area of research77 and
holds promise for therapeutic interventions in the future.
activates complement,44 causes activation of the coagulation
cascade,45 and results in the release of platelet activating
factor.46 Potential sources of endotoxin include both Gram-
negative bacteria in foci of infection and Gram-negative bac­
teria within the gut when the gut barrier fails.
Arachidonic acid makes up approximately 20% of cell
membranes, is released from these membranes in response
to a multitude of stimuli which activate phospholipases A2
and C, and is then metabolized by one of two major enzyme
systems (Fig. 31.1).
The cyclooxygenase pathway results in production of pros­
taglandins and thromboxanes, and the lipoxygenase pathway
results in the production of leukotrienes.47 The prostagland­
ins and leukotrienes interact with other mediators in a
complex fashion, and are later degraded by enzyme systems,
which are dispersed throughout the body.48
Arachidonic acid, which is metabolized via the cyclooxyge­
nase pathway, results in the formation of prostaglandins and
thromboxanes. Prostacyclin inhibits platelet aggregation,
thrombis formation, and gastric secretion.49 Thromboxane A2
(TXA2) causes platelet aggregation, has profound vasocon­
stricting effects on both the splanchnic and pulmonary micro­
vasculature, and causes bronchoconstriction and increased
membrane permeability.50 It is studied via its longer-lived
but inactive metabolite, TXB2. Aspirin has its physiological
effects by inhibiting thromboxane synthetase.51
Arachidonic acid metabolized via the lipoxygenase
pathway results in the formation of leukotrienes. There are
two types based on their metabolism after the action of
Figure 31.1  The cyclooxygenase and lipoxygenase pathways of
arachidonic acid metabolism.
Membane
phospholipids
Arachidonic
acid
Cyclooxyygenase
pathway
Prostaglandin G2
(PGG2)
PGD2
PGE2
PGF2
LTB4
LTC4
LTD4
PGF
LTE4
PGI2
5-Hydroperoxy-
eicosatetraenoic
acid (5-HPETE)
Leukotriene A4
(LTA4)
Lipoxygenase
pathway
Phospholipases

Total Burn Care
31
364
inadequate perfusion (Table 31.1). Dealing with these issues
is far more practical than dealing with an incompletely
understood complex web of mediators. The discussion that
follows will address prevention of sepsis via proper wound
management and attention to unusual causes of sepsis,
support of the gut, and prevention of inadequate oxygen
delivery. Subsequently, the potential role of nutritional and
specific immunomodulators will be addressed.
Prevention of sepsis
In the burn patient, prevention of multisystem organ failure
is greatly facilitated by prevention of wound sepsis via an
aggressive surgical approach to deep wounds. The increasing
survival of burn patients has paralleled the evolution of this
approach to the burn wound.89–91 Not only is overt wound
sepsis prevented by early removal of devitalized tissue, but
multiple smaller septic insults are also prevented, as mani­
pulation of heavily colonized burn wounds is a frequent
source of transient bacteremia.92,93 Such multiple occult bac­
teremias occurring during frequent manipulation of heavily
colonized wounds could contribute to the development of
multisystem organ failure by priming immune cells, making
Oxygen radicals, such as hydrogen peroxide and supero­
xide anion, are released by activated neutrophils in response
to a variety of stimuli.78 They are also released when xanthine
oxidase is activated after reperfusion in ischemia-reperfusion
models. These highly reactive products cause cell membrane
dysfunction, increased vascular permeability, and release of
eicosanoids.
Nitric oxide, released when citrulline is formed from
arginine (Fig. 31.2), was only identified as an endothelial
product in the middle 1980s.79 Its half-life is only a few
seconds, as it is quickly oxidized, but it has profound local
microvascular effects. Nitric oxide synthesis is stimulated by
various cytokines, endotoxin, thrombin, and by injury to the
vascular endothelium. It is a potent vasodilator,80 but its
actions vary depending on the vascular bed and presence of
other mediators.81 Nitric oxide is one of the major mediators
of the hypotensive response to sepsis.82,83
Antigen–antibody complexes activate the complement
cascade, and complement fragments thus generated can
interact with other cytokines to promulgate the inflamma­
tory response.84 Diminished levels of a natural inhibitor of
C5a have been demonstrated in patients with adult respira­
tory distress syndrome (ARDS)85 and administration of anti-
C5a antibody diminishes hypotension in an animal model
of endotoxemia.86 Complement fragments may be involved
in the development of burn wound edema.87
Our understanding of the incredibly complex cellular and
subcellular biology, of which multisystem organ failure is
but one manifestation, is poorly understood at the present
time. This dim understanding highlights the important role
that prevention plays in managing the syndrome.
Prevention of multisystem organ failure
Once established, multisystem organ failure is very difficult
to reverse, emphasizing the importance of prevention.88 Pre­
vention is based on our crude knowledge of the ‘engines’
that drive the process – sepsis, the gut, the wound, and
Figure 31.2  Nitric oxide metabolism. (From Cobb et al. 1993,189 with permission.)
H2N
H3N
COO –
NH2
NH
H2N
OH
H3N
COO –
COO –
N
H
NH
NADPH
L-Arginine
N-Hydroxy-L-arginine
H2N
H3N
+NO
O
NH
Nitric
oxide
Guanylate
cyclase
↑cGMP
GTP
L-Citrulline
Blood
Smooth muscle
Endothelium
O2
NADPH
O2
Table 31.1  Multiple organ failure etiology and established
preventive measures
Etiology
Prevention
Sepsis
Early excision and biologic closure of deep wounds
Anticipation and early treatment of occult septic foci
Gut barrier
failure
Optimize whole-body hemodynamics
Early enteral feedings
Reduced organ
perfusion
Optimize whole-body hemodynamics
Enhanced oxygen delivery

Etiology and prevention of multisystem organ failure
365
failure prevention than in the early detection and aggressive
treatment of occult septic foci.
Support of the gut
Bacteria and their products released when the gut barrier
fails may fuel the multiorgan failure syndrome. Gut mucosal
integrity suffers when mesenteric flow is inadequate and gut
blood flow is decreased after burn injury, a response exacer­
bated by the release of TXA2.107 Thus, support of splanchnic
blood flow is an important aspect of multisystem organ
failure prevention,108 and this is best done by careful atten­
tion to whole-body hemodynamics. There is no substitute
for a carefully monitored burn resuscitation.
The enterocyte may be better supported by intraluminal,
rather than parenteral feedings, as gut deprived of intralumi­
nal feedings develops mucosal atrophy.109 Early enteral feed­
ings are tolerated in the burn patients110 and may reduce the
magnitude of the hypermetabolic response to the injury.111
Parenteral feedings do not prevent gut mucosal atrophy as
well as isocaloric and isonitrogenous intraluminal feeds,112
although convincing human data are not available to support
the clinical significance of this point.
The value of specific nutrients to support the enterocyte is
far less clear than the value of providing adequate mesenteric
blood flow and perhaps intraluminal nutrition. However,
this is an exciting and active area of research. Glutamine,
a non-essential amino acid, is the preferred fuel of the small
bowel enterocyte113 as well as other rapidly dividing cells.
Sepsis has been shown to decrease glutamine uptake by the
small bowel enterocyte, which may result in barrier failure,114
and the addition of glutamine to the nutritional regimen has
been theorized to improve barrier function. Glutamine is not
a component of commercial parenteral nutritional formulas
because of its short shelf life, although the dipeptide is well
tolerated parenterally, and has a longer shelf-life.115 Although
supplemental glutamine may improve protein balance in
surgical patients,115 and may partially reverse gut atrophy,116
it has not been shown to improve gut barrier function when
given parenterally.117
The role of specific nutrients in support of the large intes­
tinal mucosa is less clear, but butyrate, a fatty acid liberated
by fiber fermentation, is a favored fuel of the colonic mucosal
cell.118 Enteral pectin may help support the colonic mucosa,
but the value of such support in the hypermetabolic burn
patient is as yet unclear. Limited work has been done
suggesting possible benefit of probiotics for gut barrier
support.119
A decontaminated gut lumen might diminish the impact
of gastrointestinal barrier failure. Attempts have been made
to access the impact of selective decontamination of the
gut120 and coating enteric bacteria to inhibit their ability to
attach to the intestinal mucosa and translocate.121 Although
there is a suggestion that the rate of pneumonia may be
decreased by such maneuvers, there is no apparent impact
on mortality.
Support of the gut in an effort to prevent multisystem
organ failure is certain to have real value. Maintenance of
adequate mesenteric perfusion via careful attention to
whole-body hemodynamics is crucial. There are some data
to support the contention that enteral feedings have benefi­
cial effects on outcome in injured patients when compared
them react more intensively to each subsequent insult.12 The
role of perioperative antibiotics in minimizing bacteremias
in the perioperative period has yet to be defined clearly.
However, they are clearly beneficial in patients with injuries
greater than 60% of body surface and in any other patient
in whom the probability of bacteremia with wound manipu­
lation is felt to be high.94 Appropriate perioperative antibiot­
ics are guided by surface cultures. Burn patients are prone
to a large number of unusual and often occult infectious
complications95 which can result in sepsis and potentially
contribute to the development of multiorgan failure. Rapid
diagnoses and treatment are facilitated by a high index of
suspicion.
Intravascular infections such as suppurative thrombophle­
bitis and endocarditis typically present in burn patients with
fever and bacteremia without localizing signs. Burn patients
with endocarditis develop a new murmur in only 9% of
cases,96 and only 10% have been reported to present ante­
mortem.97 Of those with septic thrombophlebitis, 68% have
no localizing signs and present with fever and positive blood
cultures only.98 The diagnosis is made in patients without
localizing signs only by thorough examination of all sites of
prior cannulation, with surgical exposure of any suspicious
sites and complete excision of any involved veins.99 Vigilant
care and scheduled replacement of intravascular devices will
minimize the occurrence of catheter-related sepsis. Occult
intracompartmental sepsis can also present with fever and
bacteremia without localizing signs, and is diagnosed only
by careful examination and exploration of suspicious
compartments.100
Pneumonia, seen in approximately 35% of patients with
inhalation injury, adds between 20 and 60% to the expected
mortality of burn patients.101 Although a difficult diagnosis
to make in critically ill patients, pneumonia should be vigi­
lantly anticipated and aggressively treated with appropriate
endobronchial toilet and specific antibiotics. The incidence
of nosocomial pneumonia increases with longer durations
of intubation,102 emphasizing the importance of judicious
use of mechanical ventilation.
Suppurative sinusitis is being recognized with increasing
frequency in the intensive care unit, and may be more fre­
quent in patients who are nasotracheally intubated.103 Diag­
nosis may require examination and culture of material
obtained by antral puncture, in addition to plain radio­
graphs and computed tomography. Although there is some
controversy about the role of the nasotracheal tube in causing
sinusitis,104 treatment involves replacing nasotracheal devices
with topical decongestants and appropriate antibiotics. Sur­
gical drainage is reserved for recalcitrant cases.
Acalculous cholecystitis often presents with generalized
sepsis without localizing signs in the burn patient, and, like
intravascular infection, is a very difficult diagnosis to
make.105 Recently, bedside placement of percutaneous
cholecystostomy tubes under ultrasonic guidance has
become an option in the management of suspected chole­
cystitis in critically ill patients.106 This technique allows an
accurate diagnosis to be made and the condition to be
temporarily treated in patients too unstable for immediate
operation.
Sepsis accounts for at least half of cases of multisystem
organ failure. In perhaps no other area can the vigilance of
the burn team have a greater impact in multisystem organ

