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

30  •  Etiology and Prevention of Multisystem Organ Failure
310
0
2
4
6
8
10 12
log (p value)
Ca2+ T cell apoptosis
ICDS-iCGSL signaling in T cells
CTLA4 signaling in CD8 T cells
CD28 signaling in T cells
T-cell receptor signaling
CD8 T-cell-mediated apoptosis
Role of NFAT in immune response
IL-4 signaling
Primary immunodeficiency signaling
Purine metabolism
Downregulated Pathways
D
0
2
4
6
8 10 12 14
log (p value)
Upregulated Pathways
Integrin signaling
Leukocyte extravasation
Fcy receptor-mediated phagocytosis
IL-10 signaling
Toil-like receptor signaling
Ephrin receptor signaling
IL-6 signaling
TREM1 signaling
Actin cytoskeleton signaling
B cell receptor signaling
C
B
Effect of severe blunt injury
on probe expression
30
2
4
6
8
10
12
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16
18
20
22
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cm r2m
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Patients ordered by TTR
Days after injury
Degree of multiple organ failure
(MCF)
2
4
6
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10 12 14 16 18 20 22 24 26 28
A
Fig. 30.2  The genomic response of leukocytes to burn injury. (From Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J
Exp Med. 2011;208(13):2581–2590.)
Magnitude of response
Magnitude of response
Dysregulated Innate Immune Response
Dysregulated Adaptive Immune Response
Complicated outcome
Uncomplicated outcome
B
Magnitude of response
Magnitude of response
Trauma
2nd
hit
SIRS
SIRS: Excessive Innate Immune Response
CARS: Suppressive Adaptive Immune Response
Uncomplicated outcomes
Complicated outcome
with “second hit”
SIRS
CARS
A
Fig. 30.3  Comparison of the genomic response of leukocytes to burn in complicated and uncomplicated outcomes. (From Xiao W, Mindrinos MN, Seok
J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590.)

30  •  Etiology and Prevention of Multisystem Organ Failure
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in foci of infection and within the gut when the gut barrier
fails.
Arachidonic acid (AA) makes up approximately 20% of
cell membranes and is released from these membranes in
response to a multitude of stimuli, which activate phospho­
lipases A2 and C, and is then metabolized by active media­
tors. The cyclooxygenase pathway yields prostaglandins
and thromboxanes, whereas the lipoxygenase pathway
results in the production of leukotrienes.55 Prostaglandins
and leukotrienes interact with other mediators in a complex
fashion and are later degraded.56 Cyclooxygenase products
like prostacyclin inhibit platelet aggregation, thrombus for­
mation, and gastric secretion,57 whereas other products like
thromboxane A2 (TXA2) cause platelet aggregation, have
profound vasoconstricting effects on both the splanchnic
and pulmonary microvasculature, and induce bronchocon­
striction and increased membrane permeability.58 Aspirin
irreversibly inhibits cyclooxygenase, driving AA down the
lipoxygenase pathway.59 The lipoxygenase pathway results
in the formation of leukotrienes. There are two types based
on their metabolism after the action of 5-lipoxygenase, leu­
kotrienes (LT) C4, D4, and E4 (the sulfidopeptide group), and
LTB4.51 Multiple stimuli by several cell types, including neu­
trophils, macrophages, and monocytes, generate leukotri­
enes.52 Vessel walls are also capable of generating
leukotrienes.60 LT C4, D4, and E4 have variable actions on
vascular tone dependent on the presence or absence of
other mediators, including cyclooxygenase products.61 In
addition to their variable effects in redirecting blood flow, LT
C4, D4, and E4 increase vascular permeability62 and are ele­
vated immediately prior to the development of pulmonary
failure.63 The principal effect of LT B4 is enhancement of
neutrophil chemotaxis.64 Thus, leukotrienes as a group
may be involved in the edema formation and pulmonary
and systemic vascular changes seen in MOF.
Cytokines are regulatory proteins secreted by immune
cells and have multiple paracrine and endocrine effects.
There are six major classes:65 interleukins, TNF, interferons,
colony-stimulating factors, chemotactic factors, and growth
factors. Those most extensively characterized in sepsis are
IL-1, IL-6, and TNF.
IL-1 and IL-6 are elevated in septic states; high levels are
associated with fatal outcomes66 and predict systemic infec­
tion.67 IL-1β causes hypotension and decreased systemic
vascular resistance, which may be synergistic with the
effects of TNF.68 TNF causes hypotension, cardiac depres­
sion, and pulmonary dysfunction in animals.69,70 When
administered to humans, TNF causes fever, hypotension,
decreased systemic vascular resistance, increased protein
turnover, elevation of stress hormone levels,66,71 and activa­
tion of the coagulation cascade.68
PAF is a nonprotein phospholipid secreted by many cells
including platelets and endothelial and inflammatory
cells,72 and it is a major mediator of the pulmonary73 and
hemodynamic74 effects of endotoxin. The major effects of
PAF are vasodilation, cardiac depression, and enhancement
of capillary leak. Its complex interactions with other media­
tors remain poorly understood.
Although tissue injury can occur in the absence of neu­
trophils,75 the inflammatory process results in local accu­
mulation of activated inflammatory cells that release
various local toxins such as oxygen radicals, proteases,
with lactulose as the tracer, passed more readily through
the gastrointestinal membrane after injury.41 Both intra-
and transcellular processes allow transloaction.42,43 Conse­
quences of loss of the gastrointestinal barrier are profound.
Translocating whole bacteria can be a direct source of
sepsis or can activate Kupffer cells2,3 and promulgate an
inflammatory response in conjunction with bacterial prod­
ucts such as endotoxin.
COMMON GROUND: HUMORAL MEDIATORS
In patients receiving critical care (fluid resuscitation and
wound care) for the acute burn injury and its attendant
burn shock, the principal determinants of organ failure are
humoral mediators.44 Investigators are unraveling these
humoral factors using blocking antibodies, soluble recep­
tors, and receptor antagonists.45
Further studies of leukocyte transcriptome after severe
trauma and burn injury demonstrated that humoral inflam­
matory mediators underlie cascades responsible for mortal­
ity in burn patients. Sood and Herndon used early leukocyte
mRNA genomics to correlate transcriptome changes with
outcomes in 324 severely burned patients. In many ways
their mortality findings were as expected. Ages older than
60 carry a relative risk of death (RR) of 4.53, burns greater
than 40% carry an RR of 4.24, and inhalation carries
an RR of 2.08, all independently associated with mortal­
ity. They found 39 gene signatures within the leukocyte
transcriptome inherent in the “genomic storm” associated
with platelet activation and degranulation, cellular prolif­
eration, and downregulation of proinflammatory cytokines
(see Fig. 30.1).46
Jeschke and Herndon worked to differentiate burn survi­
vors from nonsurvivors based on profoundly different tra­
jectories in inflammatory and hypermetabolic responses.
Nonsurvivors had significantly higher IL-6, IL-8, granulo­
cyte colony-stimulating factor, monocyte chemotactic
protein-1, C-reactive protein, glucose, insulin, blood urea
nitrogen, creatinine and bilirubin, and hypermetabolic
response.47 IL-8 is a major mediator for inflammatory
responses and tracks correspondingly with body surface
area burned and incidence of MOF. High levels were associ­
ated with sepsis, MOF, and mortality suggesting that IL-8
may provide a valid biomarker for monitoring sepsis, infec­
tions, and mortality in burn paitents.48
The humoral inflammatory mediators believed to under­
lie MOF in burn injury are the same factors and cascades
governing the fundamental human responses to severe
injury and have been discussed for decades: endotoxin, ara­
chidonic acid metabolites, cytokines, platelet activating
factor (PAF), activated neutrophils and adherence mol­
ecules, nitric oxide, complement, and oxygen free radicals.
Endotoxin, a lipopolysaccharide component of Gram-
negative bacteria outer cell walls, induces many of the
symptoms associated with sepsis: fever, hypotension, the
release of acute-phase proteins, and the production of mul­
tiple cytokines including TNF and IL-1 via interaction with
TLRs.49 Endotoxin injection alone causes the same changes
in the leukocyte transcriptome as severe burn injury.23 It
also activates complement50–52 and the coagulation
cascade53 and results in the release of PAF.54 Potential
sources of endotoxin include both Gram-negative bacteria

30  •  Etiology and Prevention of Multisystem Organ Failure
312
carbon dioxide production, hyperdynamic circulation,
increased minute ventilation, altered immune responses,
and catabolism. Persistently higher metabolic rates are seen
in nonsurvivors.4 An essential component of modern
burn management is attenuating the hypermetabolic
response. Reducing the patient’s metabolic demand via
management of the external environment has been an
indispensable component of burn care for decades.20 Pres­
ently, β-adrenergic blockade with propranolol is the most
efficacious anabolic pharmacologic therapy. While effects of
growth hormone91 were even more profound, it was associ­
ated with more adverse outcomes. Insulin-like growth
factor, intensive insulin therapy, and oxandrolone have all
been studied.91
Anabolic steroids such as oxandrolone have been used to
reduce post burn catabolism and help shift patients to an
anabolic state. Sousse and Suman demonstrated that long-
term administration of oxandrolone significantly reduced
hypermetabolism and increased height percentile, bone
mineralization, lean body mass, and strength. They showed
improved pulmonary functions with greater maximum
expired ventilation and higher maximum voluntary venti­
lation.92 Inhalation injury did not increase burn-induced
hypermetabolic stress.93 Promising investigations continue
into the use of anabolic agents to treat severe burn injury,
and they are rapidly becoming a standard of care in centers
around the world.
CARDIOVASCULAR
Several hours post burn, a profound shock state devel­
ops due to loss of preload as burn edema advances. In
the immediate post-burn ebb phase, cardiac function
is depressed in an IL-1B- and TNFα-dependent manner
that can be blocked with a CD14 knockout or halted with
nuclear factor (NF-κB) blockers. By 48 h post burn the
myocardium becomes tachycardic with increased cardiac
output and hyperinflammatory in a β-adrenergic-mediated
manner.94 The decrease in right ventricular ejection frac­
tion seen after endotoxemia can be alleviated by blockade
of thromboxane.95 Initially, systemic vascular resistance is
increased; however, as systemic inflammation and sepsis
emerge during the flow phase, vasoplegia ensues and exac­
erbates the cardiogenic and distributive shock states that
promote MOF.96
Twenty-four to 48 hours after injury the ebb phase ends,
the cardiac pathology enters the flow phase, marked by
eicosanoids, PAF, and others. When unregulated, such
accumulations of activated cells can cause tissue injury.76
The initial attachment of neutrophils to the vascular endo­
thelium at an inflammatory site is facilitated by the interac­
tion of adherence molecules on the neutrophil and
endothelial cell surfaces.77
Induced by numerous stimuli, these neutrophil adher­
ence receptors are, intriguingly, reduced after major
thermal and nonthermal injury,78 perhaps explaining in
part the increased incidence of infection. The importance
of this adherence mechanism can be seen in patients defi­
cient in one integrin class of neutrophil adherence recep­
tors, CD-18, who suffer from frequent bacterial infections.79
The biology of the transmembrane polypeptides governing
these complex cell-to-cell interactions is an active area of
research80 and holds promise for therapeutic interventions.
Oxygen radicals, such as hydrogen peroxide and superox­
ide anion, are released by activated neutrophils in response
to a variety of stimuli81 and when xanthine oxidase is acti­
vated after reperfusion in ischemia–reperfusion models.
These highly reactive products cause cell membrane dys­
function, increased vascular permeability, and release
eicosanoids.
Nitric oxide, released when citrulline is formed from argi­
nine, was identified as an endothelial product in the mid-
1980s.82 Its half-life is merely a few seconds because it is
quickly oxidized, but it has profound local microvascular
effects. Nitric oxide synthesis is stimulated by various cyto­
kines, endotoxin, thrombin, and injury to the vascular
endothelium. It is a potent vasodilator,83 but its actions vary
depending on the vascular bed and presence of other medi­
ators.84 Nitric oxide is one of the major mediators of hypo­
tensive response to sepsis.85,86
Antigen–antibody complexes activate the complement
cascade, and complement fragments thus generated inter­
act with other cytokines to promulgate the inflammatory
response.87 Diminished levels of the natural inhibitor of
C5a have been demonstrated in patients with ARDS.88
Administration of anti-C5a antibody diminishes hypoten­
sion in an animal model of endotoxemia.89
Organ-Specific Failure
and Prevention
MOF reversal is challenging, making prevention para­
mount.90 Genomic data have demonstrated that patients
with MOF began on the same path as those who recover
without complications.23 Prevention is based on arresting
the “engines” that drive and amplify the process: sepsis,
gut barrier breakdown, the wound, and inadequate perfu­
sion (Table 30.4). With current surgical and pharmacologic
modalities, it is more practical to halt these engines than deal
with an inadequately understood complex web of media­
tors. The interplay between organ systems and engines of
MOF in the burned patient are complex. For expedience, we
will discuss major organ systems sequentially.
HYPERMETABOLISM
Severe injury is associated with the hypermetabolic
response, marked by increased oxygen consumption and
Table 30.4  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