Total Burn Care
31
366
output has been expanded to include lactic acid and base
deficit.133 Advanced hemodynamic monitoring tools are
increasingly incorporated in burn resuscitation and may
soon include esophageal Doppler, which may help improve
resuscitation accuracy, minimizing the morbidity of under
and over-resuscitation. Recent work in trauma patients has
highlighted the inflammatory complications of massive crys­
talloid resuscitation.134 This has stimulated a renewed inter­
est in the role of colloid in burn resuscitation. The variability
of the physiologic response to injury, and clinical response
to intervention, makes the specifics of fluid resuscitation an
oft-debated art, which is well described in other chapters of
this text.
Inadequate oxygen delivery clearly leads to organ dysfunc­
tion. At a minimum, the clinician should insure that injured
patients are resuscitated to the conventional clinical end­
points of appropriate urine output, skin perfusion, blood
pressure, and sensorium. In selected critically ill patients,
invasive monitoring is justified to document oxygen delivery
and consumption, extraction ratio, and the possible pres­
ence of supply dependency in which circumstance supra­
normal levels of oxygen delivery with plateau of oxygen
consumption is an appropriate resuscitation endpoint.
The potential role of nutritional and
specific immunomodulators
The holy grail of those who study the complex biology of
the multisystem organ failure syndrome is an ability to mod­
ulate the common pathways that lead to organ dysfunction
and death. The three general approaches to this goal are
nutritional, nonspecific, and specific immunomodulation.
Nutritional immunomodulation
Three categories of substances show some promise as poten­
tial nutritional immunomodulators in burn patients: long-
chain fatty acids; arginine, glutamine, and branched-chain
amino acids; and nucleotides. Short- and medium-chain
fatty acids are commonly utilized for energy, whereas long-
chain fatty acids are important constituents of cell mem­
branes and can profoundly influence cell function.135
Omega-3 long-chain fatty acids play a particularly important
role in the membranes of immunocompetent cells.136 There
are animal data suggesting that supplementation of the diet
with omega-3 fatty acids may improve immune function
after burn injury;137 however, there are no clear clinical data
yet available to support the routine administration of
omega-3 fatty acids as a dietary supplement in injured
patients.
The potential immunostimulating effects of specific amino
acids, particularly arginine, glutamine, and the branched-
chain amino acids leucine, isoleucine, and valine, are an
active area of research. Arginine is a nonessential amino acid
with important functions in the urea cycle and in the genera­
tion of nitric oxide.138 It also may have important effects
in insuring immune cell competence.139,140 Although there
are some animal data suggesting improved immunocompe­
tence and outcome after burn with supplementation of
arginine,141–143 human data are not yet adequate to support
its routine administration to burn patients. Glutamine, the
with parenteral feedings, possibly via an enhancement of
gastrointestinal barrier integrity.122 However, these data
require confirmation prior to general application. Data sup­
porting the administration of specific mucosal substrates or
gut decontamination are less convincing, but further research
in these important areas may show such benefit.
Insuring adequate oxygen delivery
The normal intracellular partial pressure of oxygen is
0.5 mmHg, and this small amount of mitochondrial oxygen
allows for the aerobic generation of most of the cell’s adeno­
sine triphosphate (ATP). When cells have to adapt to a lower
oxygen tension, ATP generation continues at a lower rate by
anaerobic channels,123 possibly triggered by the build-up of
adenosine diphosphate (ADP). As outlined by Gutierrez, the
anaerobic reactions which generate ATP are glycolysis, the
creatine kinase reaction, and the adenylate kinase reaction.123
Glycolysis describes the conversion of glucose to lactate with
the generation of two ATP molecules. The creatine kinase
reaction is the breakdown of the high-energy phosphate
storage molecule, phosphocreatine, with the generation of
ATP and creatine. The adenylate kinase reaction describes the
combination of nucleotides to form ATP and AMP which,
although generating ATP, depletes the cells of adenine nucle­
otides. In conjunction with this conversion to anaerobic ATP
generation, the intracellular concentration of hydrogen ion
increases, the amount of adenine nucleotides within the cell
decreases, and intracellular calcium levels increase with
decreased function of the ATP-driven sodium–calcium
pump.124 There also may be an increase in the liberation of
intracellular oxygen free radicals with the activation of xan­
thine oxidase.125 If low oxygen tensions continue, membrane
phospholipids may be degraded by the combined effects of
elevated calcium, oxygen free radicals, and the decreased
synthetic capabilities coincident with decreased levels of
ATP.126 These effects may be magnified if there is also sys­
temic sepsis as cellular oxygen extraction may be impaired.
That such cellular hypoxic dysfunction is involved in the
development of organ dysfunction is implied by the fact that
cocarboxylase, which enhances ATP generation by ischemic
cells, ameliorates some of the metabolic and hemodynamic
consequences of endotoxic shock in an animal model.127
Perhaps the most at-risk phase of care for provision of
adequate oxygen delivery is during burn resuscitation.128 At
a local level, inflammatory cells aggregating to wounds
secrete histamine and other mediators which disrupt
endothelial junctions resulting in extravasation from the
intravascular space into the surrounding tissues. This is in
turn associated with intracellular sodium retention and cel­
lular edema. As burns become larger, this phenomenon
becomes generalized, creating a diffuse capillary leak, local
vasoconstriction and systemic vasodilation, with secondary
distributive and hypovolemic shock. Vascular collapse ensues
unless effective resuscitation can be accomplished.129–130
The practical details of resuscitation, particularly resuscita­
tion endpoints, remain controversial. The Rivers et al.131
study highlighted the utility of aggressive pursuit of pre-
determined resuscitation endpoints in septic shock; these
principles have been endorsed by the 2008 Surviving Sepsis
Campaign.132 A similar strategy is likely to be effective in
burn patients. The traditional primary endpoint of urine

Etiology and prevention of multisystem organ failure
367
Significant efforts have also been made toward modifying
the actions of arachidonic acid metabolites or eicosanoids,
both cyclooxygenase and lipoxygenase products. Numerous
animal models of sepsis and endotoxemia exist, and
cyclooxygenase
pathway
blockade
with
nonsteroidal
anti-inflammatory agents has demonstrated improved
survival,158,159 improved pulmonary hemodynamics,160 and
improved mesenteric blood flow.161 There has been little
work documenting outcome improvement in human
patients, but it has been suggested that nonsteroidal anti-
inflammatory agents improve symptoms associated with
endotoxin infusion in normal volunteers162 and septic
patients,163 and may improve immune function after surgical
trauma.164 In an animal model, infusion of the vasodilating
arachidonic acid metabolite, prostacyclin, ameliorates the
pulmonary dysfunction associated with endotoxin infu­
sion.165 Less work has been done with lipoxygenase pathway
inhibitors. Survival is enhanced in a murine model of
endotoxin infusion with lipoxygenase pathway blockade.166
Endotoxin-associated pulmonary dysfunction is diminished
in sheep167 and pigs168 when this pathway is blocked. The
ultimate role of lipoxygenase blockade in human remains
uninvestigated.
Cytokines are difficult to measure accurately and their
complex interactions are poorly understood. The production
of IL-1 receptor antagonist is increased in human endo­
toxemia,169 and, in an animal model, its administration
enhances survival.170 However, infusion of IL-1 may improve
immune function in humans.171 Clearly our understanding
of the complex functions of this cytokine are inadequate to
allow intelligent intervention.
Tumor necrosis factor is produced by macrophages and
other inflammatory cells when stimulated by endotoxin.172
In animal models, the physiological effects of both endo­
toxin infusion and Gram-negative sepsis173,174 are attenuated
by TNF blockade with monoclonal antibodies. Circulating
levels of TNF are high immediately after sepsis begins and
then fall, implying that only anti-TNF pretreatment would
be beneficial.175 However, even anti-TNF administration
prior to experimental sepsis176 and endotoxemia177 has vari­
able effects, at best, on survival. Again, our incomplete
understanding precludes effective intervention.
Interference with the effects of platelet activating factor
(PAF) has been shown to decrease neutrophil priming by
human burn serum,178 to improve endotoxin-induced pul­
monary dysfunction,179 to decrease eicosanoid release,180 and
to attenuate thromboxane release and improve survival181 in
various animal models of endotoxemia. These exciting initial
results, and the availability of several blockers and receptor
antagonists, portend a future use for PAF modification.
Efforts to modulate both the adherence and function of
inflammatory cells are an exciting area of research, as acti­
vated neutrophils clearly play an important role in the devel­
opment of multiple organ failure. Blockade of neutrophil
adhesion receptors with monoclonal antibodies enhances
survival in animal models of endotoxic and hemorrhagic
shock.182,183 Again, our basic understanding is not yet ade­
quate to intelligently modify such important processes.
Oxygen free radicals generated by activated neutrophils or
xanthine oxidase may oxidize membrane lipids, forming
lipid peroxides, resulting in membrane dysfunction.184
Native antioxidant systems do exist, but can be overwhelmed.
most common amino acid in the body, and a preferred fuel
of rapidly dividing cells, may be conditionally essential in
hypermetabolic patients,113,114 and its administration has
been proposed as a method to support the gut barrier,
thereby abrogating the consequences of barrier failure.
The hyperdynamic and catabolic physiology that typifies
the post-resuscitation period has deleterious consequences
for many patients.143,144 Nutrition is critical in support of this
physiology. Some efforts to modify the catabolic state have
been successful. Beta-blockade has been shown to decrease
resting oxygen expenditure, attenuate muscle catabolism and
lipolysis, and have favorable effects on some aspects of
immune function.145,146 The anabolic agent oxandrolone
reduces loss of lean body in some patients.147
Non-specific and specific immunomodulation
It seems intuitively unlikely that there exists a magic immu­
nomodulating bullet that will prevent the development of
multisystem organ failure in critically ill surgical patients,
particularly if sepsis is uncontrolled, the integrity of the gut
barrier is compromised, burn wounds are unaddressed, or
patients are inadequately supported hemodynamically.
However, such efforts have tremendous potential to facilitate
our understanding of cellular and subcellular biology and
may, in time, provide a clinical dividend. Efforts at non­
specific immunomodulation have included the use of
steroids,147 immunoglobulin G,148 and naloxone149 with no
significant impact on patient outcomes. With the exception
of steroids for those with suspected adrenal insufficiency150
and naloxone for those with opiate intoxication, there is no
role for these substances in critically ill burn patients.
Although there have been efforts to absorb lipopolysac­
charide,151 and to prevent endotoxemia with prophylactic
polymyxin B in burn patients,152 the greatest efforts at spe­
cific immunomodulation have been applied to the develop­
ment of anti-endotoxin antibodies. The earliest clinical
efforts used human serum with anti-J5 activity and demon­
strated an enhanced survival in patients with Gram-negative
septic shock.153 Later, two monoclonal IgMs were developed,
and human trials were completed. The first was anti-E5, a
murine monoclonal antibody. Clinical trials suggested a
benefit in septic patients without refractory shock.154 Large
numbers of treated patients developed antibodies to the
murine monoclonal, and although these patients were not
retreated, attention turned more toward a human product.
A subsequent effort with this murine monoclonal did not
show statistically significant improvements in outcome.155
HA-1A, a human monoclonal IgM, was trailed in a large
multicenter effort without statistically significant improve­
ment in outcome, except in a subgroup of patients that had
Gram-negative bacteremia and shock.156 Multiple confound­
ing factors made these marginally beneficial results suspect,
leaving the ultimate utility of HA-1A still unclear.
Anti-endotoxin monoclonal therapy, which may have
potential to be beneficial if significantly refined, has also
been criticized for its expense. It is estimated that it would
cost $24 100 per year of life saved should this technology be
used widely.157 Integrating such advanced and expensive
technology into common practice poses tremendous practi­
cal problems, and is therefore very unlikely to happen soon
when one considers its lack of clear efficacy and high expense.

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368
interfere in such complex, and poorly understood processes.
Vigilant clinical care in the intensive care unit, with the
prevention of sepsis, proper management of burn wounds,
support of the gut barrier, and careful attention to whole-
body hemodynamics is a much more fruitful area in which
a vigilant clinician can make a difference. On the near
horizon is an exciting new understanding of the molecular
mechanisms of critical illness that is likely to lead to effective
targeted interventions.199
Further reading
Alam HB, Rhee P. New developments in fluid resuscitation. Surg Clin
North Am. 2007;87(1):55-72.
A review of the colloid-heavy resuscitation strategies becoming established in
trauma.
Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
International guidelines for management of severe sepsis and
septic shock. Crit Care Med. 2008;36:296-327.
SCCM practice guidelines for sepsis management, recently updated.
Herndon DN, Tompkins RG. Support of the metabolic response to
burn injury. Lancet. 2004;363:1895-1902.
A complete review of the complexities of the metabolic response to burns as
they are now understood.
Herndon DN, Hart DW, Wolf SE. Reversal of catabolism by beta-
blockade after severe burns. N Engl J Med. 2001;345:1223-1229.
The NEJM paper in which the benefits of beta-blockade in burn patients are
reported.
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in
the treatment of severe sepsis and septic shock. N Engl J Med.
2001;345:1368-1377.
The original Rivers paper that identified the impact of early goal-directed
therapy for septic shock.
Sheridan RL. Sepsis in pediatric burn patients. Pediatr Crit Care Med.
2005;6(3 Suppl):S112-S119.
A review of the many varieties of sepsis in burn patients.
Williams FN, Herndon DN, Jeschke MG. The hypermetabolic response
to burn injury and interventions to modify this response. Clin Plast
Surg. 2009;36(4):583-596.
A nice review of the post-burn hypermetabolic response and various ways it
can be modified.
Wolf SE, Edelman LS, Mealyan N. Effects of oxandrolone on outcome
measures in the severely burned: A multicenter prospective
randomized double-blind trial. J Burn Care Res. 2006;27:
131-139.
A controlled study demonstrating the benefits of anabolic steroids in burn
patients.
Circulating levels of vitamin E, a natural antioxidant, are low
in patients with ARDS.185 Efforts to modify oxidant activity
have included blockade of free radical generation, addition
of free radical scavengers, augmentation of host antioxidant
defenses, and prevention of amplification of tissue damage
by neutrophils.184 Particularly exciting are free radical scav­
engers such as superoxide dismutase186 and spin-trapping
nitrones187 which improve survival in animal models of
endotoxic and hemorrhagic shock. But, despite such encour­
aging initial animal work, such therapy is not yet appropriate
in human patients.
The continuous synthesis of nitric oxide (Fig. 31.2) plays
an important role in the regulation of pulmonary and sys­
temic vascular tone in sepsis188 and this presents potential
opportunities for intervention.189 Aerosolized nitric oxide
has been shown to be useful in reversing the pulmonary
hypertension associated with ARDS190 and nitric oxide syn­
thesis blockade may improve the hypotension and renal
dysfunction associated with sepsis. However, its complex
interactions with other cytokines and variable effects on dif­
ferent vascular beds render any nitric oxide-based interven­
tions investigational at the present time.
Recently, recombinant activated protein C (rAPC) has
been shown to have a favorable influence in patients with
sepsis-induced multiple organ failure, after it demonstrated
a 6% absolute reduction in mortality in a large multicenter
trial.191 Institutional criteria for administration of rAPC
infusion vary, but generally include those patients with
vasopressor-dependent septic shock and multiple organ
failure of recent onset. Its major complication is bleeding,
which has precluded its general use in septic shock in burn
patients. However, it may ultimately have a role in septic
shock associated with isolated inhalation injury.192
Most patients who die in the burn unit after surviving
resuscitation succumb to multiple organ failure.193 Although
modification of the cascade of events leading to multiorgan
failure at the cellular and subcellular level is an enticing pos­
sibility, our fragmented understanding of these processes
mitigates against such therapy in human patients at the
present time. That TNF enhances the ability of neutrophils
to kill invading bacteria194 and of rats to survive Gram-
negative sepsis;195 that cyclooxygenase inhibition increases
TNF production after burn;196 that PGE2 is important in renal
autoregulation;197 and that cytokine levels vary significantly
over the course of critical illness198 makes one loath to
 
Access the complete reference list online at

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adult respiratory distress syndrome, and effects of
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4801-4806.

©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00032-1
Renal failure in association with
thermal injuries
Jeremy Goverman, Naoki Aikawa, Shawn P. Fagan
Introduction
Acute renal dysfunction is a major complication affecting the
thermally injured individual and is commonly associated
with a high mortality rate. Currently, the incidence of acute
renal failure in burn patients varies between 0.5% and 30%,
with a reported mortality rate between 54% and 100%.1–10
Prior to 1965 there were no reported survivors from acute
renal failure following burns.11 While advances have been
made in the understanding of the etiology of acute renal
failure in association with thermal injury, little has been
accomplished with the actual treatment; and it remains
unclear whether or not the application of renal replacement
therapy (RRT) as a treatment modality has significantly
changed the mortality rate of individuals suffering from
acute renal failure.12 The best treatment for acute renal
dysfunction is prevention, by understanding the pathophy­
siology of renal dysfunction in the thermally injured indi­
vidual. This chapter will review the definition, etiology,
pathophysiology, diagnosis, and treatment of acute renal
dysfunction in association with thermal injury (Fig. 32.1).
Definition
Historically, acute renal failure has been defined as an abrupt
and sustained decrease in renal function. Until recently,
there was no consensus regarding an absolute definition for
acute renal failure. This is exemplified by more than 30 dif­
ferent definitions having been used in the literature, creating
much confusion and making comparisons between studies
impossible.7,13,14 Although the definitions are numerous, the
common theme of all definitions in the literature is an
abrupt decline in glomerular filtration rate (GFR) with the
inability of the kidneys to appropriately regulate fluid,
electrolytes, and acid–base homeostasis. Furthermore, acute
renal failure represents an end-stage process, with the phases
leading up to it having important clinical and prognostic
value. The need to grade the severity of injury, rather than
consider only the most severe form, has led to a new clas­
sification system. The term acute kidney injury, or acute
kidney insufficiency (AKI), is now preferred.14–16
In an effort to standardize the definition of renal insuffi­
ciency, the International Acute Dialysis Quality Initiative
(ADQI) group has developed the RIFLE criteria (Fig. 32.2).
The RIFLE criteria are a classification system that uses the
GFR or urine output to define increasing levels of renal insuf­
ficiency. RIFLE defines three grades of acute kidney injury of
increasing severity (risk, injury, failure), based on changes
in either serum creatinine or urine output, as well as two
outcome categories (loss and end-stage kidney disease). The
RIFLE classification system has been validated in a number
of clinical scenarios, including burn injury, with increasing
grades corresponding to increasing mortality.5–10,17–19 In an
attempt to include a time component for changes in creati­
nine, the ADQI have since modified the RIFLE criteria to the
Acute Kidney Injury Network (AKIN) criteria (Table 32.1).
The AKIN criteria define acute kidney injury as an abrupt
reduction in kidney function (≤48 hours) and may allow for
earlier recognition of AKI in the ICU setting.16 Comparisons
between RIFLE and AKIN have been published but have not
demonstrated clear benefit of one classification system over
the other.20–22 These new classification systems should aid in
future experimental design and allow for improved com­
parison between studies investigating AKI associated with
thermal injuries.
Etiology of acute renal failure
Burn-related renal insufficiency is most commonly observed
during the period of initial resuscitation after burn injury
(early AKI) or as a component of the multiorgan dysfunction
syndrome, often associated with severe sepsis (late-onset
AKI). The development of early AKI in the burn individual
is multifactorial: hypovolemia, inflammatory mediators,
cytokines, extensive tissue destruction and release of dena­
tured proteins, iatrogenic causes (nephrotoxic agents), and
cardiac dysfunction have all been implicated.3,4,23,24 Histori­
cally under-resuscitation and hypovolemia were the primary
focus; however, more recent studies have demonstrated that
AKI is not solely dependent on the amount of fluid received.
AKI develops in the thermally injured patient despite aggres­
sive fluid resuscitation and a normal urine output, and is
more likely dependent on the degree of shock following
injury. Global parameters of perfusion, i.e. lactate and base
deficit, may better predict AKI, as they have been demon­
strated to predict an increased risk of systemic inflammatory
response syndrome (SIRS), acute respiratory distress syn­
drome (ARDS), multiorgan dysfunction syndrome (MODS),
and mortality.5,25–29
CHAPTER 32 
Access the complete reference list online at

IN THIS CHAPTER
PowerPoint Presentation Online

Total Burn Care
32
370
Figure 32.1  Autopsy specimen from a patient with acute tubular necrosis
and renal failure. Note the edema and the alteration of medullar pyramids.
Acute renal failure in burn patients carries a high mortality.
Figure 32.2  RIFLE classification scheme for
acute renal failure (ARF). (From Bellomo R, Ronco C,
Kellum JA, Mehta RL, Palevsky P, and the ADQI workgroup.
Acute renal failure – definition, outcome measures, animal
models, fluid therapy and information technology needs:
the Second International Consensus Conference of the
Acute Dialysis Quality Initiative (ADQI) Group. Crit Care
2004; 8:R204-R212.)
GFR criteria*
Risk
Injury
Failure
High sensitivity
Oliguria
Increased SCreat × 1.5 or
GFR decrease > 25%
Increased SCreat × 2 or
GFR decrease > 50%
Increased SCreat × 3
GFR decrease 75%
or SCreat ≥4mg/dL
Acute rise ≥0.5mg/dL
Urine output criteria
UO< 0.5ml/kg/h
× 6 hr
UO < 0.5ml/kg/h
× 12 hr
UO < 0.3ml/kg/h
× 24 hr or
Anuria × 12 hrs
Loss
ESKD
High specificity
Persistent ARF** = complete loss
of kidney function > 4 weeks
End stage kidney disease
(> 3 months)
Table 32.1  RIFLE and AKIN criteria
RIFLE
category
Serum creatinine criteria
UO criteria
(A)  The Acute Dialysis Quality Initiative (ADQI) criteria for the definition
and classification of AKI (i.e. RIFLE criteria)
Risk
Increase in serum creatinine
≥1.5X baseline or decrease in
GFR ≥25%
<0.5 mL/kg/h for
≥6 h
Injury
Increase in serum creatinine
≥2.0X baseline or decrease in
GFR ≥50%
<0.5 mL/kg/h for
>12 h
Failure
Increase in serum creatinine
≥3.0X baseline or decrease in
GFR ≥75% or an absolute serum
creatinine ≥354 µmol/L with an
acute rise of at least 44 µmol/L
<0.3 mL/kg/h ≥24 h
or anuria ≥12 h
AKIN
criteria
Serum creatinine criteria
UO criteria
(B)  The proposed Acute Kidney Injury Network (AKIN) criteria for the
definition and classification of AKI
Stage 1
Increase in serum creatinine
≥26.2 µmol/L or increase to
≥150–199% (1.5- to 1.9-fold)
from baseline
<0.5 mL/kg/h for
≥6 h
Stage 2
Increase in serum creatinine to
200–299% (>2–2.9 fold) from
baseline
<0.5 mL/kg/h for
≥12 h
Stage 3
Increase in serum creatinine to
≥300% (≥3-fold) from baseline
or serum creatinine
≥354 µmol/L with an acute rise
of at least 44 µmol/L or
initiation of RRT
<0.3 mL/kg/h ≥24 h
or anuria ≥12 h
(From Brochard L, Abroug F, Brenner M, Broccard AF, Danner RL, Ferrer M, Laghi F,
Magder S, Papazian L, Pelosi P, Polderman KH, on behalf of the ATS/ERS/ESICM/
SCCM/SRLF Ad Hoc Committee on Acute Renal Failure. An official ATS/ERS/ESICM/
SCCM/SRLF statement: prevention and management of acute renal failure in the
ICU patient: an international consensus conference in intensive care medicine.
Am J Respir Crit Care Med. 2010; 181(10):1128–1155.).
Hypovolemia
Burns affecting >20% total body surface area (TBSA) are of
sufficient size to induce decreased renal blood flow from
local and systemic cytokine release as well as extravascular
fluid loss.30,31 This concept is supported by the observations
of Kim et al. that burn size is an independent predictor of
acute renal failure in the burn population.32 Depressed renal
blood flow results in ischemia and cellular death. The
ischemic insult is known to produce oxygen free radicals that
cause direct tubular damage, as well as disruption of tight
junctions, resulting in obstructing casts which further reduce
effective GFR. The duration of ischemic time is critically