30  •  Etiology and Prevention of Multisystem Organ Failure
313
investigated the integrity of airway epithelium in autopsy
specimens of 72 severely burned children, finding airway
epithelial loss corresponded to inhalation injury and age.98
Mortality of inhalation injury was 16.4% and was associ­
ated with increased length of mechanical ventilation and
length of stay.99
Lopez and Enkhbaatar demonstrated that nebulized
epinephrine limited pulmonary vascular hyperpermeabil­
ity to water and protein flux in an ovine burn model with
smoke inhalation. This preserved dynamic compliance,
mean airway pressure, and P/F ratio.100 In their ovine burn
with inhalation injury model, Traber et al. administered
γ-tocopherol, a reactive oxygen species scavenger. They
found decreases in arginase and collagen, significantly
improved diffusion capacity, decreased lung water, reduced
pulmonary shunt fraction, and reduced peak pressures
and bronchiolar obstruction, indicating that free radical
scavengers may reduce smoke-induced chronic pulmonary
dysfunction.101,102
In an ovine model of inhalation injury with Pseudomo­
nas infection there was severe deterioration in pulmonary
gas exchange and increased lung lymph flow and protein
content, lung water, nitrite/nitrate concentrations, tra­
cheal blood flow, and vascular endothelial growth factor
(VEGF) expression.103 In a different study with this model
evaluating microcirculatory changes in response to acti­
vated protein C, significant reductions in heart rate and
cardiac output were observed. The changes in microvas­
cular blood flow to the trachea, kidney, and brain were
normalized.104
For nearly 20 years the ARDSnet doctrine of limited
tidal volumes, pressure-limited ventilation, positive end-
expiratory pressure (PEEP), and permissive hypercapnea
have dominated the field of pulmonary critical care.105
Application of these principles to burn care has been
limited due to increased CO2 production resulting from the
hyperdynamic state requiring higher minute ventilation,
pulmonary edema from resuscitation increasing the A-a
gradient, and decreasing compliance and airway injury
from inhaled toxins causing increased resistance and
mucosal sloughing and plugging. For more than 28 years,
Sousse and Mlcak analyzed pulmonary outcomes in 932
burned pediatric patients with inhalation injury, stratifying
for tidal volume. Their findings are staggeringly divergent
from ADRSnet data; they determined high tidal volume
(15 ± 3 mL/kg) corresponded to significantly decreased
ventilator days and maximum PEEP and significantly
increased maximum peak inspiratory pressure. ARDS was
significantly decreased, but the pneumothorax rate was
increased. They concluded that high tidal volumes might
interrupt the events leading to lung injury following inha­
lation injury.106 Of note, this study was performed in the
setting of early spontaneous breathing trials and aggres­
sive discontinuation of mechanical ventilation. It remains
unclear whether these data are an aberration or, as we
suspect, there is a fundamental difference in the physiology
of burned lungs. In the setting of severe inhalation injury
with hypoxia and hypercapnia, we have seen the remark­
able ability of pediatric lungs to heal with eventual nor­
malization of gas exchange several months post injury; this
phenomenon may be attributable to a still-active stem cell
population.107
elevated cardiac outputs. The pathophysiology of this phase
of cardiac dysfunction has been thoroughly described.94
Two primary drivers are prolonged elevated levels of cate­
cholamines and sepsis. Sepsis can continue to produce myo­
cardial dysfunction in a cytokine-mediated process.
Persistent β-adrenergic receptor activation causes uncou­
pling from G-proteins, decreases cyclic adenosine mono­
phosphate (cAMP) production and altered phosphorylation
down the mitogen-activated protein kinase (MAPK) and
Akt (protein kinase B) pathways away from the target of
rapamycin (mTOR), and reduces sarcoplasmic reticulum
calcium ATPase 2 (SERCA2) and ryanodine receptor (RyR).
Collectively these make the myocardium less responsive to
catecholamines and perturb calcium homeostasis. Further
nitric oxide secretion from inflamed and burned tissue alters
mitochondrial respiration and competes with calcium for
binding sites on myosin, thus furthering the calcium dys­
regulation. The prolonged leakage of calcium from the sar­
coplasmic reticulum depletes calcium stores and depresses
contractility. These changes conjointly drive the myocar­
dium toward apoptosis, which is detected within 3 hours
postburn in the ebb phase but can continue into the flow
phase.94
Additionally, pulmonary hypertension and right ventric­
ular failure have a high mortality. In burn patients this can
result from sepsis-related myocardial effects or acute fluid
overload with resuscitation and/or edema mobilization. Left
heart failure, acute pulmonary embolism, sepsis, acute
lung injury, and perioperative state are other common
causes.97 Jeschke reported nonsurvivors having a 30%
higher cardiac index at 29–34 days and 91–180 postburn
than survivors, thus demonstrating the increased cardiac
demand required in the persistent hyperdynamic state typi­
fying MOF. The data suggest that these patients may need a
supraphysiologic cardiac index to meet their hypermeta­
bolic needs, although no definitive studies currently exist.
Effective and expeditious management of cardiovascular
failure is important to preventing or ameliorating MOF and
is a critical component of burn center care.
There is mounting evidence that propranolol improves
cardiac outcomes after burn injury by reducing heart rate
and cardiac work, thus dampening hypermetabolism and
hypercatabolism. Carvedilol may hold additional promise
with its added α-blocking and free radical scavenging
activities.
LUNGS
Pulmonary failure is caused by direct injury from inhala­
tion of toxins, fluid overload, heart failure, and pulmonary
edema resulting from resuscitation, injury from inflamma­
tory and septic mediators draining from the burn wounds
to the pulmonary capillary beds, pneumonia, and iatro­
genic ventilator injury.11 Prevention of the pulmonary com­
ponent of MOF is based on infectious prophylaxis (early
ventilator weaning/daily spontaneous breathing trials, suc­
tioning, oral hygiene, chest physiotherapy, elevating head-
of-bed) and limiting factors that exacerbate pulmonary
injury. Current treatments such as administration of nebu­
lized heparin, albuterol, cortisol, and epinephrine and chest
physiotherapy as well as mucolysis improve pulmonary
ventilation, function, and outcomes.4 Cox and Hawkins

30  •  Etiology and Prevention of Multisystem Organ Failure
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the colonic mucosa, but the value of such support in the
hypermetabolic burn patient remains unclear.
Limited research suggests possible benefits of probiotics
for gut barrier support.124 Probiotics may improve gastro­
intestinal barrier function, avoiding colonization with
pathogenic microorganisms and immunomodulation. They
reduce bacterial translocation in the gut of burned rats.125
Interestingly, they seem to increase diarrhea rates. Accu­
mulating data suggest probiotics may reduce ventilator-
associated pneumonia rates. There are some concerns in
the current datasets that the control groups have too high
an incidence of ventilator-acquired pneumonia (VAP), and
there have been case reports of sepsis from probiotic organ­
isms in high-risk patients.126 In a series of 20 severely
burned children, probiotics were found to be safe and tended
toward fewer surgeries and less time to achieve complete
wound closure.127
Decontamination of the gut lumen might diminish the
impact of gastrointestinal barrier failure. Attempts have
been made to assess the impact of selective decontamina­
tion of the gut128 by coating enteric bacteria to inhibit their
ability to attach to the intestinal mucosa and translocate.129
While the rate of pneumonia may decrease by such mecha­
nisms, there is no apparent impact on mortality.
Acute pancreatitis is also notable after severe burn injury
as defined as a threefold increase in amylase or lipase with
abdominal pain or feeding intolerance. In a pediatric cohort,
Rivero and Jeschke reported an incidence of 13/2699 or
0.05% and found pathological evidence in 11/78 autopsies.
This is in contrast to 40% of patients developing a hyper­
amylasemia or hyperlipidemia without symptoms. They
postulated that the etiology of these pancreatitis cases was
from ischemic injuries due to shock. They also noted
increased mortality in the pancreatitis cohort.130
In a severe burn the liver plays a pivotal role in modulat­
ing inflammatory processes, immune functions, metabolic
pathways, and the acute-phase response. Thermal injury
causes hepatic damage by inducing hepatic edema, fatty
infiltration, apoptosis, and the metabolic derangements
associated with insulin resistance. Insulin administra­
tion decreases the rate of infections and the synthesis of
proinflammatory cytokines and improves hepatic struc­
ture and function in severely burned and critically ill
patients.131
Burn injury promotes catabolism and lipolysis in burned
children.132 The resulting free fatty acids are re-esterified in
the liver to triglycerides where they are not secreted as very-
low-density lipoprotein (VLDL) due to downregulation of
transport proteins, thus leading to progressive fatty liver
metamorphosis. Carbohydrates are utilized as a major
energy source for critically burned patients. Lee and
Herndon demonstrated that low-fat, high-carbohydrate
feeds promote shorter ICU stay per %TBSA, a lower inci­
dence of sepsis, and decreased hepatic steotosis.133
Acute liver failure (ALF) is uncommon after burn but
carries a high mortality. It presents with hepatic encepha­
lopathy, jaundice, and coagulopathy in the absence of
chronic liver disease and carries a mortality rate of 40–50%.
The cause of death is cerebral herniation in 34%, refractory
hypotension, and MOF. Herndon et al. studied 142 consec­
utive cases of ALF in the ICU and found that 70% were due
to heart failure, 13% from respiratory failure, and 13%
Systemic factors beyond sepsis also affect pulmonary
failure. For example, inflammation associated with burns
leads to hyperglycemia. A threshold of greater than
150 mg/dL leads to overwhelming growth of bacteria in
the bronchopulmonary system. Pneumonia on mechanical
ventilation and ARDS were higher in patients with average
daily glucose greater than 150; they had significantly
longer ventilation and more infection and sepsis.108
GASTROINTESTINAL DYSFUNCTION
DENVER2 and SOFA scores only address the gut failure
pertaining to the liver. However, other aspects of gastro­
intestinal dysfunction also cause significant morbidity and
contribute to mortality. Intestinal circulatory disturbances,
atony, ileus, edema, swelling, and loss of mucosal barrier
function gut dysfunction are an engine of MOF that Laut­
enschlager et al. studied with isolated rat small intestine
perfused with PAF. They induced mesenteric vasoconstric­
tion, translocation of fluid and macromolecules from the
vasculature to the lumen, edema, and the loss of motility
seen in intestinal failure. In this model quinidine, a sodium
channel blocker, inhibited this pathology whereas dexa­
methasone did not.109 Oliveira and Herndon studied the
role of cyclooxygenase-2 inhibitors on gastric and small
bowel ileus in prostaglandin-mediated etiology for postburn
ileus.110 Gut mucosal integrity suffers when mesenteric flow
is inadequate, and gut blood flow is decreased after burn
injury, exacerbated by TXA2 release.111 Support of splanch­
nic blood flow is an important aspect of MOF preven­
tion112 accomplished as part of whole-body hemodynamic
support.
In a chronic porcine model of burn injury, burned pigs
were given endotoxin bolus, causing a marked decrease in
systemic vascular resistance, blood pressure, cardiac index,
and mesenteric blood flow. This state increased gut bacterial
translocation into mesenteric lymph nodes, spleen, and
burn wounds, possibly due to mesenteric ischemia and
reperfusion injury.113
Enteral feedings have beneficial effects on outcomes com­
pared with parenteral feedings, possibly via an enhance­
ment of gastrointestinal barrier integrity.114 Enterocytes
are principally supported by intraluminal feedings. Guts
deprived of intraluminal feedings develop mucosal
atrophy.115 Early enteral feedings are tolerated in burn
patients116 and attenuate their hypermetabolic response.117
The value of specific nutrients to support the enterocyte is
murkier than that of providing adequate mesenteric blood
flow and intraluminal nutrition. Glutamine is the preferred
fuel of the small bowel enterocyte.118 Sepsis has been shown
to decrease glutamine uptake by the small bowel enterocyte,
which may result in barrier failure,119 and the addition of
glutamine to the nutritional regimen is theorized to improve
barrier function. Glutamine is not a component of com­
mercial parenteral nutritional formulas because of its short
shelf life, although the dipeptide is well tolerated and has a
longer shelf life.120 While supplemental glutamine may
improve protein balance in surgical patients115 and partially
reverse gut atrophy,121 it has not been shown to improve gut
barrier function when given parenterally.122 The large intes­
tinal mucosa are trophic to butyrate, a fatty acid liberated
by fiber fermentation.123 Enteral pectin may help support

30  •  Etiology and Prevention of Multisystem Organ Failure
315
increasing creatinine or decreased urine output, the finding
of granular casts on centrifuged microscopic urinalysis is
helpful in promptly differentiating organ damage (tubular
necrosis) from appropriate renal response to decreased
blood flow (prerenal state) and can promptly guide therapy.
Prevention of Sepsis
Sepsis is a major engine of MOF, and MOF predisposes
patient to sepsis; a lethal feed-forward loop. The post-burn
surge of proinflammatory mediators and resultant hyper­
metabolic response and protein wasting contribute to infec­
tion and sepsis.4 In multiple series all mortalities with MOF
were septic. MOF patients may have more major infections
(non-MOF 2.1 versus MOF 3.3), and they do experience
more sepsis (non-MOF 5%, MOF 31%).4 Early burn excision,
wound closure, regular wound surveillance and culture,
and strict infection control remain the principal adjuncts to
control invasive infections in burn patients.140 Sepsis
accounts for at least half of MOF cases. Overt wound sepsis
and smaller septic insults are prevented by early removal of
devitalized tissue because manipulation of heavily colo­
nized burn wounds is a frequent source of transient bacte­
remia.141,142 Multiple episodes of occult bacteremia
occurring during frequent manipulation of heavily colo­
nized wounds contribute to the development of MOF by
priming immune cells, making them react more intensively
to each subsequent insult.25
The role of perioperative and prophylactic antibiotics in
minimizing bacteremia in the perioperative period remains
controversial. There is a clear benefit to patients with inju­
ries greater than 60% TBSA and for any patient in whom
the probability of bacteremia with wound manipulation is
considered to be high.143 Culture-directed antibiotics are an
important consideration because burn patients are prone to
a large number of unusual and often occult infections.144
Rapid diagnosis and treatment are assisted by a high index
of suspicion.
Intravascular infections such as suppurative thrombo­
phlebitis and endocarditis typically present in burn patients
with fever and bacteremia without localizing signs. Burn
patients with endocarditis rarely develop a murmur (just
9% of cases)145 with only 10% reported antemortem.146
Septic thrombophlebitis often presents without localizing
signs, with 68% of cases having only fever and positive
blood cultures.147 Diagnosis is made by thorough examina­
tion of all sites of prior cannulation, surgical exposure of
suspicious sites, and complete excision of involved veins.148
Vigilant care, scheduled replacement, and early removal of
intravascular devices will minimize the occurrence of
catheter-related sepsis. Occult intracompartmental sepsis
can also present with fever and bacteremia without local­
izing signs and is diagnosed only by careful examination
and exploration of suspicious compartments.149
Pneumonia, seen in approximately 35% of patients with
inhalation injury, adds 20–60% to the expected mortal­
ity.150 Pneumonia should be vigilantly anticipated and
aggressively treated with pulmonary care and specific anti­
biotics. The incidence of nosocomial pneumonia increases
with longer durations of intubation,151 emphasizing the
importance of judicious use of mechanical ventilation and
from toxins or sepsis.134 Most commonly, low flow states
cause ALF. The liver receives most of its blood flow via the
portal system, and the dependence on portal supply is
increased in critical illness because the arterial supply is
reduced while the central lobular oxygen requirements
increase due to metabolic and synthetic demands. In the
setting of heart failure, high central venous pressures, asso­
ciated with fluid overload or the need for high preload,
decrease the pressure gradient across the liver and compro­
mise portal flow (and oxygenation), leading to centrilobular
necrosis. Thus, most post-burn acute liver failure is hypox­
emic liver failure, with high hepatic (central) venous pres­
sures a major (unrecognized) cause of reduced hepatic
oxygen delivery.134 Less common causes are toxins and
viruses. Many drugs used in the burn ICU can cause acute
liver failure: acetaminophen, amoxicillin, moxifloxacin,
trimethoprim-sulfamethoxazole, fluconazole, voriconazole,
amiodarone, metformin, isoflurane, opiates, phenytoin,
ibuprofen, iron, and anabolic steroids make up a short list.
Immunosuppression associated with burn injury predis­
poses activation of latent hepatitis and herpes viruses (espe­
cially cytomegalovirus), which can cause ALF. Loss of
clotting factors causes coagulopathy, whereas loss of anti­
coagulants can causes thrombosis, collectively promoting
disseminated intravascular coagulation (DIC). Burn patients
with liver dysfunction become prone to hypoglycemia due
to loss of glucose homeostasis.135 ALF feeds back into MOF
causing vasoplegia with diminished hepatic clearance of
circulating vasoactive compounds, increased nitric oxide
(NO) production, acute renal failure due to ischemia, and
acute tubular necrosis (ATN), and it may progress to hepa­
torenal and/or compartment syndromes.
RENAL
To survive a burn injury adequate renal clearance is essen­
tial. Twenty-four h following resuscitation it is necessary
to clear the excess volume administered. Renal function is
critical to clear extensive metabolic wastes associated with
injury and the hyperdynamic state.136 Concurrently the
kidney is subjected to prerenal insults, such as hypovolemia
and shock, and to direct renal toxins, such as myoglobin and
medications.137 Aggressive treatment of compartment syn­
dromes to prevent myoglobinemia, monitoring of abdomi­
nal compartment pressures to prevent compromise of renal
blood flow, and avoidance of nephrotoxic medications are
critical to maintaining renal function. Mason and Jeschke
et al. prospectively analyzed 330 resuscitations dividing the
patients relative to the Parkland formula resuscitation. The
groups receiving greater than Parkland resuscitation had a
higher APACHE score. Patients resuscitated with less than
Parkland resuscitation demonstrated greater probability
of acute kidney injury (AKI) (odds ratio [OR] 3.25; 95%
confidence interval [CI] 1.18–8.94) without difference in
infectious complications.138 Maintenance of sufficient renal
blood flow with appropriate volume resuscitation is vital to
maintaining renal function. In a retrospective review of
41,179 burned Finnish patients, 86 had AKI related to the
burn and 43 developed end-stage renal disease (ESRD) and
required renal replacement therapy (RRT).139 In the absence
of diuretics, urine output of 0.5–1 mL/kg per hour gener­
ally indicates sufficient renal perfusion. In patients with