Renal failure in association with thermal injuries
371
rapidly re-establish adequate renal blood flow by correcting
the diminished preload state while keeping in mind the
impact of burn injury on the entire cardiovascular system.
Patients suffering burns >50% TBSA are subject to decreased
cardiac output, increased myocardial workload, myocardial
ischemia, and acute cardiac infection from the large area
of wounded skin.46–51 Several authors have suggested
theories to explain the decreased cardiac output associated
with thermal injury: 1) increased sympathetic activity
with impaired adrenal response, 2) hypovolemia resulting
in
myocardial
ischemia
and
3)
direct
myocardial
suppression.48–50,52–54 Of the potential theories, direct myo­
cardial suppression by tumor necrosis factor (TNF, i.e. myo­
cardial depressant factor) has gained substantial interest.
TNF is known to be released by myocytes stimulated by
endotoxin or direct thermal injury.55–61 The effects of TNF on
cardiac function include reversible biventricular dilatation,
decreased ejection fraction, and decreased stimulation to
catecholamines (Fig. 32.1).57,62–63 Although most early
cardiac dysfunction caused by TNF can be reversed by ino­
tropic support, the key is early diagnosis to prevent ineffec­
tive renal perfusion and thus prevent the morbidity and
mortality associated with renal insufficiency.
Denatured proteins
Rhabdomyolysis and free hemoglobin have both been impli­
cated in the development of AKI and subsequent renal
failure.64 Rhabdomyolysis in particular has been shown to
contribute to AKI following severe burns. Rhabdomyolysis
can arise secondary to direct thermal damage or compart­
mental syndrome and is commonly seen following severe
electrical injury. The release of myoglobin, or unconjugated
hemoglobin, into the systemic circulation results in blockage
of renal tubules, constriction of afferent arterioles, and the
generation of oxygen free radicals.65 The extent of renal
injury is directly related to the amount of iron-containing
molecules released, the state of hydration, and the degree of
acidosis.66 Myoglobinuria occurs when serum myoglobin
exceeds 1500–3000 ng/mL Elevated creatinine at baseline
and creatine kinase levels >5000 U/L have been associated
with the development of AKI and the need for RRT.67 Fortu­
nately, the incidence of denatured proteins causing burn-
associated acute renal insufficiency is low, and the overall
prognosis is favorable if the pathological source is identified
early and appropriate treatment is initiated.68 For those
patients at risk, intensive hydration with isotonic crystalloids
is recommended. The use of sodium bicarbonate is unneces­
sary, as it has not been shown to be superior to saline for
alkalization of the urine.16,67
Sepsis
There have been significant advances in the treatment of
burn injuries since 1965. Early aggressive resuscitation and
excision have significantly influenced the course of acute
renal failure immediately associated with thermal injury.69,70
Acute renal dysfunction associated with the septic syndrome
nonetheless continues to cause significant mortality.71
Sepsis and septic shock are the most common cause of
death in the intensive care unit (ICU) and are seen in up to
87% of cases of acute renal dysfunction in the burn ICU.8,9
important to the development of AKI. Nguyen et al. found
initial management of the thermally injured individual to
be critically important to overall survival. Aggressive hydra­
tion had a protective effect against acute renal failure.33 Simi­
larly the Shriners Burn Institute for Children, Galveston,
observed that the time to initiation of resuscitative fluids was
directly related to the incidence of renal dysfunction and
overall mortality. They concluded that early aggressive fluid
resuscitation lessens kidney damage and thus prevents renal
dysfunction, which improves overall outcome.34
Hypervolemia, intra-abdominal hypertension,
and abdominal compartment syndrome
Although aggressive fluid resuscitation may reduce the risk
for AKI, it does not eliminate its occurrence. Studies have
shown that AKI develops in burn-injured patients despite
fluid resuscitation volumes in excess of that recommended
by the Parkland formula, and despite normal average urine
output (0.5–1.0 mL/kg/h).5 Furthermore, the risks of over-
resuscitation have been well documented and include pneu­
monia, ARDS, compartment syndromes, and an overall
increase in mortality.35–37
Burns >20% TBSA generally require intravenous resuscita­
tive efforts, and the initial volume of fluids should be pro­
portional to the area of burn injury. Despite a physician’s
greatest effort to monitor endpoints of resuscitation, obliga­
tory intercompartmental fluid shifts will occur during resus­
citation.38 These intercompartmental fluid shifts can be
particularly hazardous if they occur into fascial bound com­
partments, such as the peritoneal cavity. Numerous studies
from the trauma literature have described the adverse phy­
siologic effects of increasing intra-abdominal pressure on
visceral perfusion.39–41 Intra-abdominal hypertension (IAH)
is a known pathological process that may occur during initial
burn resuscitation as defined by intra-abdominal pressures
(IAP) >12 mmHg. Abdominal compartment syndrome
(ACS) is defined as an IAP >20 mmHg with at least one
concomitant organ failure. The exact incidence of ACS, the
point of decreased visceral perfusion, is currently unknown
during burn shock resuscitation.42–45 O’Mara et al. demon­
strated that the volume and type of fluid resuscitation affects
the development of ACS in the burn patient and suggested
that fluid resuscitation with crystalloid >0.475 L/kg should
alert the clinician to possible IAH/ACS and to monitor for
decreased cardiac output, decreased lung compliance, or
decreased renal perfusion – signs of ACS. In a mixed popula­
tion of critically ill patients, a multicenter prospective trial
has demonstrated that the occurrence of IAH during the ICU
stay was an independent outcome predictor.45
Cardiac dysfunction
Cardiac dysfunction is known to result in reduced renal
blood flow and hence to contribute to AKI. Although dimin­
ished cardiac output following thermal injury has been
attributed to decreased preload or hypovolemia, there is
increasing evidence of direct myocardial suppression. Myo­
cardial dysfunction after thermal injury is commonly over­
looked by physicians owing to the concentrated effort to
correct the overwhelming state of hypovolemic shock and
electrolyte abnormalities.46 An effective burn surgeon must

Total Burn Care
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372
endothelin) as well as the inability of locally secreted vasodi­
lators (endothelial and inducible nitric oxide) to counterbal­
ance these sepsis-associated vasoconstrictors.71,74 Finally, as
mentioned previously, sepsis induces a procoagulant state by
affecting the expression of complement and the fibrinolytic
cascade.75–77 This alteration in the homeostasis of coagula­
tion may result in a state of disseminated intravascular coag­
ulation (DIC) with direct injury to the kidney by glomeruli
microthrombi.78 The net result is a lack of perfusion to the
kidneys during sepsis that will ultimately culminate in acute
tubular necrosis secondary to ischemic injury.
Diagnosis of acute kidney injury
The key to the diagnosis of AKI following thermal injury is
to have a strong fund of knowledge in the pathophysiology
affecting the burned patient throughout their treatment
course. Significant renal injury may be present despite
normal urine output or significant changes in the biochemi­
cal markers of renal injury. Physicians must constantly review
the global physiological state of a thermally injured patient
and anticipate conditions that may affect the renal system,
so that a stepwise approach to the diagnosis and treatment
may be initiated.
Of the physiologic parameters of renal function, altered
urine output is probably the first and most recognized sign
of renal dysfunction. Urine output has been demonstrated
to be a very specific but unfortunately not very sensitive
measure of renal function.79 Most clinicians regard urine
output of little diagnostic value in the evaluation of renal
dysfunction, since severe renal injury may exist with any
volume of urinary output. This variability is due to the fact
that urine output is not determined by the GFR alone but
by the difference between GFR and tubular reabsorption.
The one clinical scenario in which urine output may be
diagnostic is the presence of anuria (<50 mL/day) or com­
plete cessation of GFR.80 The most common cause of anuria,
excluding postrenal obstruction, is a severe prerenal condi­
tion. Although it is true that other conditions (acute cortical
necrosis, bilateral arterial occlusion and rapidly progressive
acute glomerulonephritis) may cause anuria, their incidence
is low and the diagnosis is usually readily apparent owing
to additional clinical signs.
Although urinary output is commonly non-diagnostic
regarding the type of renal injury, microscopic and biochem­
ical analysis may aid in the diagnosis and thus guide treat­
ment options.81 Microscopic examination of urinary sediment
is an easy and inexpensive initial evaluation of AKI to deter­
mine the underlying renal pathology. The combination of
normal urinary sediment, hyaline casts, and oliguric/anuric
urinary output would suggest a prerenal condition. The pres­
ence of epithelial casts and abundant tubular epithelial cells
is pathognomonic for acute tubular necrosis. Similarly, the
identification of pigmented casts on microscopic evaluation
signifies the diagnosis of myoglobinuria, likely secondary to
rhadbomyolysis. If microscopic evaluation is non-diagnostic,
urinary electrolytes will allow for evaluation of the renal
response to the individual’s physiologic state.
The primary goal of evaluating urinary electrolytes in a
thermally injured individual is to differentiate between the
prerenal and renal forms of AKI. It has been well established
Several authors have found the degree of sepsis to be directly
related to the incidence of acute renal dysfunction72,73 (Table
32.2). The key to treatment is an understanding of the patho­
physiology of AKI associated with sepsis, the basis of which
is multifactorial in nature but begins clinically with a gener­
alized arterial vasodilatation secondary to a decreased sys­
temic vascular resistance (Fig. 32.3). Initially, bacteria or
their products activate sepsis-associated mediators (cytokines)
locally at the site of direct invasion. In sepsis, the homeo­
static balance between production and inactivation of these
mediators is altered, allowing for systemic release, causing
direct damage to the endothelium, vasoparalysis, and a pro­
coagulant state. It has been theorized that acute renal insuf­
ficiency associated with sepsis is the result of each of these
pathological processes. The vasoparalysis seen in sepsis
results in a profound state of hypotension which activates
the neurohumoral axis. In an effort to maintain systemic
arterial circulation, the sympathetic nervous system and the
renin–angiotensin–aldosterone axis respond by increasing
cardiac output and by direct renal arteriolar vasoconstric­
tion. This response may actually worsen renal perfusion
by inducing a prerenal state, which is further aided by
the release of other vasoconstricting agents (i.e. TNF,
Table 32.2  Renal failure dysfunction and sepsis
Sepsis
Severe
sepsis*
Septic
shock†
Acute renal dysfunction
19%
23%
51%
*Sepsis associated with lactic acidosis or altered mental status.
†Sepsis associated with hypotension.
Figure 32.3  Multifactorial etiology of sepsis-induced acute renal failure.
Multifactorial etiology of sepsis-induced acute renal failure.
Ineffective local vasodilators
• Decreased inducible nitric
oxide
– depletion of cGMP
• Decreased endothelial
nitric oxide
– direct endothelial damage
– direct inhibition by iNOS
Relative systemic
hypovolemia
• Systemic arterial
vasodilatation
– activation of inducible
nitric oxide synthase
• Depletion of
vasopressin


Vasconstrictors
• Norepinephrine and angiotensin II
• Tumor necrosis factor
– release of endothelin
• Neural-mediated vasoconstriction
secondary to endotoxemia
Decreased Renal Perfusion