30  •  Etiology and Prevention of Multisystem Organ Failure
316
urine output, skin perfusion, blood pressure, and senso­
rium. In selected critically ill patients, invasive and nonin­
vasive monitoring is justified to optimize preload, afterload,
inotropy, and oxygen delivery and consumption particu­
larly in patients where urine output becomes an unreliable
endpoint.
The Potential Role of Nutritional
and Specific Immunomodulators
Prevention of MOF by modulating the common pathway
that leads to organ dysfunction is the holy grail of critical
care. The three general approaches to this goal are nutri­
tional, nonspecific, and specific immunomodulation.
NUTRITIONAL IMMUNOMODULATION
Three categories of substances show promise as potential
nutritional immunomodulators: long-chain fatty acids;
arginine, glutamine, and branched-chain amino acids; and
nucleotides. Long-chain fatty acids are important constitu­
ents of cell membranes and can profoundly influence cell
function.161 Omega-3 long-chain fatty acids play a particu­
larly important role in the membranes of immunocompe­
tent cells.162 Animal data suggest that supplementation of
a diet with omega-3 fatty acids may improve immune func­
tion after burn injury;163 however, there are no clear clinical
data.
The potential immunostimulating effects of specific
amino acids, particularly arginine, glutamine, and the
branched-chain amino acids leucine, isoleucine, and
valine, remain an area of research. Arginine has impor­
tant functions in the urea cycle and in generating nitric
oxide and may have important effects on immunity.164–166
Animal data suggest improved immunocompetence and
outcome after burn with arginine supplementation,167–169
but human data are not adequate to support its routine
administration. Glutamine may be essential in hypermeta­
bolic patients,118,119 and its administration may support the
gut barrier, thereby abrogating the consequences of barrier
failure.
NONSPECIFIC AND SPECIFIC
IMMUNOMODULATION
It seems unlikely that a magic immunomodulating bullet
will prevent the development of MOF in critically ill patients,
particularly with uncontrolled sepsis, compromised gut
barrier, unaddressed burn wounds, or inadequate hemody­
namic support. Efforts at nonspecific immunomodulation
include the use of steroids,170 immunoglobulin G,171 and
naloxone172 with no significant impact on patient outcomes.
With the exception of steroids for adrenal insufficiency173
and naloxone for those with opiate intoxication, there is
currently no role for these substances in critically ill burn
patients.
Addressing toxicity of lipopolysaccharide has been
attempted by absorption,174 prevention with polymyxin
B,175 and antiendotoxin antibodies. Although multiple trials
have been attempted with multiple antibodies no compelling
data have yet brought one into broad clinical practice.176– 179
early extubation protocols such as daily spontaneous
breathing trials.
Suppurative sinusitis is a rare cause of sepsis in the ICU
traditionally described as resulting from transnasal tube
placement in a case series published in 1986.152 Many burn
centers routinely use prolonged nasotracheal tubes due to
their dramatically lower rates of dislodgement and lower
sedation requirements and do not report high rates of
sinusitis. Subsequent studies have brought this etiology into
question, and, in our experience, we have had zero episodes
in the past 20 years.153 Furthermore this is not a typical
cause of septic shock even when it occurs. If suppurative
sinusitis does occur, it is treated with tube removal, topical
decongestants, and appropriate antibiotics, rarely requiring
surgical drainage.
Acalculous cholecystitis presents with generalized sepsis
without localizing signs, making diagnosis difficult.154 Per­
cutaneous cholecystectomy tube drainage has become the
management of choice in suspected cholecystitis in criti­
cally ill patients.155 This allows diagnosis and decompres­
sion in patients too unstable for immediate operation.
Ensuring Adequate
Oxygen Delivery
Oxygen is one of the most sensitive substrates in cells. The
normal intracellular partial pressure of oxygen is 0.5 mm
Hg for all mitochondrial function. Failure to deliver ade­
quate oxygen resulting in organ dysfunction is a definition
of shock and a common cause of MOF. Inadequate oxygen
delivery shifts cells to anaerobic metabolism and increases
in the liberation of intracellular oxygen free radicals with
the activation of xanthine oxidase.156
Sufficient oxygen delivery requires adequate resuscita­
tion and re-establishment of cardiovascular and pulmo­
nary homeostasis. The practical details of resuscitation,
particularly resuscitation endpoints, remain controversial.
The Rivers et al.157 study highlighted the utility of aggres­
sive pursuit of predetermined resuscitation endpoints in
septic shock. Large trials failed to replicate their results,
which may be the result of the early goal-directed therapy
protocols becoming the standard of care with resultant
improvements in control group mortality. Regardless, opti­
mizing preload, assuring appropriate afterload, optimizing
inotropy, and tracking end organ perfusion remain the hall­
marks of critical care support in algorithms from the
Advanced Burn Life Support to the Surviving Sepsis Cam­
paign.158 Additional resuscitation endpoints beyond urine
output, such as lactic acid and base deficit,159 and advanced
hemodynamic monitoring tools are improving resuscita­
tion accuracy and minimizing the morbidity of under- and
overresuscitation. Computerized resuscitation algorithms
help achieve sufficient fluid resuscitation while minimizing
overresuscitation. Resuscitation strategies and their effects
are discussed at length in other chapters of this text. Com­
plications of anasarca caused by massive crystalloid resus­
citation can be reduced with the addition of colloid to
resuscitation.160
Inadequate oxygen delivery leads to organ dysfunction.
Clinicians should ensure that injured patients are resusci­
tated to conventional clinical endpoints of appropriate

30  •  Etiology and Prevention of Multisystem Organ Failure
317
with monoclonal antibodies enhances survival in animal
models of endotoxic and hemorrhagic shock.198
Oxygen free radicals generated by activated neutrophils
or xanthine oxidase may oxidize membrane lipids, forming
lipid peroxides and resulting in membrane dysfunction.199
Native antioxidant systems do exist but can be overwhelmed.
Circulating levels of vitamin E, a natural antioxidant, are
low in patients with ARDS.200 Efforts to modify oxidant
activity include blockade of free radical generation, addi­
tion of free radical scavengers, augmentation of host anti­
oxidant defenses, and prevention of amplification of tissue
damage by neutrophils.199 Particularly intriguing are free
radical scavengers such as superoxide dismutase201 and
spin-trapping nitrones,202 which improve survival in animal
models of endotoxic and hemorrhagic shock. Despite
encouraging initial animal studies, such therapy is not yet
appropriate in human patients.
The continuous synthesis of NO plays an important
role in the regulation of pulmonary and systemic vascular
tone in sepsis,203 and this presents potential opportunities
for intervention.204 Aerosolized NO has been shown to be
useful in reversing the pulmonary hypertension associ­
ated with ARDS as well as in improving V:Q mismatch,205
and NO synthesis blockade may improve the hypotension
and renal dysfunction associated with sepsis. Its complex
interactions with other cytokines and variable effects on
different vascular beds currently render any NO-based
interventions investigational or for selected critical care
indications.
Most patients who die in the burn unit after surviving the
initial injury and resuscitation succumb to MOF.206 Modify­
ing the cascade leading to MOF at the cellular and subcel­
lular levels is enticing, but our fragmented understanding
of these processes mitigates against such therapy in human
patients at present.
Complete references available online at

Immunomodulation has also targeted arachidonic acid
metabolites or eicosanoids, both cyclooxygenase and lipoxy­
genase products. Animal models of sepsis demonstrate that
cyclooxygenase pathway blockade has demonstrated
improved survival,180 improved pulmonary hemodynam­
ics,181 and improved mesenteric blood flow.182 Human data
are currently lacking, but it has been suggested that non­
steroidal antiinflammatory agents improve symptoms asso­
ciated with endotoxin infusion in normal volunteers183 and
septic patients184 and may improve immune function after
surgical trauma.181 In an animal model, infusion of the
vasodilating AA metabolite prostacyclin ameliorates the
pulmonary dysfunction associated with endotoxin infu­
sion.38 Lipoxygenase pathway blockade reduces pulmonary
dysfunction in mice,185 sheep,186 and pigs.187 The ultimate
role of lipoxygenase blockade in human remains to be
investigated.
Cytokines have also been targeted. IL-1 receptor antago­
nist enhances survival in an animal model.188 Infusion of
IL-1 may improve immune function in humans.189 Current
understanding of the complex functions of this cytokine is
inadequate to allow intelligent intervention. TNF blockade
attenuated the physiological effects of both endotoxin infu­
sion and Gram-negative sepsis in animal models.190,191 Anti-
TNF administration prior to experimental sepsis192 and
endotoxemia193 has variable effects on survival.
Interference with the effects of PAF has been shown to
decrease neutrophil priming by human burn serum,194
improve endotoxin-induced pulmonary dysfunction,195
decrease eicosanoid release,196 attenuate thromboxane
release, and improve survival197 in various animal models
of endotoxemia. These exciting initial results, and the avail­
ability 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 because
activated neutrophils play an important role in the develop­
ment of MOF. Blockade of neutrophil adhesion receptors

317.e1
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318
Acute Renal Failure in
Association with Thermal Injury
JOSHUA S. CARSON, JEREMY GOVERMAN, and SHAWN P. FAGAN
31 
0.3 mg/dL or more as sufficient to define a stage I injury. In
2012, the Kidney Disease Improving Global Outcomes
(KDIGO) Acute Kidney Injury Work Group published a con­
sensus definition of renal injury that essentially merged the
two previous frameworks, with slight adjustments.16
While the proliferation of consensus definitions may
seem to undermine the basic goal of establishing a uni­
versal metric for research and clinical applications, the
three systems have proved fairly interchangeable. Mul­
tiple studies applying the different scoring systems to the
same patient populations have found that they ultimately
yield similar results.17,18 Specifically in burn popula­
tions, Chung et al. found that RIFLE and AKIN identified
similar subpopulations when applied to a large cohort of
patients.19
Etiology
Burn-associated acute kidney injuries can generally be
divided into two categories, early and late. AKI presenting
within the first 48 hours of the burn injury (i.e., early AKI)
typically results from either uncontrolled burn shock,
underresuscitation, or protein degradation products. Renal
injury manifesting later in the course of acute burn care
(i.e., late-onset AKI) typically represents either a medication
toxicity or a complication of sepsis.
EARLY
Within the first 24–28 hours of a massive burn injury,
AKI results from the pathologic response to thermal injury.
Early burn-associated AKI is multifactorial, with hypovo­
lemia, inflammatory mediators, cytokines, extensive tissue
destruction and release of denatured proteins, iatrogenic
causes (nephrotoxic agents), and cardiac dysfunction all
contributing to the renal insult. In the setting of delayed
resuscitation, hypovolemia is the most immediate threat
to renal function. And yet AKI can still develop in the
thermally-injured patient despite aggressive fluid resus­
citation and a normal urine output. In such cases, renal
injury might reflect a fluid-refractory, inflammatory shock
in response to the burned tissue, cardiac dysfunction, or
injury from nephrotoxins, which can be either endoge­
nous (denatured proteins) or exogenous (medications) in
nature.20,21
Hypovolemia
In large surface area burns, decreased renal blood flow
results from massive fluid shifts and losses. Local and sys­
temic cytokine release leads to “capillary leak,” shifting
Introduction
Acute renal dysfunction represents a critical complication
of an acute thermal injury and is associated with a signifi­
cant increase in morbidity and mortality. Currently, the
incidence of acute renal failure (ARF) in burn patients
varies between 0.5% and 30%, and the risk of mortality
associated with renal failure in burn patients has been
reported to be as high as 54–100%.1–11
Prior to 1965, there were no reported survivors from
ARF following a thermal injury.12 Clearly the care of patients
with renal injuries has improved during the past 50 years.
However, while advances have been made in the under­
standing of burn-associated ARF, very few specific inter­
ventions have been clearly shown to change outcomes in
these patients. Even renal replacement therapy (RRT), one
of the core milestones of modern medical progress, has yet
to show a significant improvement in the mortality rate of
burn patients suffering from ARF.13 As such, the optimal
treatment for acute renal failure remains prevention.
This chapter will review the definition, etiology, patho­
physiology, diagnosis, and treatment of acute renal failure
in association with thermal injury (Fig. 31.1).
Definition
Intuitively ARF is easily understood as an abrupt decline in
renal function. Precisely how to quantify renal function and
where to place the threshold for “failure” has long been
open to interpretation. Until 2004, with no consensus
regarding a definition for ARF, more than 30 different defi­
nitions were used within the literature at the time. The need
for a common working definition of renal failure prompted
an effort to standardize the definition of renal insufficiency,
with the International Acute Dialysis Quality Initiative
(ADQI) group developing the RIFLE criteria for kidney inju­
ries in 2004. The RIFLE criteria divided renal compromise
into five discrete categories: Risk, Injury, Failure, Loss, and
End-stage renal disease (Fig. 31.2). In addition to establish­
ing a common definition, the RIFLE criteria provided a
means to quantify degrees of acute kidney insufficiency or
injury (AKI).14 In 2007, the Acute Kidney Injury Network
(AKIN) introduced an updated definition of acute kidney
injury; see Tables 31.1 and 31.2.15 The AKIN definition
simplified the stratification of renal injury into three stages
(I, II, and III), with the RIFLE Failure, Loss, and End-stage
renal disease categories folded into grade III. There was also
an increased sensitivity (relative to the RIFLE criteria) by
virtue of use of an absolute increase in serum creatinine of

31  •  Acute Renal Failure in Association with Thermal Injury
319
resulting in renal ischemia. 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 that further reduce effective glomerular
filtration rate (GFR).
Hypovolemia can develop within the course of minutes
in the absence of appropriate fluid replacement. As such,
hypovolemia represents by far the most likely source of AKI
Fig. 31.1  Autopsy specimen from a patient with acute tubular necrosis
and renal failure. Note the edema and the alteration of medullar pyra­
mids. Acute renal failure in burn patients carries a high mortality.
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
Fig. 31.2  Multifactorial etiology of sepsis-induced acute renal failure
(ARF).
Table 31.1  Comparison of Serum Creatinine Criteria in RIFLE, AKIN, and KDIGO Systems
SERUM CREATININE CRITERIA FOR THE DEFINITION AND CLASSIFICATION OF ACUTE KIDNEY INJURY
RIFLE Criteria—The Acute Dialysis Quality
Initiative (ADQI)
AKIN Criteria—Acute Kidney Injury
Network
KDIGO Criteria—Kidney Disease Improving
Global Outcomes
Risk
Increase in serum creatinine ≥1.5 times
baseline
OR
Decrease in GFR ≥25%
Increase to 1.5–1.9 times baseline
OR
Increase in serum creatinine of ≥3 
mg/dL (26.2 µmol/L) from baseline
Increase to 1.5–1.9 times baseline
OR
Increase in serum creatinine of
≥0.3 mg/dL (26.2 µmol/L) from
baseline
Stage I
Injury
Increase in serum creatinine ≥2.0 times
baseline or decrease in GFR ≥50%
Increase in serum creatinine to 2–2.9
times baseline
Increase in serum creatinine to 2–2.9
times baseline
Stage II
Failure
Increase in serum creatinine ≥3.0 times
baseline
OR
Decrease in GFR ≥75%
OR
An absolute serum creatinine
≥354 µmol/L with an acute rise of at
least 44 µmol/L
Increase in serum creatinine to ≥3 times
baseline
OR
Serum creatinine ≥4.0 mg/dL
(354 µmol/L) with an acute rise of
≥05 mg/dL (44 µmol/L)
OR
Initiation of renal replacement therapy
Increase in serum creatinine to a level
≥4.0 mg/dL (353.6)
OR
Initiation of renal replacement
therapy
Stage III
Note—Urine output-based criteria are the same in all three systems.
From Brochard L, Abroug F, Brenner M, et al., 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 ARF in the ICU patient: an international consensus conference in intensive care medicine.
Am J Respir Crit Care Med. 2010;181(10):1128–1155. Updated with current reference to published KDIGO guidelines.
fluids from the intravascular to interstitial space. Burn-
induced compromise of the water-tight dermal barriers
results in rapid evaporative losses from the extravascular
compartment, which facilitates further extravasation of the
intravascular compartment in a vicious cycle.22 Given the
sheer speed and volume fluid shift seen in burn shock, pro­
found intravascular hypovolemia can result. Renal blood
flow is restricted in a compensatory response to hypovolemia

31  •  Acute Renal Failure in Association with Thermal Injury
320
in any burn patient showing signs of renal insult within 24
hours of their burn.
Overresuscitation and Abdominal
Compartment Syndrome
Unfortunately, overadministration of fluids can be just as
harmful as underresuscitation. Studies have shown that
AKI can develop in burn 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 per hour).5,23 Furthermore the risks of overresuscitation
have been well-documented and include pneumonia, acute
respiratory distress syndrome (ARDS), compartment syn­
dromes, and an overall increase in mortality.23,24
Despite the physician’s greatest effort to monitor end­
points of resuscitation, obligatory intercompartmental
fluid shifts will occur during resuscitation.25 These inter­
compartmental fluid shifts can be particularly hazardous if
they occur into fascial bound compartments, such as the
peritoneal cavity. Numerous studies from trauma literature
have described the adverse physiologic effects of increasing
intraabdominal pressure on visceral perfusion.6,26,27 Intra­
abdominal hypertension (IAH) is a known pathological
process that may occur during initial burn resuscitation as
defined by intraabdominal pressures (IAPs) of greater than
12 mm Hg. Abdominal compartment syndrome (ACS) is
defined as an IAP of greater than 20 mm Hg with at least
one concomitant organ failure. The exact level of abdomi­
nal hypertension required to compromise visceral perfusion
varies depending on a variety of patient factors and is dif­
ficult to predict.28–30 O’Mara et al. demonstrated that the
volume and type of fluid resuscitation affects the develop­
ment of ACS in the burn patient and suggested that fluid
resuscitation with crystalloid of greater than 0.475 L/kg
should alert the clinician to possible IAH/ACS and to
monitor for decreased cardiac output, decreased lung com­
pliance, or decreased renal perfusion. In a mixed population
of critically ill patients, a multicenter prospective trial has
demonstrated that the occurrence of IAH during the ICU
stay was an independent outcome predictor.28
Table 31.2  Comparison of Serum Creatinine Criteria in
RIFLE, AKIN, and KDIGO Systems
KDIGO CRITERIA FOR RENAL INJURY
Stage
Serum Creatinine Criteria
UO Criteria
I
Increase to 1.5–1.9 times baseline
OR
Increase in serum creatinine of
≥0.3 mg/dL (26.2 µmol/L) from
baseline
<0.5 mL/kg/h for ≥6 h
II
Increase in serum creatinine to
2–2.9 times baseline
<0.5 mL/kg/h for >12 h
III
Increase in serum creatinine to a
level ≥4.0 mg/dL (353.6)
OR
Initiation of renal replacement
therapy
<0.3 mL/kg/h ≥24 h or
anuria ≥12 h
From Khwaja A. KDIGO clinical practice guidelines for acute kidney injury.
Nephron Clin Pract. 2012;120(4):c179–184.
Rhabdomyolysis
Rhabdomyolysis frequently presents within 24 hours of
thermal injury and represents a well-documented risk for
AKI and subsequent renal failure.31 Rhabdomyolysis can
arise secondary to direct thermal damage or compartment
syndrome and is commonly seen following a severe electri­
cal injury. The release of myoglobin into the systemic circu­
lation results in blockage of renal tubules, constriction of
afferent arterioles, and the generation of oxygen free radi­
cals. Myoglobinuria occurs when serum myoglobin exceeds
1500–3000 ng/mL. Myoglobinuria does not always result
in renal injury, but certain risk factors have been identified.
The risk of renal injury is directly related to the amount of
iron-containing molecules released, the state of hydration,
and the degree of associated acidosis.32 Elevated creatinine
at baseline and creatinine kinase levels greater than
5000 U/L have been associated with the development of
AKI and the need for RRT, both in general trauma popula­
tions and in studies of burn patients.32,33
Cardiac Dysfunction
Patients suffering burns greater than 50% total body
surface area (TBSA) are subject to decreased cardiac output,
increased myocardial workload, and myocardial ische­
mia. 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 myocar­
dial ischemia, and (3) direct myocardial suppression.34–40
Of the potential theories, direct myocardial suppression
by tumor necrosis factor (TNF; i.e., myocardial depressant
factor) has gained substantial interest. TNF is known to
be released by myocytes stimulated by endotoxin or direct
thermal injury.41–47 The effects of TNF on cardiac func­
tion include reversible biventricular dilatation, decreased
ejection fraction, and decreased stimulation to catechol­
amines (Fig. 31.2).41,48,49 This is typically a transient phe­
nomenon, and, with adequate support, it usually resolves
within 24–72 hours. Without appropriate support, though,
frank heart failure can develop, bringing a myriad of com­
plications with long-lasting or even permanent sequelae.
Although most early cardiac dysfunction caused by TNF
can be reversed by inotropic support, the key is early
diagnosis to prevent ineffective renal perfusion and thus
prevent the morbidity and mortality associated with renal
insufficiency.
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 also
evidence of direct myocardial suppression, The impact of
this suppression can range from clinically undetectable to
frank cardiac shock. Often, this presents as a lack of appro­
priate cardiac compensation for distributive burn shock.
Myocardial dysfunction after thermal injury is commonly
overlooked by physicians due to the concentrated effort to
correct the overwhelming state of hypovolemic shock and
electrolyte abnormalities. In a patient presenting with burn
shock (i.e., hypoperfusion) and found to have a cardiac
index in “normal” range (rather than the expected supra-
normal values), serious consideration should be given to