Renal failure in association with thermal injuries
373
kidney. The amount of creatinine excreted is approximately
10–20% greater than the amount filtered, therefore the cal­
culated creatinine clearance by definition overestimates the
true GRF during normal steady-state conditions.85 Creatinine
is thus not an ‘ideal’ marker but a ‘reasonable’ marker of GRF
in a normal host.
The impact of illness appears to have a significant effect
on the use of creatinine as a marker of GFR due to the non-
steady-state environment. Plasma creatinine is not only
dependent on its urinary clearance but also on its produc­
tion and volume of distribution within the body. Several
studies have demonstrated the impact of illness on each of
these parameters79,86 (Table 32.5). In critically ill patients,
serum creatinine appears to be an inaccurate absolute deter­
minant of GFR. In fact, serum creatinine has been demon­
strated to often lag behind the true degree of progressive
renal dysfunction and renal recovery.79 In these conditions
serum creatinine should be viewed with respect to the degree
of change over time, which in turn grossly reflects the degree
of GFR change over time.
Moran and Myers demonstrated the importance of under­
standing the degree of creatinine change over time.87 They
investigated creatinine kinetics following ischemic postop­
erative acute renal failure, and based on their observations
they developed hypothetical profiles of acute renal failure
and recovery focusing on changes in GFR and their corre­
sponding changes in serum creatinine. Their work suggested
that the two variables were not always inversely proportional
but often dissociate during acute renal failure and recovery.
That is, a rising serum creatinine is not always indicative of
worsening GFR and a decreasing serum creatinine is not
always indicative of an improving GFR. What did appear to
be prognostic in acute renal failure is the number of days the
plasma creatinine continued to rise after the initial ischemic
insult. Post-insult day 4 was found to be the significant
determinant of the state of recovery. An abrupt insult fol­
lowed by immediate recovery caused the serum creatinine to
peak at approximately post-insult day 4. If serum creatinine
continued to rise beyond post-insult day 4, renal recovery
had not begun, and this was followed by a severe protracted
course of acute renal insufficiency. Although this study was
not conducted in a burn population, the underlying patho­
physiology (ischemic) is germane to the burn population,
especially after initial resuscitation.
A clinician should understand the limitations of any
marker used to calculate or follow GRF during renal injury.
Albeit not an ‘ideal marker’, creatinine is the gold standard
that a prerenal state in the presence of a functional nephron
is associated with enhanced absorption of sodium or a low
fractional excretion of sodium. The fractional excretion of
sodium (FeNa) is defined as:
FeNa
urine sodium
plasma creatinine /
plasma sodium
urin
=
×
×
[(
)
(
ary creatinine)]
with a value <1% associated with a prerenal condition and
a value >1% associated with a renal condition.82 Although
this is the accepted rule, there are conditions that affect renal
absorption of sodium and thus have been shown to affect
the calculated value (Table 32.3). Additionally, chronic renal
insufficiency has been demonstrated to be associated with
altered sodium homeostasis, and therefore the interpreta­
tion of the FeNa in the setting of renal insufficiency is dif­
ficult. In this situation, an alternative agent such as urea may
be appropriate. Recently, fractional excretion of urea (<0.35)
was suggested to be more specific and sensitive than sodium
in distinguishing between prerenal and renal forms of acute
renal failure.83 The prerenal state not only affects the homeo­
stasis of sodium and urea: several additional indexes can be
used to differentiate between the two forms of acute renal
failure (Table 32.4).
Ideally a biochemical marker for AKI would: 1) allow early
detection of renal injury, 2) identify the nephron segment
affected, 3) reflect improvement and worsening of renal
function and 4) be easily and rapidly measured.84 Currently
no such ‘ideal’ biomedical filtration marker exists; however,
creatinine has been used as the standard marker for deter­
mining GFR. Serum creatinine is freely filtered across the
glomerulus and neither absorbed nor metabolized by the
Table 32.3  Factors that affect fractional secretion of sodium
Condition
Effect on fractional
sodium excretion
Glycosuria
Increase
Diuretics
Increase
Mannitol
Increase
Dopamine
Increase
Myoglobinuria
Decrease
Radiocontrast media
Decrease
Table 32.4  Differential diagnosis of acute renal failure
Urinary index
Prerenal
Renal
Uosm (mOsmol/L)
>500
<350
UNa (mEq/L)
<20
>40
Specific gravity
1.020
1.010
Ucreat/Pcreat
>40
<20
Fractional excretion of sodium
<1
>2
Fractional excretion of urea
<35
>50
Table 32.5  Factors affecting serum creatinine
Factors
Effect on serum creatinine
Liver insufficiency
Decreased production
Decreased muscle mass:
  deconditioning
Decreased production
  aging
Decreased production
Trauma
Increased production
Fever
Increased production
Immobilization
Increased production

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374
Although establishing an effective circulating volume is of
prime importance, an astute clinician should also carefully
assess myocardial contractility to exclude myocardial dys­
function as a contributing factor to ineffective renal per­
fusion. The primary goal is to re-establish effective renal
perfusion through a well thought-out resuscitation plan
based on demonstrated resuscitation formulas and modified
by variables correlated with the degree of resuscitation.
The etiology of late renal dysfunction is multifactorial and
often associated with the development of sepsis and organ
failure. The most effective therapy is prevention or early
recognition of the septic state (Box 32.1). Every thermally
injured patient should be continuously monitored for early
markers of sepsis (feeding intolerance, increasing insulin
resistance, elevation of acute-phase reactants) so that early
therapy may be initiated. Once a clinically significant infec­
tious organism is identified, early goal-directed therapy
should be initiated. Rivers et al. demonstrated a significant
reduction in mortality if early goal-directed therapy is applied
to the septic patient.92 This work has recently been acknowl­
edged and summarized by the Surviving Sepsis Campaign,
published as a consortium agreement of several different
governing bodies.93 The principle is simple: establish early
source control while providing effective antibiotic therapy
and maximizing global, and therefore renal, perfusion. The
strategy is effective and important, as no renal protective
for this calculation. GFR calculations based on creatinine
clearance should be made over short time intervals, with the
serum creatinine value reflecting the mean of the values
obtained at the beginning and end of the collection interval.
New markers of AKI, such as cystatin-C, have shown promise
as earlier detectors of changes in GFR.88–90
Treatment of acute renal failure
The key to the treatment of AKI is prompt diagnosis coupled
with a rapid reversal of the underlying pathophysiology
while preventing iatrogenic injury. If the process is progres­
sive despite initial therapeutic maneuvers, renal replacement
therapy (RRT) is indicated. This section will focus on the
prevention of early and late AKI and the current theories
behind RRT.
As stated previously, early AKI is secondary to ineffective
renal perfusion. Several authors have demonstrated that the
timing of initiation of resuscitative fluids is directly related
to the incidence of renal dysfunction.12,13 Resuscitative efforts
should therefore begin immediately to re-establish effective
renal perfusion. Several resuscitative formulas have been
established based on multivariate logistic regression analysis
(Table 32.6). Which formula to use is unimportant, but the
clinician should recognize that these formulas are estimates
of the volume of fluid needed over a period of time. The true
amount is directly dependent on the patient’s own physio­
logic status and degree of injury. A clinician should continu­
ously monitor parameters of regional and global perfusion
in order to guide fluid therapy and prevent over-resuscitation.
If the true volume status (preload) or ability to assess effec­
tive renal perfusion is difficult, one should initiate monitor­
ing of central pressures or global volume related variables
(i.e. global end-diastolic volume, extravascular lung water
volume, intrathoracic blood volume).91 The best means to
measure the degree of resuscitation is unknown; however, if
adequate volume loading does not produce sufficient mean
arterial pressure (60–65 mmHg), the use of vasopressors is
indicated.16
Table 32.6  Burn formulas for estimating initial resuscitation
Crystalloid
Colloid
Colloid:
  Evans
NS 1 mL/kg/%burn
1 mL/kg/%burn
Crystalloid:
  Parkland
4 mL/kg/%burn
  Modified Brooke
2 mL/kg/%burn
Pediatric formulas:
  Cincinnati Shriners
4 mL/kg/%burn +
1500 mL/m2
    Institute for Burn
    Children
TBSA
  Galveston Shriners
5000 mL/m2 BSA +
2000 mL/m2
    Institute for Burn
    Children
TBSA
TBSA, total body surface area; BSA = burn surface area.
Box 32.1  Definition of sepsis in burns
At least three of the following:
I. Temperature >39° or <36.5°C
II. Progressive tachycardia
A. Adults >110 bpm
B. Children >2 SD above age-specific norms (85% age-adjusted
max heart rate)
III. Progressive tachypnea
A. Adults >25 bpm not ventilated
i. Minute ventilation >12 l/min ventilated
B. Children >2 SD above age-specific norms (85% age-adjusted
max resp. rate)
IV. Thrombocytopenia (will not apply until 3 days after initial
resuscitation)
A. Adults <100 000/mcl
B. Children <2 SD below age-specific norms
V. Hyperglycemia (in the absence of pre-existing diabetes mellitus)
A. Untreated plasma glucose >200 mg/dl or equivalent mM/L
B. Insulin resistance—examples include
i. >7 units of insulin/hr intravenous drip (adults)
ii. Significant resistance to insulin (>25% increase in insulin
requirements over 24 hours)
VI. Inability to continue enteral feedings >24 hours
A. Abdominal distension
B. Enteral feeding intolerance (residual >150 ml/hr in children or
two times feeding rate in adults)
C. Uncontrollable diarrhea (>2500 ml/d for adults or >400 ml/d in
children)
In addition, it is required that a documented infection is identified via:
A. Culture positive infection, or
B. Pathologic tissue source identified, or
C. Clinical response to antimicrobials

Renal failure in association with thermal injuries
375
Table 32.7  Advantages and disadvantages of intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT)
Intermittent hemodialysis
Continuous renal replacement therapy
I.  Advantages
Disadvantages
Rapid clearance of acidosis, uremia, potassium, and certain toxins
Slow
Patient mobility
Immobility
Can perform without anticoagulation
More frequent need for anticoagulation
Reduced exposure to artificial membrane
Continuous exposure to artificial membrane
*Reduced incidence of hypothermia
*Interventions required to prevent hypothermia
Masks fever temporarily
Masks fever continuously
Less blood loss from monitoring and/or filter clotting
Greater potential blood loss from monitoring and/or filter clotting
Lower costs in most centers
Higher costs in most centers
Less risk of dialysate compounding errors
Greater risks of replacement fluid and/or dialysate compounding errors
*Less removal of amino acids, endogenous hormones, and cofactors
*Increased removal of amino acids, endogenous hormones, and cofactors
II.  Disadvantages
Advantages
Rapid solute and fluid shifts
Gradual solute and fluid shifts
  –hemodynamic instability
  –greater hemodynamic stability
  –disequilibrium syndrome
  –no or little risk of disequilibrium syndrome
  –worsens brain edema
  –no worsening of brain edema
Frequent need for fluid or nutritional restrictions
Less need tor fluid or nutritional restrictions
Only allows for intermittent adjustment of prescription; less control
of uremia, acidosis, phosphate, and fluid balance
Allows for continuous titration and integration of renal support with other
ICU care and treatment goals
In many centers, requires a dialysis nurse and other resources that
may limit ability to provide extended run-times and/or daily therapy
in selected patients
Procedure performed by ICU nursing staff overall better clearance of
uremia, correction of acidosis, and removal of excess fluid
*Even with high flux membranes, removes fewer 'middle' molecules
*When configured to use convection as its primary mechanism of solute
clearance, removes more ‘middle molecules’
*Differences of unknown or hypothetical importance.
(From Brochard L, Abroug F, Brenner M, Broccard AF, Danner RL, Ferrer M, Laghi F, Magder S, Papazian L, Pelosi P, Polderman KH, on behalf of the ATS/ERS/ESICM/SCCM/SRLF
Ad Hoc Committee on Acute Renal Failure. An official ATS/ERS/ESICM/SCCM/SRLF statement: prevention and management of acute renal failure in the ICU patient: an
international consensus conference in intensive care medicine. Am J Respir Crit Care Med. 2010; 181(10):1128–1155.)
pharmacological agent has been demonstrated to prevent or
limit renal dysfunction. The importance of infectious surveil­
lance in the thermally injured patient cannot be overstated.
The goal is to effectively treat local infections and prevent
systemic dissemination to avoid the morbidity and mortality
of septic shock.
Fortunately, owing to major advances in burn care resus­
citation and the treatment of sepsis, renal failure requiring
RRT is a rare event.94 The reported incidence is approxi­
mately 1–3%, but the overall mortality associated with renal
failure requiring RRT approaches 80%.2,3,7,9 Burn patients
with pre-existing renal insufficiency are at particular risk for
RRT owing to the large positive fluid balances associated
with the initial resuscitation therapy, enhanced catabolism
leading to elevated urea levels, and the need for substantial
nutritional support to maintain a positive nitrogen balance.94
RRT was previously performed using peritoneal dialysis;95
however, this form of therapy is limited by clearance rates
and the need for catheter insertion through the abdominal
wall: a common donor site or burned area. Over the past
two decades a number of RRT modes have been studied in
general ICU patients: intermittent hemodialysis (IHD), con­
tinuous renal replacement therapy (CRRT), and sustained
low-efficiency dialysis (SLED). No consensus exists as to
which mode is superior, as each has advantages and disad­
vantages depending on the clinical scenario16,96 (Table 32.7).
It has been suggested that CRRT is best suited for those
patients demonstrating severe hemodynamic instability, per­
sistent ongoing metabolic acidosis, and large fluid removal
requirements. Preliminary reports using CRRT in the
thermally injured population have demonstrated improved
survival.97,98
The optimal time to initiate RRT in the thermally injured
patient with AKI has not been determined. Traditional
thresholds, i.e. absolute indications, used to initiate dialysis
in the setting of chronic renal failure, are less relevant in the
thermally injured patient. Burn injury predisposes to organ
failure, catabolism causes increased urea generation, large
open wounds result in electrolyte shifts, and nephrotoxic
agents are often required as treatment. Although very early
initiation of RRT in ICU patients has not clearly been dem­
onstrated to improve outcome, preliminary evidence exists