31  •  Acute Renal Failure in Association with Thermal Injury
321
by direct renal arteriolar vasoconstriction. Furthermore,
the systemic inflammatory response results in the release of
additional vasoconstricting cytokines (i.e., TNF, endothe­
lin), locally secreted vasodilators (endothelial and inducible
nitric oxide) to counterbalance these sepsis-associated vaso­
constrictors.50,54 Ultimately, this compensatory response
comes at the cost of renal perfusion by further exaggerating
the prerenal state.
Finally, as mentioned previously, sepsis induces a pro­
coagulant state by affecting the expression of comple­
ment and the fibrinolytic cascade.55–57 This alteration in
the homeostasis of coagulation may result in a state of
disseminated intravascular coagulation (DIC) with direct
injury to the kidney by glomeruli microthrombi.58 The net
result is a lack of perfusion to the kidneys during sepsis
that will ultimately culminate in ischemic acute tubular
necrosis.
TOXINS
Antibiotics
Given the immunocompromise associated with massive
burn injuries, burn patients tend to accrue significant expo­
sure to systemic antibiotics over the course of their care.
Unfortunately, many of the systemic antimicrobial agents
most commonly used in burn patients carry significant risk
of nephrotoxicity.
With meticillin-resistant Staphylococcus aureus (MRSA)
now endemic in most hospital systems, vancomycin has
become a standard first-line agent for empiric coverage of
nosocomial infections in ICUs, including burn units. Given
the well-documented nephrotoxic potential of vancomycin,
alternative options should always be considered in patients
already showing signs of early AKI, especially when cul­
tures or Gram stains indicate a source of infection other
than MRSA.
When vancomycin is clearly indicated, there are mea­
sures one can take to minimize the risk of nephrotoxity.
Multiple studies have indicated that longer duration of
therapy and higher serum concentration troughs are asso­
ciated with increased risks of vancomycin-associated renal
injury.59,60 As concomitant aminoglycoside therapy has also
been shown to significantly increase the chance of renal
insult, these agents are best avoided when using vancomy­
cin as a component of combination antimicrobial therapy.
Some have advocated treatment with continuous infusion
of vancomycin rather than intermittent boluses to avoid
renal injury. In aggregate, though, the literature supporting
this approach is fairly underwhelming. Meta-analysis by
Hanrahan et al. identified a trend toward decreased rates of
AKI in patients treated with vancomycin via continuous
infusion versus intermittent bolus administration, but this
did not reach statistical significance.
The incidence of multiresistant organisms is and will
continue to be an ongoing challenge. This had led to the use
of antimicrobial agents that carry a significant risk of neph­
rotoxicity. The use of these potentially nephrotoxic antimi­
crobial agents must be weighed on a risk–benefit scale due
to the potential morbidity associated with inducing AKI.
Antimicrobial therapy should be based on culture data,
with the goal of down escalating therapy to the fewest
inotropic support, particularly when accompanied by the
finding of a low systemic vascular resistance index.
In any case of suspected cardiac dysfunction, a typical
workup should be performed to rule out any coronary or
mechanical etiology. Absent any such finding, an effective
burn surgeon must rapidly reestablish adequate renal blood
flow by correcting the diminished preload state while
keeping in mind the impact of burn injury on the entire
cardiovascular system.
LATE
AKI presenting later in the course of treatment for a massive
burn typically occurs as a component of multiorgan failure,
most commonly from sepsis. Given the high risk for infec­
tion and the difficulty of diagnosing such infections in this
patient population, underlying infection and sepsis must be
seriously considered in any patient found to have new or
worsening renal failure more than 48 hours out from their
initial injury.
Iatrogenic renal injury is also an important consideration
in late burn-associated AKI, particularly given these
patients’ frequent exposure to multiple antibiotics and
diuretics.
Sepsis
Early aggressive resuscitation and excision have signifi­
cantly influenced the course of ARF immediately associated
with thermal injury. Acute renal dysfunction associated
with the septic syndrome nonetheless continues to cause
significant mortality.50,51
Sepsis and septic shock are the most common cause of
death in the ICU and are seen in up to 87% of cases of acute
renal dysfunction in the burn ICU.9,10 Several authors have
found the degree of sepsis to be directly related to the inci­
dence of acute renal dysfunction (Table 31.3).52,53 The
pathophysiology of AKI associated with sepsis is multifacto­
rial in nature but begins clinically with a generalized arte­
rial vasodilatation secondary to a decreased systemic
vascular resistance (Fig. 31.2). Initially bacteria or their
products activate sepsis-associated mediators (cytokines)
locally at the site of direct invasion. The homeostatic
balance between production and inactivation of these
mediators is altered, allowing for systemic release and
causing direct damage to the endothelium and vasoparesis,
as well as a procoagulant state. It has been theorized that
acute renal insufficiency associated with sepsis is the result
of each of these pathological processes.
The vasoparesis 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
Table 31.3  Renal Failure Dysfunction and Sepsis
Sepsis
Severe Sepsisa
Septic Shockb
Acute renal
dysfunction
19%
23%
51%
aSepsis associated with lactic acidosis or altered mental status.
bSepsis associated with hypotension.

31  •  Acute Renal Failure in Association with Thermal Injury
322
the 24-hour assay and provides a more responsive measure
of real-time function.
A significant disadvantage of creatinine clearance is that
it becomes less accurate as GFR drops. This is due to the fact
that renal tubules secrete a small amount of creatinine into
the urine (in addition to that which is filtered). Normally,
renal tubular secretion is so minor that it does not signifi­
cantly impact the creatinine clearance calculations at
normal GFRs, but can create significant distortion as the
real GFR drops. The impact of these variations in tubular
creatinine secretion can be largely overcome by administer­
ing cimetidine, which inhibits tubular creatinine secretion,
an hour before urine collection.62,63
FeNa
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 estab­
lished 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
urina
=
×
×
[(
)
(
ry creatinine)]
with a value less than 1% associated with a prerenal
condition and a value greater than 1% associated with
organ dysfunction (i.e., “renal” renal failure).62 There are
several conditions which affect renal absorption of sodium
and thus have been shown to affect the calculated value
(Table 31.4).
Fractional excretion of urea (<0.35) has shown margin­
ally improved sensitivity and specificity over sodium in dis­
tinguishing between prerenal and renal forms of ARF.64
Several additional indexes can be used to differentiate
between the two forms of ARF (Table 31.5).
Microscopy
Microscopic examination of urinary sediment is an easy
and inexpensive initial evaluation of AKI that often lends
insight into the underlying renal pathology.20,65 The combi­
nation of normal urinary sediment, hyaline casts, and
oliguric/anuric urinary output would suggest a prerenal
condition. The presence of epithelial casts and abundant
tubular epithelial cells is pathognomonic for acute tubular
necrosis. Similarly the identification of pigmented casts on
necessary antimicrobials and safest complication profile
(i.e., the least nephrotoxic).
Diagnosis
Technically, using the consensus definitions discussed
earlier, diagnosing AKI requires no more than measuring
serum creatinine, eGFR, and/or urine output and identify­
ing injury when any of these measures meet criteria set by
the chosen definition (i.e., AKIN, RIFLE, or KDIGO).
However, additional investigation is often warranted in
order to delineate the nature and etiology of each individual
case of AKI to allow for more informed treatment. Further­
more, a vigorous research effort is ongoing to identify novel
biomarkers which might serve as a means to identify
impending AKI earlier in the process.
URINE VOLUME
Urine represents by far the simplest and most intuitive
monitor of renal function. Urine volume is a specific but,
unfortunately, not very sensitive test for renal failure.61
Most clinicians regard the presence of “adequate” urine
output of little diagnostic value in the evaluation of renal
dysfunction since severe renal injury may exist with any
volume of urinary output. Urine output is not determined
by the GFR alone but by the difference between GFR and
tubular reabsorption. As such, AKI-associated tubular dys­
function can offset the decline in GFR, resulting in preserved
urine output volume.
However anuria—a urine output of less than 50 mL/day
or complete cessation of GFR—is a clinically significant
finding.9 By far, the most common cause is a severe prerenal
condition. Although it is true that other conditions (acute
cortical necrosis, bilateral arterial occlusion, and rapidly
progressive acute glomerulonephritis) may cause anuria,
their incidence is exceedingly low in the acute burn care
setting, and the diagnosis is usually readily apparent due to
additional clinical signs.
While a return of urine output in the oliguric or anuric
patient may offer encouragement, it does not necessarily
indicate reversal of the inciting renal injury. Of particu­
lar concern, one must be careful to watch for a conver­
sion of anuric or oliguric renal failure to polyuric renal
failure. Failure to appreciate a polyuric renal failure
and replace inappropriate fluid losses could result in a
second prerenal insult, increasing the risk of permanent
damage.
URINALYSIS
Creatinine Clearance
Creatinine clearance is an inexpensive, consistent, time-
tested technique for providing a rough estimate of GFR and
renal function. Creatinine clearance measurement does
involve the inconvenience of sustained urine collection, tra­
ditionally over a 24-hour period. However, this can be
markedly simplified by forgoing the 24-hour convention for
a more practical short-term (e.g., 6 hours or even 2 hours)
collection, which has been shown to be just as accurate as
Table 31.4  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

31  •  Acute Renal Failure in Association with Thermal Injury
323
NGAL
Neutrophil gelatinase-associated lipocalin (NGAL) is a poly­
peptide released by damaged nephron tubular cells in the
setting of local inflammation.64 In multiple settings, NGAL
has been shown to be identifiable in the serum and urine
within 1–4 hours of ischemic renal insult and highly pre­
dictive of AKI. Multiple groups have found NGAL elevations
earlier in a patient’s course to be predictive of subsequent
AKI. Sen et al. and Yang et al. demonstrated that elevations
in whole-blood levels of NGAL occurred as early as 4 hours
postburn. Furthermore, on multivariate analysis, NGAL
levels identified a risk for subsequent AKI well before urine
output rates or changes in serum creatinine.66
Others
Various investigators have identified additional novel early
markers in burn patients. Serum uric acid levels,
interleukin-18, and a novel protein named “kidney injury
molecule-1” have all been found to predict AKI shortly after
injury in isolated single-institution studies.67,68
Treatment
The key to the treatment of AKI is prompt diagnosis coupled
with a rapid reversal of the underlying pathophysiology
while avoiding iatrogenic injury. Early in the course of
acute burn care, the emphasis is on treating the underly­
ing burn shock and minimizing the exposure to second­
ary injury from nephrotoxic injury products. Later in the
course of acute care, the focus is on monitoring for the
emergence of new signs of renal injury and eliminating
or treating the underlying cause—typically infection or
chemotherapeutic nephrotoxicity. In either context, the
most effective approach is one that detects the presence (or
imminence) of renal injury as early as possible such that
the underlying insult can be minimized or reversed as soon
as possible.
Any injury that progresses to fulminant renal failure
despite initial therapeutic maneuvers requires RRT. This
section will address treatment and prevention of burn-
associated renal injuries.
RENAL PROTECTION IN THE EARLY PHASE OF
ACUTE BURN CARE
Resuscitation
As stated previously, the vast majority of cases of AKI pre­
senting within 24 hours of injury results from inadequate
renal perfusion.7,69 Several authors have demonstrated that
the timing of initiation of resuscitative fluids is directly
related to the incidence of renal dysfunction. Resuscitative
efforts should therefore begin immediately to reestablish
effective renal perfusion. Several resuscitative formulas
have been established based on multivariate logistic regres­
sion analysis (Table 31.7). Which formula to use is far less
important than the flexibility and care with which they are
applied. The clinician must recognize that these formulas
are estimates to be used as starting points. The true amount
is directly dependent on the patient’s own physiologic status
microscopic evaluation signifies the diagnosis of myoglo­
binuria, likely secondary to rhabdomyolysis.
SERUM BIOMARKERS
Creatinine
For generations, creatinine has served as the most widely
used marker of renal function. There is no question that
creatinine levels correlate to renal function, and acute ele­
vations of creatinine are clearly associated with an increased
risk of renal failure and additional mortality. Indeed, serum
creatinine levels (and changes therein) are central compo­
nents to all of the three consensus AKI definition and
staging systems proposed in the past 15 years.
Despite these advantages, serum creatinine levels cannot
be counted on for accurate real-time assessment of renal
function. Creatinine rises slowly in response to an acute
drop in GFR, with a lag time of hours to days seen between
the actual drop in GFR and the increase in serum creatinine
levels. As serum creatinine levels reflect a balance between
the rate of production and excretion of this endogenous
protein, it takes time for serum creatinine levels to reach a
new equilibrium when one side of this equation (excretion)
changes (see Table 31.6). Therefore, even once the serum
creatinine has begun to rise, it is typically hours to days
before it reaches a new steady state. This makes it difficult
to identify real-time changes in renal function and impos­
sible to recognize the real-time stabilization or resolution of
renal injuries.
Table 31.5  Differential Diagnosis of Acute Renal
Failure
Urinary Index
Pre-Renal
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 31.6  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

31  •  Acute Renal Failure in Association with Thermal Injury
324
benefit from the use of higher mean arterial pressure (MAP)
endpoints.
As critical as volume repletion is to effective resuscitation,
it does not follow that more is always better. Rather, what is
required is the continuous application of enough fluid to
maintain perfusion and avoid ischemic insult. Administer­
ing fluids in excess of those immediately required at any
point in time provides no additional benefit and certainly
does not help in reversing any prior renal insult.
It must be emphasized that the exact amount of fluid
required for any particular burn is not a constant, predeter­
mined value but an ongoing function of the injured patient’s
dynamic physiology. Several studies of AKI incidence in
large burn series found that patients with and without AKI
showed no significant difference in the total fluid volumes
received in the first 24–48 hours. In contrast, multiple
studies have identified longer time to resuscitation as a clear
risk factor for early AKI in burn patients. Likewise markers
of hypoperfusion (e.g., serum lactate levels, base deficits,
and SOFA scores) consistently have been shown as signifi­
cant associations with renal injury and failure.7,21,69,75–77
The key to renal protective resuscitation is not so much in
providing adequate fluid over the period of resuscitation as
it is a matter of minimizing the amount of time the patient
spends in a state of hypoperfusion and, thus, minimizing
the cumulative ischemic injury.
The primary goal is to reestablish effective renal perfusion
through a well thought out resuscitation plan based on
demonstrated resuscitation formulas and modified by vari­
ables correlated with the degree of resuscitation.
Other Acute Issues
Heart. Although establishing an effective circulating
volume is of prime importance, an astute clinician should
also carefully assess myocardial contractility to exclude
myocardial dysfunction as a contributing factor to ineffec­
tive renal perfusion (see preceding discussion).
Remove Nephrotoxins. In addition to the effects of shock
and dehydration, a burn injury can result in a renal injury
indirectly via secondary rhabdomyolysis. Burn patients can
develop rhabdomyolysis via a variety of mechanisms. Most
commonly, restrictive eschars from circumferential burns
can combine with the burn-associated edema to create a
tourniquet effect on the extremities, resulting in ischemic
muscle injury. Muscle can also be injured by direct thermal
injury in fourth-degree burns or via mechanical trauma in
the setting of coincident nonthermal trauma. Unfortu­
nately any significant burden of muscle necrosis results in
marked swelling and (if untreated) a spiral of compartment
syndrome and additional rhabdomyolysis.
Rhabdomyolysis clearly increases the risk for AKI in burn
patients because free myoglobin is quite nephrotoxic in sus­
tained exposures. Fortunately, this is reversible if the patho­
logical source is identified early and appropriate treatment
is initiated.76,78 In the setting of rhabdomyolysis, intensive
hydration with isotonic crystalloids is recommended. While
alkaline-diuresis with sodium bicarbonate solution and
mannitol was long held as the standard therapy for this
condition, the theoretic advantages of this therapy failed to
translate into any improved outcomes when studied in a
clinical setting.33 Of first priority, though, is arresting the
and degree of injury, neither of which can be fully captured
by a single formula.
Burns of greater than 20% TBSA generally require intra­
venous resuscitative efforts, and the initial volume of fluids
should be proportional to the area of burn injury. Kim et al.
showed that burn size is an independent predictor of ARF in
the burn population.70 The timeliness of resuscitation is par­
ticularly critical because the duration of ischemic time is
critically important to the development of AKI. Nguyen et al.
found initial management of the thermally injured individ­
ual to be critically important to overall survival.71 Early
aggressive hydration had a protective effect against ARF.
Similarly, the Shriners Burn Institute for Children, Galves­
ton, 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.72
The clinician must continuously monitor parameters of
regional and global perfusion in order to guide fluid therapy
and prevent overresuscitation. If the ability to assess true
volume status (preload) or effective renal perfusion is diffi­
cult, one should initiate monitoring of central pressures or
global volume-related variables (i.e., global end diastolic
volume, extravascular lung water volume, intrathoracic
blood volume).73 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 mm Hg), the use of vasopressors is indicated. While
there has been some recent interest in the strategy of titrat­
ing to a higher mean arterial pressure as a possible means
of protecting renal function in shock, a multiinstitutional
randomized clinical trial comparing resuscitation strategies
using high (80–85 mm Hg) versus standard (65–70 mm
Hg) goals for mean arterial pressure found no improvement
in renal outcomes in those patients in the high-target
group.74 The one exception to this finding was the subgroup
of patients with premorbid hypertension who did indeed
Table 31.7  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.

31  •  Acute Renal Failure in Association with Thermal Injury
325
Once a clinically significant infectious organism is identi­
fied, early goal-directed therapy should be initiated. Rivers
et al. demonstrated a significant reduction in mortality if
an early goal-directed algorithm is applied to the septic
patient.79 The principle is simple: establish early source
control while providing effective antibiotic therapy and
maximizing global, and therefore renal, perfusion. While
larger, more recent studies have raised questions about the
specific monitoring techniques and intervention thresholds
used in the Rivers trial, the basic principle of early diagnosis
and treatment remains invaluable.80
Rapid identification and correction of underlying
sepsis are critical to the preservation of renal function
because no renal protective pharmacological agent has
been demonstrated to prevent or limit renal dysfunction.
The importance of infectious surveillance in the ther­
mally injured patient cannot be overstated. The goal is to
effectively treat local infections and prevent systemic dis­
semination to avoid the morbidity and mortality of septic
shock.
Medical Therapy: Fenoldopam. Naturally, there has
long been much interest in identifying a pharmacologic
agent capable of protecting the kidney from injury in high-
risk settings. For many years, intensivists regularly employed
low-dose (aka “renal-dose”) dopamine infusions with hopes
of preserving renal function. In theory, the receptor activa­
tion profile of dopamine in these dose ranges should result
in selective augmentation of renal perfusion pressure.
Unfortunately multiple clinical trials consistently failed to
identify any improvement in renal outcomes associated
with renal-dose dopamine treatment.
More recently, interest has emerged in the possibility that
fenoldopam, another selective adrenergic agonist, might
provide more consistent, targeted support of renal perfu­
sion. Fenoldopam is a pure α1 agonist that decreases renal
vascular resistance in an NO2-independent manner. This
offers a distinct advantage in the setting of postischemic
AKI, where nitric synthase activity is typically saturated
early in the course of injury. As of yet, the role of fenoldo­
pam remains unclear. The largest randomized controlled
trial of fenoldopam infusion for renal protection (to date)
was performed in the context of cardiac surgery and failed
to show any reduction in renal outcomes. However the
current literature documenting the use of fenoldopam in
burn patients is limited to a single retrospective study that
did indicate a renal-protective effect in burn patients at high
risk for AKI. 81,82
Renal Replacement Therapy
Fortunately, due to major advances in burn care resuscita­
tion and the treatment of sepsis, renal failure requiring RRT
is unusual in the burn setting.83 The reported incidence is
approximately 1–3%. Unfortunately, though, the overall
mortality associated with renal failure requiring RRT
approaches 80%.8,10
Burn patients with preexisting renal insufficiency are at
particular risk for RRT due to the large positive fluid bal­
ances 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.83
underlying process by halting progressive ischemia with
aggressive escharotomy and fasciotomy and resecting any
necrotic muscle to remove the source of myoglobin
poisoning.
Late
Workup. An AKI presenting late in the burn patient’s course
can owe to any combination of a myriad of pathologies. Any
indication of new-onset renal injury late in the burn victim’s
course should prompt a rapid and comprehensive screen
for typical sources of renal injury—hypovolemia, cardiac
dysfunction, nephrotoxins, obstruction, and the like. Natu­
rally, any such pathology should be addressed immediately
if encountered. However, because infection and sepsis are
by far the most common etiology of renal failure in a burn
patient’s course, an intensive search for occult infection
should be undertaken immediately upon recognizing a new
renal insult regardless of any other identified contributors.
Sepsis Treatment. The most effective therapy is preven­
tion or early recognition of the septic state (Box 31.1). Every
thermally injured patient should be continuously moni­
tored for early markers of sepsis (feeding intolerance,
increasing insulin resistance, elevation of acute-phase
reactants) so that early therapy may be initiated.
Box 31.1  Definition of Sepsis in Burns
At least three of the following:
I. Temperature >39°C 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/µL

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 per hour intravenous drip (adults)

ii. Significant resistance to insulin (>25% increase in
insulin requirements over 24 h)
VI. Inability to continue enteral feedings >24 h

A. Abdominal distension

B. Enteral feeding intolerance (residual >150 mL/h in children
or two times feeding rate in adults)

C. Uncontrollable diarrhea (>2500 mL/d for adults or >  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

31  •  Acute Renal Failure in Association with Thermal Injury
326
in the thermally injured patient. Burn injury predisposes to
organ failure, catabolism causes increased urea generation,
large open wounds result in electrolyte shifts, and nephro­
toxic agents are often required as treatment. For intensive
care populations at large, the standard of care is to initiate
CRRT only upon evidence of extreme metabolic derange­
ments or other life-threatening events.88 However, there
continues to be interest in the potential benefit of initiat­
ing RRT earlier in the course of AKI, with ongoing clinical
studies indicating potential advantages of early RRT.89,90 A
recent randomized multicenter trial by Gaudry et al. chal­
lenged this hypothesis by suggesting early RRT has no sur­
vival advantages over delayed RRT.91 In addition, they found
potential benefits to delayed RRT if close monitoring of the
patient is performed in the ICU setting. Emerging trials con­
tinue to offer evidence on both sides of the argument—a
controversy which will likely be with us for years
to come.92,93
Although very early initiation of RRT in ICU patients has
not clearly been demonstrated to improve outcome, prelimi­
nary evidence exists to suggest a more aggressive approach
to RRT initiation in the thermally injured patient.86,87 As
Modalities. Peritoneal dialysis has a long history of suc­
cessful use in both acute and chronic settings.84 However,
in burn patients, 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 hemodi­
alysis (IHD), continuous renal replacement therapy (CRRT),
and sustained low-efficiency dialysis (SLED). No consensus
exists as to which mode is superior because each has advan­
tages and disadvantages depending on the clinical scenario
(Table 31.8).83,85 It has been suggested that CRRT is best
suited for those patients demonstrating severe hemody­
namic instability, persistent ongoing metabolic acidosis,
and large fluid removal requirements. Preliminary reports
using CRRT in the thermally injured population have dem­
onstrated improved survival.86,87 These studies are limited
to single-institutional data.
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 dialy­
sis in the setting of chronic renal failure) are less relevant
Table 31.8  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
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
aLess removal of amino acids, endogenous hormones, and
cofactors
bIncreased 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
aEven with high flux membranes, removes fewer ‘middle’ molecules.
bWhen configured to use convection as its primary mechanism of solute clearance, removes more “middle molecules.”
From Brochard L, Abroug F, Brenner M, et al. 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 ARF in the ICU patient: an international consensus conference in intensive care medicine.
Am J Respir Crit Care Med. 2010;181(10):1128–1155.