Total Burn Care
32
376
constantly review the global physiological state of a ther­
mally injured patient and anticipate conditions that may
affect the renal system, so that a stepwise approach to the
diagnosis and treatment may be initiated. Currently there are
no pharmacological agents that prevent or treat AKI, there­
fore the best treatment option is prevention. Should renal
insufficiency develop, RRT should be initiated early to
prevent an edematous state and before extreme metabolic
derangements occur.
Further reading
Brusselaers N, Monstrey S, Colpaert K, et al. Outcome of acute kidney
injury in severe burns: a systematic review and meta-analysis.
Intensive Care Med. 2010;36:915-925.
Chung KK, Lundy JB, Matson JR, et al. Continuous venovenous
hemofiltration in severely burned patients with acute kidney
injury: a cohort study. Crit Care. 2009;13(3):R62.
Davies MP, Evans J, McGonigle RJ. The dialysis debate: acute renal
failure in burns patients. Burns. 1994;20(1):71-73.
Mosier MJ, Pha, TN, Klein MB, et al. Early acute kidney injury predicts
progressive renal dysfunction and higher mortality in severely
burned adults. J Burn Car Res. 2010;31(1):83-92.
Palmieri T, Lavrentieva A, Greenhalgh DG. Acute kidney injury in
critically ill burn patients. Risk factors, progression and impact on
mortality. Burns. 2010;36:205-211.
to suggest a more aggressive approach to RRT initiation in
the thermally injured patient.97,98 A recent consensus sug­
gested that RRT in critically ill patients with AKF begins
before the development of extreme metabolic derangements
or other life-threatening events.16
An additional theoretical benefit of continuous hemofil­
tration is the removal of proinflammatory mediators, which
may be associated with the development of multiple organ
failure.99 The experimental and clinical data suggest that the
rate of hemofiltration and the biologic nature of the filters
affect the overall results.100 Currently there are insufficient
data to recommend continuous hemofiltration solely on the
basis of removal of inflammatory mediators. Future ran­
domized prospective studies may resolve this theoretical
benefit.
Major advances in the treatment of the thermally injured
individual have been accomplished over the past four
decades. Early aggressive resuscitation coupled with early
excision has significantly reduced the early complications of
burn injury, including renal insufficiency. This is exemplified
by the fact that prior to1965 there were no reported survivors
from acute renal failure following burn injury. Although the
incidence of acute renal insufficiency following burn injury
has been reduced, the disorder is still clinically apparent
following prolonged delayed initial resuscitation and follow­
ing the development of sepsis. Therefore, a physician must
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376.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
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35. Klein MB, Hayden D, Elson C, et al. The association between
fluid administration and outcome following major burn: a
multicenter study. Ann Surg. 2007;245(4):622-628.
36. Cancio LC, Chávez S, Alvarado-Ortega M, et al. Predicting
increased fluid requirements during the resuscitation of
thermally injured patients. J Trauma. 2004;56(2):404-413.
37. Saffle JI. The phenomenon of ‘fluid creep’ in acute burn
resuscitation. J Burn Care Res. 2007;28(3):382-395.
38. Hobson KG, Young KM, Ciraulo A, et al. Release of abdominal
compartment syndrome improves survival in patients with burn
injury. J Trauma. 2002;53(6):1129-1134.
39. Richardson JD, Trinkle JK. Hemodynamic and respiratory
alterations with increased intra-abdominal pressure. J Surg Res.
1976;20(5):401-404.
40. Kashtan J, Green JF, Parsons EQ, et al. Hemodynamic effect of
increased abdominal pressure. J Surg Res. 1981;30(3):249-255
41. Harman PK, Kron IL, McLachlan HD, et al. Elevated intra-
abdominal pressure and renal function. Ann Surg. 1982;196(5):
594-597.
42. O’Mara MS, Slater H, Goldfarb IW, et al. A prospective,
randomized study of intra-abdominal pressure with crystalloid
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2005;58(5):1011-1018.
43. Greenhalgh DG, Warden GD. The importance of intra-
abdominal pressure measurements in burn children. J Trauma.
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44. Ivy ME, Atweh NA, Palmer J, et al. Intra-abdominal hypertension
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45. Malbrain ML, Chiumello D, Pelosi P, et al. Incidence and
prognosis of intraabdominal hypertension in a mixed
population of critically ill patients: a multiple-center
epidemiological study. Crit Care Med. 2005;33(2):315-322.
46. Mukherjee GD, Basu PG, Roy S, et al. Cardiomegaly following
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47. Munster AM. Alterations of the host defense mechanism in
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48. Merriam TW Jr. Myocardial function following thermal injury.
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49. Fozzard HA. Myocardial injury in burn shock. Ann Surg.
1961;154:113-119.
50. Baxter CR, Cook WA, Shires GT. Serum myocardial depressant
factor of burn shock. Surg Form. 1966;17:1-2.
51. Fang RH, Chen JS, Lin JT, et al. A modified formula of GIK
(glucose-insulin-potassium) therapy for treatment of extensive
burn injury in dogs. J Trauma. 1989;29(3):344-349.
52. Leffler JN, Litvin Y, Barenholz Y, et al. Proteolysis in formation
of a myocardial depressant factor during shock. Am J Physiol.
1967;213:492-498.
53. Lefer AM Cowgill R, Marshall FF, et al. Characterization of a
myocardial depressant factor present in hemorrhage shock. Am J
Physiol. 1967;213(2):492-498.
54. Reilly JM, Cunnion RE, Burch-Whitman C, et al. A circulating
myocardial depressant substance is associated with cardiac
dysfunction and peripheral hypoperfusion (lactic acidemia) in
patient with septic shock. Chest. 1989;95(5):1502-1503.
55. Giroir BP, Horton JW, White DJ, et al. Inhibition of tumor
necrosis factor (TNF) prevents myocardial dysfunction during
burn shock. Am J Physiol. 1994;267(1 pt 2):H118-124.
56. Herbertson MJ, Werner HA, Goddard CM, et al. Anti-tumor
necrosis factor-alpha prevents decreased ventricular contractility
in endotoxemic pigs. Am J Resp Circ Care Med. 1995;152(2):
480-488.
57. Bryant D, Becker L, Richardson J, et al. Cardiac failure in
transgenic mice with myocardial expression of tumor necrosis
factor-alpha. Circulation. 1998;97(14):1375-1381.
58. Odeh M. Tumor necrosis factor-alpha as a myocardial depressant
substance. Int J Cardiol. 1993;42(3):231-238.
59. Kapadia S, Lee J, Torre-amiore G, et al. Tumor necrosis factor-
alpha gene and protein expression in adult feline myocardium
after endotoxin administration. J Clin Invest. 1995;96(2):
1042-1052.
60. Torre-amiore G, Kapadia S, Lee J, et al. Tumor necrosis factor-
alpha and tumor necrosis factor receptors in the failing human
heart. Circulation. 1996;93(4):704-711.
61. Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic
shock. Crit Care Clin. 2000;16(2):251-287.
62. Hegewisch S, Weh HJ, Hossfeld DK. TNF-induced
cardiomyopathy. Lancet. 1990;335(8684):294-295.
63. Habib FM, Springall DR, Davies GJ, et al. Tumor necrosis factor
and inducible nitric oxide synthase in dilated cardiomyopathy.
Lancet. 1996;347(9009):1151-1155.
64. Lazarus D, Hudson DA. Fatal rhabdomyolysis in a flame burn
patient. Burns. 1997;23(5):446-450.
65. Sharp LS, Rozycki GS, Feliciano DV. Rhabdomyolysis and
secondary renal failure in critically ill surgical patients. Am J
Surg. 2004;188(6):801-806.
66. Morris JA Jr, Mucha P Jr, Ross SE, et al. Acute posttraumatic
renal failure: a multicenter perspective. J Trauma. 1991;31(12):
1584-1590.
67. Brown CV, Rhee P, Chan L, Evans K, Demetriades D, Velmahos
GC. Preventing renal failure in patients with rhabdomyolysis: do
bicarbonate and mannitol make a difference? J Trauma. 2004;
56(6):1191-1196.
68. Rosen CL, Adler JN, Rabban JT, et al. Early predictors of
myoglobinuria and acute renal failure following electrical injury.
J Emerg Med. 1999;17(5):783-789.
69. Jeschke MG, Barrow RE, Wolf SE, et al. Mortality in burned
children with acute renal failure. Arch Surg. 1998;133(7):
752-756.
70. Chrysopoulo MT, Jeschke MG, Dziewulski P, et al. Acute renal
dysfunction in severely burned adults. J Trauma. 1999;46(1):
141-144.
71. Schrier RW, Wang W. Acute Renal Failure and Sepsis. N Engl J
Med. 2004;351(2):159-169.
72. Riedemann NC, Guo RF, Ward PA. The enigma of sepsis. J Clin
Invest. 2003;112(4):460-467.
73. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural
history of the systemic inflammatory response syndrome (SIRS):
a prospective study. JAMA. 1995;273(2):117-123.
74. Hohlfeld T, Klemm P, Thiemermann C, et al. The contribution
of tumor necrosis factor-alpha and endothelin-1 to the increase
of coronary resistance in hearts from rats treated with endotoxin.
Br J Pharmacol. 1995;116(8):3309-3315.
75. Riedemann NC, Guo RF, Neff TA, et al. Increased C5a receptor
expression in sepsis. J Clin Invest. 2002;110(1):101-108.
76. Huber-Lang MS, Riedeman NC, Sarma JV, et al. Protection of
innate immunity by C5aR antagonist in septic mice FASEB J.
2002;16(12):1567-1574.
77. Czermak BJ, Sarma V, Pierson CI, et al. Protective effects of C5a
blockade in sepsis. Nat Med. 1999;5(7):788-792.
78. Reinhart K, Bayer O, Brunkhorst R, et al. Markers of endothelial
damage in organ dysfunction and sepsis. Crit Care Med.
2002;30(5 Suppl):S302-S312.
79. Lameire N, Hoste E. Reflections on the definition, classification,
and diagnostic evaluation of acute renal failure. Curr Opin Criti
Care. 2004;10(6):468-475.
80. Miller PD, Krebs RA, Neal BJ, et al. Polyuric prerenal failure.
Arch Intern Med. 1980;140(7):907-909.
81. Anderson RJ, Barry DW. Clinical and laboratory diagnosis of
acute renal failure. Best Pract Res Clin Anaesthesiol. 2004;18(1):
1-20.
82. Steiner RW. Interpreting the fractional excretion of sodium. Am J
Med. 1984;77(4)699-702.
83. Carvounis CP, Nisar S, Guro-Razuman S. Significance of the
fractional excretion of urea in the differential diagnosis of acute
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84. Han WK, Bonventre JV. Biological markers for the early
detection of acute kidney injury. Curr Opin Crit Care. 2004;
10(6):476-482.
85. Doolan PD, Alpen EL, Theil GB. A clinical appraisal of the
plasma concentration and endogenous clearance of creatinine.
Am J Med. 1962;32:65-72.
86. Clark WR, Mueller BA,Kraus MA, et al. Quantification of
creatinine kinetic parameters in patients with acute renal failure.
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87. Moran SM, Myers BD. Course of acute renal failure studied by a
model of creatinine kinetics. Kidney Int. 1985;27(6):928-937.
88. Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection
of acute renal failure by serum cystatin C. Kidney Int. 2004;66:
1115-1122.
89. Royakkers AA, van Suijlen JD, Hofstra LS, et al. Serum cystatin
C: a useful endogenous marker of renal function in intensive
care unit patients at risk for or with acute renal failure? Curr Med
Chem. 2007;14:2314-2317.
90. Villa P, Jimenez M, Soriano MC, et al. Serum cystatin C
concentration as a marker of acute renal dysfunction in critically
ill patients. Crit Care. 2005;9:R139-R143.
91. Poeze M, Solberg BC, Greve JW, et al. Monitoring global
volume-related hemodynamic or regional variables after initial
resuscitation: What is a better predictor of outcome in critically
ill septic patients? Crit Care Med. 2005;33(11):2494-2500.
92. Rivers E, Nguyen B, Havstad S, et al. Early goal directed therapy
in the treatment of severe sepsis and septic shock. N Engl J Med.
2001;345(19):1368-1377.

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93. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis
Campaign guidelines for management of severe sepsis and septic
shock. Crit Care Med. 2004;32(3):858-873.
94. Leblanc M, Thibeault Y, Querin S. Continuous haemofiltration
and haemodiafiltration for acute renal failure in severely burned
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Appleton and Lange; 1990:69-96.

Introduction
Over 500 000 people are burned and seek medical care in
the United States every year; most of these have minor inju­
ries and are treated in the outpatient setting. However,
approximately 50 000 burns per year (10%) are moderate to
severe and require hospitalization for treatment. Some of
these will require critical care for at least part of their hospi­
talization, and some for months. About 4000 die each year
from complications related to the burn.1,2 Burn deaths gener­
ally occur in a bimodal distribution, either immediately after
the injury, or weeks later due to multiple organ failure, a
pattern similar to all injury-related deaths.
Morbidity and mortality from burns are decreasing in inci­
dence. Recent reports revealed a 50% decline in burn-related
deaths and hospital admissions in the USA over the last 20
years.2 The declines were likely most affected by prevention
efforts, with fewer potentially fatal burns, and improved
critical care and wound management for those who still
sustain the injury. In 1949, Bull and Fisher reported 50%
mortality rates for children aged 0–14 years with burns of
49% of total body surface area (TBSA), 46% TBSA for patients
aged 15–44, 27% TBSA for those aged between 45 and 64,
and 10% TBSA for those 65 and older.3 These dismal statis­
tics have improved, with the latest studies reporting a 50%
mortality for >95% TBSA burns in children 14 years and
under, 75% TBSA burns in adults, and around 30% TBSA in
the elderly.4 Therefore, a healthy young patient with almost
any size burn should be expected to live, whereas the pros­
pects for those who are older are certainly improving with
modern wound treatment and critical care techniques.
Burned patients generally die from one of two causes:
‘burn shock’ and immolation resulting in early deaths, and
multiple organ failure and sepsis leading to late deaths. With
the advent of vigorous fluid resuscitation protocols in the
severely burned, irreversible burn shock has been replaced
by sepsis and subsequent multiple organ failure as the
leading cause of death associated with burns in those who
do not die at the scene by a margin of 2 to 1.4 Those with
some risk of mortality who do not die precipitously will be
treated by what is termed critical care, a service performed
in specialized units containing the equipment, supplies,
and personnel to institute intensive monitoring and life-
sustaining organ support to promote recovery.
Critical illness in burned patients is most commonly asso­
ciated with sepsis. In a pediatric burn population with
massive burns > 80% TBSA, 17.5% of the children developed
sepsis, defined as bacteraemia with clinical signs of infec­
tion.5 Mortality in the whole group was 33%, most of whom
succumbed to multiple organ failure. Some were bacteremic
and ‘septic,’ but the majority were not. These findings high­
light the observation that the development of severe critical
illness and multiple organ failure is often associated with
infection, but it is by no means required to develop this
syndrome. What is required is an inflammatory focus, which
in severe burns is the massive skin injury that requires
inflammation to heal.
It is postulated that progression of patients to multiple
organ failure exists in a continuum with the systemic inflam­
matory response syndrome (SIRS).6 Nearly all burn patients
meet the criteria for SIRS as defined by the consensus confer­
ence of the American College of Chest Physicians and the
Society of Critical Care Medicine.7 It is therefore not surpris­
ing that severe critical illness and multiple organ failure are
common in burned patients.
Patients who develop dysfunction of various organs, such
as the cardiopulmonary system, renal system, and gastro­
intestinal system, can be supported to maintain homeostasis
until the organs repair themselves or a chronic support
system can be established. Critical care may be defined
loosely as the process of high-frequency physiologic moni­
toring coupled with short response times for pharmacologic
and procedural interventions. This chapter will describe the
organization of specialized burn intensive care units (BICUs),
including requirements for personnel and equipment. The
techniques used in BICUs will be described, and organ-
specific management will be addressed.
Burn intensive care unit organization
Physical plant
Optimally, a BICU should exist within a designated burn
center in conjunction with a recognized trauma center, thus
providing the capability to treat both thermal and non-
thermal injuries. This unit, however, need not be physically
located in the same space as that designated for non-burned
trauma patients. In fact, the requirements for the care of
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00033-3
Critical care in the severely burned:
organ support and management of
complications
Kevin K. Chung, Steven E. Wolf
CHAPTER 33 
Access the complete reference list online at

IN THIS CHAPTER
PowerPoint Presentation Online

Total Burn Care
33
378
wounds in burned patients necessitates additional equip­
ment such as shower tables and overhead warmers, and so
separate space dedicated to the severely burned is optimal.
This space may be located in a separate hospital with estab­
lished guidelines for transfer.8
The optimal number of beds in the unit may be calculated
by the incidence of moderate to severe burns in the referral
area, which in the USA is approximately 20 per 100 000
people per year. The Committee on Trauma of the American
College of Surgeons and the American Burn Association rec­
ommend that 100 or more patients should be admitted to
this facility yearly, with an average daily census of three or
more patients to maintain sufficient experience and accept­
able access to specialized care.8
Most moderate to severe burns with hospital admission
will require intensive monitoring for at least the day of
admission during the resuscitative phase. Thereafter, approx­
imately 20% will undergo prolonged cardiopulmonary
monitoring for inhalation injury, burn shock, cardiopulmo­
nary compromise, renal dysfunction, and the development
of SIRS and multiple organ dysfunction syndrome (MODS).
In these severely burned patients, the average length of stay
in the BICU is approximately 1 day per % TBSA burned.
Using an average of 25 days admission for a severely burned
patient (20% of the burns, 4/100 000 per capita) and 2 days
for those not so severely injured (80%, 16/100 000 per
capita), this suggests 132 BICU inpatient days per 100 000
persons in the catchment area. Thus, a 10-bed BICU should
serve a population of 3 000 000 sufficiently when consid­
ered independently. Space provided should be at least
3000 sq ft, including patient beds and support space for
nursing/charting areas, office space, wound care areas, and
storage.
Multiply-resistant bacteria and fungi are commonly
encountered in the BICU owing to the presence of open
wounds. To prevent spread of these organisms to other
patients, isolation of burned patients from one another and
from other types of patient is often recommended, and
should be considered in designing units for this purpose.
Single rooms with negative-pressure ventilation should be
considered. In addition, strict guidelines for contact precau­
tions in wound care and interventions and hand-washing are
highly recommended.
Personnel
A BICU functions best using a team approach between
surgeons/intensivists, nurses, laboratory support staff, respi­
ratory therapists, occupational and physical therapists,
mental health professionals, dietitians, and pharmacists
(Box 33.1). The unit should have a designated medical direc­
tor, ideally a burn surgeon, to coordinate and supervise per­
sonnel, quality management, and resource utilization. The
medical director will usually work with other qualified surgi­
cal staff to provide sufficient care for the patients. It is recom­
mended that medical directors and each of their associates
be well versed in critical care techniques, and care for at least
50 patients per year to maintain skills.8 In teaching hospitals,
two to three residents or other qualified medical providers
should be assigned to the 10-bed unit described above. A
coverage schedule should be devised to provide 24-hour
prompt responses to problems.
Box 33.1  Assigned burn unit personnel
•
Experienced burn surgeons (burn unit director and qualified
surgeons)
•
Dedicated nursing personnel
•
Physical and occupational therapists
•
Social workers
•
Dietitians
•
Pharmacists
•
Respiratory therapists
•
Psychiatrists and clinical psychologists
•
Prosthetists
Box 33.2  Consultants for the BICU
•
General surgery
Pediatrics
•
Plastic surgery
Psychiatry
•
Anesthesiology
Cardiology
•
Cardiothoracic surgery
Gastroenterology
•
Neurosurgery
Hematology
•
Obstetrics/gynecology
Pulmonology
•
Ophthalmology
Nephrology
•
Orthopedic surgery
Neurology
•
Otolaryngology
Pathology
•
Urology
Infectious disease
•
Radiology
Nursing personnel should consist of a nurse manager with
at least 2 years of intensive care and acute burn care experi­
ence, and 6 months of management responsibilities. The rest
of the nursing staff in the BICU should have documented
competencies specific to the care of burned patients, includ­
ing critical care and wound care.8 Owing to the high intensity
of burn intensive care, at least five full-time equivalent
nursing providers are required per ICU bed to provide suf­
ficient 24-hour care. Additional personnel are required for
respiratory care, occupational and physical therapy, and
other support. A dedicated respiratory therapist for the burn
unit at all times is optimal.
Owing to the nature of critical illness in burned patients,
complications may arise that are best treated by specialists
not generally in the field of burn care (Box 33.2). For these
reasons, these specialists should be available for consulta­
tion should the need arise.
Equipment
The equipment needs of the BICU are those items which are
common for all ICUs, and some which are specialized (Box
33.3). Each BICU bed must be equipped with monitors to
measure heart rate, continuous electrocardiography, non-
invasive blood pressure, invasive arterial and venous blood
pressures, end-tidal carbon dioxide monitoring, and right
heart cardiac output using dilution techniques or data
derived from arterial pressure tracings. Continuous arterial
blood oxygen saturation measurement is also required, but
continuous mixed venous saturation monitoring or the tech­
nical equivalent is optional. Equipment to measure weight
and body temperature should also be standard. Oxygen

Critical care in the severely burned: organ support and management of complications
379
as the patient is following the anticipated course. At other
times this is not the case, and procedural or pharmacologic
intervention is beneficial. Physiologic monitoring is then
used further to determine the adequacy of the interventions.
The following is a survey of monitoring techniques used in
the BICU.
Cardiovascular monitoring
Arterial lines
Hemodynamic monitoring is directed at assessing the results
of resuscitation and maintaining organ and tissue perfusion.
Currently used measures are only estimates of tissue per­
fusion, as the measurement of oxygen and nutrient transfer
to cells cannot be made directly at the bedside. Instead,
global physiologic measures of central pressures still serve as
the principal guides.
Measurement of arterial blood pressure is the mainstay for
the assessment of tissue perfusion. In critical illness, this
measurement can be made using cuff sphygmomanometers;
however, in practice this technique is not useful because the
measurement is episodic, and placement of these cuffs on
burned extremities is problematic. Diastolic pressures can
also be artificially elevated in the elderly and obese. Instead,
continuous monitoring for hemodynamic instability through
the use of intra-arterial catheters is generally preferable while
in the ICU for a prolonged period. Lines are typically placed
in either the radial or the femoral artery. The radial artery is
the preferred site for most critically ill patients because of
safety with the dual arterial supply to the hand should a
complication occur. However, it has been shown that radial
artery catheters are inaccurate in the measurement of central
blood pressure when vasopressors are used9 and are notori­
ously inaccurate in children because of greater vascular reac­
tivity.10 For these reasons, we recommend femoral arterial
blood pressure measurement in most burned patients.
For arterial catheters, systolic, diastolic, and mean arterial
pressures should be displayed continuously on the monitor
screen. Either systolic or mean arterial pressure can be used
to determine adequacy of pressure, although a mean arterial
pressure >70 mmHg is considered a more accurate descrip­
tion of normal tissue perfusion on the whole. Reasons for
this include the finding that as the arterial pressure wave
traverses proximally to distal, the systolic pressure gradually
increases and the diastolic pressure decreases; the mean
pressure determined by integrating areas under the curve,
however, remains constant. The adequacy of the waveform
must also be determined, with a diminished waveform
indicative of catheter damping, requiring catheter replace­
ment. Care must be taken to ensure that the diminished
waveform is not true hypotension, which can be determined
using a manual or cycling sphygmomanometer placed on
the arm or leg. Exaggerated waveforms with elevated systolic
pressure and additional peaks in the waveform (generally
only two are found) may be a phenomenon referred to as
‘catheter whip,’ which is the result of excessive movement of
the catheter within the artery. Typically, this problem is self-
limited, but care must be taken not to interpret typically
normal systolic blood pressure values with evidence of
catheter whipping as normal, as the effect generally
availability and at least two vacuum pumps must be present
for each bed.
Ventilatory equipment must also be available for all beds.
The availability of a number of types of ventilator is optimal,
including conventional ventilators with the capability to
deliver both volume-targeted and pressure-targeted breaths
as well as high-frequency ventilators that are oscillatory and/
or percussive in design. An emergency cardiac cart contain­
ing advanced cardiac life support (ACLS) medications and a
battery-powered electrocardiograph/defibrillator must be
present on the unit. Infusion pumps to deliver continuous
medications and intravenous/intra-arterial fluids must also
be readily available. A laboratory providing blood gas analy­
sis, hematology, and blood chemistry should be located on
site. Microbiologic support to complete frequent, routine
bacterial cultures should also be present.
Available specialty equipment should include various sizes
of fiberoptic bronchoscope for the diagnosis and treatment
of pulmonary disorders, as well as personnel versed in these
techniques. Fiberoptic gastroscopes and colonoscopes for
gastrointestinal complications are also necessary. For renal
support, equipment to provide peritoneal dialysis, intermit­
tent or continuous hemodialysis and hemofiltration should
be available. Portable radiographic equipment for standard
chest/abdominal/extremity radiographs must be immedi­
ately available. Equipment for computed tomography (CT),
fluoroscopy, and angiography should be available in other
parts of the hospital. Indirect calorimeters to measure meta­
bolic rate are preferable. Overhead warmers and central
heating with individualized ambient temperature controls
must be available for each room as a specialized
requirement.
Hemodynamic monitoring in the burn
intensive care unit
Most burned patients follow an anticipated course of recov­
ery, which is ‘monitored’ in the ICU by measuring phy­
siologic parameters. Experienced clinicians assess these
physiologic measures in a repeated and sequential fashion
to discern when potential interventions may be initiated to
improve outcomes. Often no intervention will be necessary
Box 33.3  Equipment for a fully equipped BICU
STANDARD
•
Monitors (heart rate, electrocardiography, blood pressure, cardiac
output, oxygen saturation, temperature)
•
Scales
•
Ventilators
•
ACLS cardiac cart
•
Laboratory support (blood gas analysis, hematology, chemistry,
microbiology)
SPECIALTY
•
Fiberoptic bronchoscopes
•
Fiberoptic gastroscopes/colonoscopes
•
Dialysis equipment (peritoneal dialysis and hemodialysis)
•
Portable plain radiography
•
Computed tomography/fluoroscopy/angiography
•
Indirect calorimeters

Total Burn Care
33
380
replacement for oliguria. Even in this condition, new tech­
nology based on arterial waveform analysis gives an estimate
of cardiac output and end-diastolic volume, which generally
gives enough information to guide appropriate therapy.14
The base deficit is a value calculated using the Henderson
BICU Hasselbach equation based on the relationship
between pH, pCO2, and serum bicarbonate:
pH
HCO
/ pCO
=
+
−
6 1
0 03
3
2
.
log(
) (
)( .
)
The base deficit is the stoichiometric equivalent of base
required to return the pH to 7.40. Base deficit is routinely
calculated on blood gas analysis, and provides a reasonable
estimate of the degree of tissue anoxia and shock at the
whole body level, particularly in hemorrhagic shock. A rising
base deficit indicates increasing metabolic acidosis, and may
stratify risk of mortality in patients after major trauma.15 The
same can be said for the use of base deficit in burn resuscita­
tion in burned patients.16,17 These studies showed a correla­
tion of higher base deficit and increased mortality, and some
have suggested this value is a better monitor of resuscitation
than the time-honored monitors of urine output and arterial
blood pressure.18 Recent studies in burned patients showed
that base deficit was higher in non-survivors during resusci­
tation, although the authors could not identify a specific
boundary for the effect.19,20 Despite its utility as an indicator
of shock, base deficit remains a non-specific indicator of
metabolic acidosis, and may be elevated with alcohol,
cocaine, and methamphetamine use. Interpretation may be
difficult under these circumstances.
Lactate is another common measure used to determine
adequacy of tissue perfusion. Under acute low-flow condi­
tions, cells transition from primarily aerobic metabolism to
anaerobic metabolism for energy production (ATP). A
byproduct of anaerobic metabolism is lactic acid. Under
ischemic conditions, then, plasma lactate concentration will
increase, leading to a decrease in pH. Measurement of lactate
is commonly performed to determine the adequacy of gen­
eralized perfusion; increases suggest ischemia. Investigators
showed that lactate does increase (along with base deficit)
in burned patients during resuscitation, and higher levels are
associated with poorer outcomes.20 Later in the course,
however, lactate concentrations must be used with some
caution, as elevated levels do not necessarily indicate
ischemia. Under hypermetabolic conditions, which are
common in the severely burned, pyruvate dehydrogenase
activity is sufficiently inefficient such that lactate levels might
be elevated without ischemia. Isolated elevations of lactate
should then be interpreted with caution, and confirmation
of ischemia or shock by physical or other laboratory findings
should be sought.
Transesophageal echocardiography
Transesophageal echocardiography has been used for a
number of years as an intraoperative monitor in high-risk
cardiovascular patients. It has not been used extensively in
other critically ill patients because of the lack of available
expertise and paucity of equipment. Since this device can be
used as a diagnostic tool for the evaluation of hemodynamic
function, it stands to reason that it could be used as a
monitor in critically ill severely burned patients. A report
documented the use of transesophageal Doppler measure­
ments of cardiac output in a series of severely burned patients
overestimates pressures. Again, use of mean arterial pressures
as the principal guideline for the assessment of blood
pressure is optimal, as the effects of catheter whip or
other problems with intra-arterial monitoring are then
diminished.
Complications associated with arterial catheters include
distal ischemia associated with vasospasm and throm­
boembolism, catheter infection, and arterial damage/
pseudoaneurysm during insertion and removal. Although
these complications are uncommon, the results can be dev­
astating. Physical evidence of ischemia in the distal hand or
foot should prompt removal of the catheter and elevation of
the extremity. If improvement in ischemic symptoms is not
seen promptly (within an hour), angiography and interven­
tion should be considered. Should thromboembolism be
found, the clot can be removed with operative embolectomy
or clot lysis at the discretion of the treating physician. If,
during angiography, extensive arterial damage is found with
ischemia, operative repair may be indicated.
Evidence of catheter infection hallmarked by purulence
and surrounding erythema should instigate removal of the
catheter, which will often suffice. With continued evidence
of infection, antibiotics and incision and drainage of the site
should be entertained. Great caution must be exercised to
avoid arterial bleeding if an incision is made over the cath­
eter site. If a pseudoaneurysm is encountered after arterial
catheterization and removal without signs of distal ischemia,
compression with a vascular ultrasound device until no
further flow is seen in the pseudoaneurysm will often allevi­
ate the problem without operative intervention.11
Cardiac output measurement
Pulmonary artery catheters placed percutaneously through a
central vein (internal jugular, subclavian, or femoral) and
‘floated’ into the pulmonary artery through the right heart
have been used extensively in hemodynamic monitoring in
ICUs. By measuring the back pressure through the distal
catheter tip ‘wedged’ into an end-pulmonary branch, an esti­
mate of left atrial pressure can be measured. In addition,
dyes or isotonic solutions injected into a proximal port can
be used to determine cardiac output from the right heart.
These data are used to estimate preload delivery to the heart,
cardiac contractility, and afterload against which the heart
must pump, which then directs therapy at restoration of
hemodynamics. These catheters are used in ICUs under con­
ditions of unexplained shock, hypoxemia, renal failure, and
monitoring of high-risk patients.
The use of pulmonary artery catheters, however, has come
under scrutiny from reports indicating no benefit from their
use. A study of 5735 critically ill adults in medical and surgi­
cal ICUs showed an increase in mortality and use of resources
when pulmonary artery catheters were used. Most of these
patients had medical conditions. The authors of this report
suggested that their results should prompt a critical evalua­
tion of the use of pulmonary artery catheters under all condi­
tions.12 This was followed by a clinical trial in the UK which
showed no benefit to the use of pulmonary artery catheters
in a general ICU setting.13 These data then suggest that this
modality has little utility in today’s practice. In fact, over the
past few years, the use of pulmonary artery catheters has
significantly diminished except in special circumstances
such as unexpected response to treatment such as volume

Critical care in the severely burned: organ support and management of complications
381
showing that intravascular volume and cardiac contractility
are significantly diminished the first day after burn in spite
of high-volume resuscitation.21 For the monitoring of burn
resuscitation, it seems that most use urine output; however,
the question has been raised whether this is the proper
measure. Investigators in China asked whether esophageal
Doppler monitoring of heart function might be an improve­
ment. They studied 21 patients with massive burns (79 ± 8%
TBSA burned) who were resuscitated with a goal of 1.0 mL/
kg/h. They found that cardiac output was predictably low
after injury and increased linearly with time by increases in
preload and contractility and decreased afterload. However,
changes in cardiac output were most closely associated with
increased cardiac contractility and decreased afterload rather
than increases in preload. Additionally, urine output was not
closely associated with cardiac output.22 These results call
into question the validity of urine output as the primary
measure of adequacy of resuscitation. Perhaps this is not the
best method? A similar study by investigators in Sweden
studying the role of cardiac function measured by echocar­
diography and myocyte damage measured by troponin
abundance in the serum showed that half their patients had
myocardial damage during resuscitation that was universally
associated with some temporary cardiac wall motion abnor­
mality. However, systolic function was not adversely
affected.23 We look for further work in the future with regard
to the optimal method of assessment of resuscitation; for the
present, however, urine output remains the standard.
Mechanical ventilation
The use of mechanical ventilation is central to the function
of the BICU. Burned patients are at risk for airway compro­
mise, necessitating endotracheal intubation and mechanical
ventilation for a number of reasons. Inhalation of smoke
causing damage to the upper airway, development of massive
whole-body edema restricting the airway, and hypoxia occur
relatively frequently during the initial resuscitation, all of
which may require endotracheal intubation and mechanical
ventilation. Thereafter, acute lung injury and acute respira­
tory distress syndrome may intervene, necessitating pulmo­
nary support with ventilators. This section will deal briefly
with indications for intubation, common ventilator strat­
egies, and monitoring of mechanical ventilation.
Indications for intubation
Intubation entails passing an endotracheal tube from either
the nose or the mouth through the pharynx into the trachea.
This tube is then connected to a mechanical ventilator to
cause inspiration and passive exhalation through the lungs.
Indications for intubation in burned patients are in general
to improve oxygenation and ventilation, or to maintain gas
exchange during clinical conditions expected to compromise
the airway (Table 33.1).
Ventilatory modes
The complexity of mechanical ventilators has increased dra­
matically since the first generation of volume cycle venti­
lators used in the 1960s. The development of positive
end-expiratory pressure (PEEP) to maintain functional
Table 33.1  Clinical indications for intubation
Criteria
Value
PaO2 (mmHg)
<60
PaCO2 (mmHg)
>50 (acutely)
P/F ratio
<200
Respiratory rate
>40
Respiratory/ventilatory failure
Impending
Upper airway edema
Severe
residual capacity was followed by the development of modes
using partial ventilatory support, such as intermittent man­
datory ventilation in the 1970s. Efficient microprocessors
were then developed that permitted modes of ventilation
such as pressure support ventilation, time-cycled pressure
control ventilation, and inverse ratio ventilation. Most
recently, new processors have been used to combine modes
of ventilation, such as pressure support and time-cycled pres­
sure control ventilation, and open lung strategies such
as airway pressure-release ventilation, with some success
(Fig. 33.1). However, even with these new developments, the
function of mechanical ventilators remains identical to those
first used. Whether these new ventilators have had any appre­
ciable effect on mortality remains to be fully elucidated,
though new evidence suggests that choice of mode may
make a difference.
The principal difference in mechanical ventilation from
spontaneous ventilation, which each of us use every minute
of the day, is the effect of positive pressure as opposed to
normal physiologic negative pressure. The use of positive
pressure improves gas exchange by recruiting alveoli and
increasing functional residual capacity (i.e., the number and
volume of open alveoli at the end of expiration), thus
improving ventilation perfusion mismatch and reducing
intrapulmonary shunting of blood past non-ventilated lung
areas (Fig. 33.2). Adverse effects of positive-pressure ventila­
tion lie in its propensity to produce trauma to the airways
(barotrauma) and its effects on intrathoracic pressure, which
can impede venous return to the heart and thus reduce
cardiac output.
Control and assist control ventilation
The volume control modes are volume-cycled settings that
deliver a preset tidal volume at a minimum respiratory rate
and inspiratory flow rate regardless of the patient’s own
respiratory efforts (Fig. 33.3). Of the two, the control mode
will not trigger with patient effort. This mode is typically very
uncomfortable for patients owing to ventilator–patient
dyssynchrony, with use limited to patients under general
anesthesia or heavy sedation. The assist control mode differs
in that a breath will be delivered regularly according to a
prescribed rate, but will also deliver a breath upon patient
negative-pressure effort to open a flow valve, at which time
the ventilator will fire, allowing the patient to control his
or her own ventilatory rate with a preset minimum rate
as a back-up. This mode is typically used in heavily
sedated patients who cannot generate enough tidal volume
under pressure support modes or intermittent mandatory