31  •  Acute Renal Failure in Association with Thermal Injury
327
morbidity and mortality. Prior to 1965, there were no
reported survivors following a major thermal injury who
unfortunately developed ARF. While significant advances
have been made in both the treatment of major thermal
injures and renal failure over the past 50 years, the com­
bined clinical scenario still represents a significant thera­
peutic challenge in modern burn therapy. Collectively we
have made advances in establishing a common definition of
renal failure and its stages, but work must continue to iden­
tify early biomarkers of renal injury so that therapeutic
interventions can be made in a more timely manner.
An astute burn surgeon or intensivist must understand
that the normal renal physiology is under constant threat
following a thermal injury. To avoid renal dysfunction, a
physician must maintain adequate effective renal perfusion
while minimizing nephrotoxic agents.
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such, we favor early initiation of RRT in severe burn-
associated AKI. However larger studies are clearly
needed to clarify the value of this approach in the burn
population.
A theoretical benefit of continuous hemofiltration is the
removal of proinflammatory mediators, which may be
associated with the development of multiple organ failure.
The experimental and clinical data suggest that the rate of
hemofiltration and the biologic nature of the filters affect
the overall results.20 Currently there are insufficient data to
recommend continuous hemofiltration solely on the basis
of removal of inflammatory mediators. Future randomized
prospective studies may resolve this theoretical benefit.
Conclusion
Acute renal dysfunction is a critical complication of an
acute thermal injury and is associated with significant

327.e1
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2002;28(2):167-172.
72. Jeschke MG, Barrow RE, Wolf SE, et al. Mortality in burned children
with acute renal failure. Arch Surg. 1998;133(7):752-756.
73. Poeze M, Solberg BCJ, Greve JWM, 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.
74. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-
pressure target in patients with septic shock. N Engl J Med.
2014;370(17):1583-1593.
75. Cochran A, Edelman LS, Saffle JR, et al. The relationship of serum
lactate and base deficit in burn patients to mortality. J Burn Care Res.
2007;28(2):231-240.
76. Heegard KD, Stewart IJ, Cap AP, et al. Early acute kidney injury in
military casualties. J Trauma Acute Care Surg. 2015;78(5):988-993.

328
Critical Care in the Severely
Burned: Organ Support and
Management of Complications
DEREK M. CULNAN, WILLIAM C SHERMAN, KEVIN K. CHUNG, and STEVEN E. WOLF
32 
It is postulated that the progression of patients to MOF
exists in a continuum with the systemic inflammatory
response syndrome (SIRS).6 Nearly all burn patients meet
the criteria for SIRS as defined by the consensus conference
of the American College of Chest Physicians and the Society
of Critical Care Medicine.7 It is therefore not surprising that
severe critical illness and MOF are common in burned
patients.
Patients who develop dysfunction of various organs,
such as the cardiopulmonary system, renal system, and
gastrointestinal system, can be supported to maintain
homeostasis until the organs repair themselves or a chronic
support system can be established. Critical care may be
loosely defined as the process of high-frequency physiologic
monitoring coupled with short response times for pharma­
cologic and procedural interventions. Entire textbooks and
many of the preceding chapters in this book are dedicated
to critical care. This chapter will focus on synthesizing a
critical care system for burn injury, including the organiza­
tion of specialized burn intensive care units (BICUs) and
organ-specific management.
Burn Intensive Care Unit
Organization
PHYSICAL PLANT
Optimally, a BICU should exist within a designated burn
center, ideally verified by the American Burn Association
(ABA), and 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 nonburned
trauma patients. In fact, the requirement for the care of
wounds in burned patients necessitates additional equip­
ment, such as shower tables and overhead warmers, so a
separate space dedicated to the severely burned should be
standard. This space may be located in a separate hospital
with established guidelines for transfer or a specialized unit.8
The optimal number of beds in the unit should be calcu­
lated by the incidence of moderate to severe burns in the
referral area, which in the United States is approximately
20 per 100,000 people per year. The Committee on Trauma
of the American College of Surgeons and the ABA recom­
mend 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 acceptable
access to specialized care.8
Videos available at
Introduction
Approximately 4000 burn victims die each year from com­
plications related to thermal injury.1,2 Burn deaths gener­
ally occur in a bimodal distribution, either immediately
after the injury or weeks later due to multisystem organ
failure (MOF), a pattern covered in Chapter 30. Recent
reports reveal a 50% decline in burn-related deaths and
hospital admissions in the United States over the previous
20 years.2 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 statistics
have improved, with the latest studies reporting a 50% mor­
tality for greater than 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, and
the prospects for the older demographic are improving with
modern wound treatment and critical care techniques.
Burned patients generally die from one of two causes:
early deaths resulting from “burn shock” and immolation,
or MOF leading to late deaths. With the advent of vigorous
fluid resuscitation protocols in the severely burned, irre­
versible burn shock has been replaced by sepsis and the
ensuing MOF 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 a risk of mortality who do not die pre­
cipitously will be treated by what is termed critical care, a
service performed in specialized units containing the equip­
ment, supplies, and personnel to institute intensive moni­
toring and life-sustaining organ support to promote
recovery.
Critical illness in burned patients is most commonly beset
by sepsis. In a pediatric burn population with massive burns
of greater than 80% TBSA, 17.5% of the children devel­
oped sepsis, defined as bacteremia with clinical signs of
infection.5 Mortality in the whole group was 33%, most of
whom succumbed to MOF. Some were bacteremic and
“septic,” but the majority were not. These findings highlight
the observation that the development of severe critical
illness and MOF often associate with infection, but they are
by no means required to develop this syndrome. What is
requisite is an inflammatory focus, which is the massive
skin injury in severe burns requiring inflammation to heal.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
329
Most moderate to severe burns with hospital admission
will require intensive monitoring for at least the day of
admission during the resuscitative phase. Thereafter
approximately 20% will undergo prolonged cardiopulmo­
nary monitoring for inhalation injury, burn shock, cardio­
pulmonary compromise, renal dysfunction, and the
development of SIRS and MOF. In these severely burned
patients, the average length of stay in the BICU is approxi­
mately 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 sug­
gests 132 BICU inpatient days per 100,000 persons in the
catchment area. Thus a 10-bed BICU should serve a popula­
tion of 3,000,000 sufficiently when considered indepen­
dently. Space provided should be at least 3,000 sq ft,
including patient beds and support space for nursing/
charting areas, office space, wound care areas, and storage.8
Multiply-resistant bacteria and fungi are commonly
encountered in the BICU owing to the presence of open
wounds. To prevent transmission of these organisms to
other patients, isolation of burned patients from all other
patients is recommended and should be considered when
designing units for this purpose. Single rooms with negative-
pressure ventilation are advisable. In addition, strict guide­
lines for contact precautions in wound care and
interventions, and hand-washing are standard.
PERSONNEL
A BICU functions best by using a team approach among
surgeons/intensivists, nurses, laboratory support staff,
respiratory therapists, occupational and physical thera­
pists, mental health professionals, prosthetists, dietitians,
and pharmacists (Box 32.1). The unit should have a desig­
nated medical director, ideally a burn surgeon, to coordi­
nate and supervise personnel, quality management, and
resource utilization. The medical director will usually work
with other qualified surgical staff to provide sufficient care
for the patients. It is recommended that medical directors
and each of their associates be well versed in critical care
techniques and that each physician care for at least 50
patients per year to maintain skills.8 In teaching hospitals,
three to four residents or other qualified medical providers
should be assigned to the 10-bed unit described. A coverage
schedule should be devised to provide 24-hour prompt
responses to problems.
Nursing personnel should consist of a nurse manager
with at least 2 years of intensive care and acute burn care
experience and 6 months of management responsibilities.
The rest of the nursing staff in the BICU should have docu­
mented competencies specific to the care of burned patients,
including critical care and wound care.8 Owing to the high
intensity of burn intensive care, at least five full-time equiv­
alent nursing providers are required per BICU bed to provide
sufficient 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 32.2). As such,
these specialists should be available for consultation when
the need arises. Given the regularity with which burn sur­
geons encounter subspecialty problems, such as corneal
injuries, routine injuries are often managed directly by the
burn surgeon without additional consultation.
EQUIPMENT
The equipment needs of the BICU include those items
common to all ICUs, but some of which are specialized (Box
32.3). Each BICU bed must be equipped with monitors to
Box 32.1  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
■ Phychiatrists and clinical psychologists
■ Prosthetists
Box 32.2  Consultants for the Burn ICU
■ 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
Box 32.3  Equipment for a Fully Equipped
Burn ICU
Standard
■ Monitors (heart rate, electrocardiography, blood pressure,
cardiac output, oxygen saturation, temperature)
■ Scales
■ Ventilators
■ Advanced cardiac life support (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

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
330
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 perfusion because 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 sphygmomanome­
ters; 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 instabil­
ity through the use of intraarterial catheters is generally
preferable when the patient is in the BICU for a prolonged
period. Lines are typically placed in either the radial or the
femoral artery. The radial artery is the preferred site for
critically ill patients because of safety, with the dual arterial
supply to the hand as backup should a complication arise.
However it has been shown that radial artery catheters are
inaccurate in the measurement of central blood pressure
when vasopressors are used11 and are notoriously inaccu­
rate in children because of greater vascular reactivity.12
Furthermore femoral cannulation sites are often unburned
due to the insulation provided by undergarments, and they
do not preclude mobilization with physical therapy or reha­
bilitation goals.13 For these reasons, we recommend femoral
arterial blood pressure measurement in most burned
patients.
For arterial catheters, systolic, diastolic, and mean arte­
rial pressures (MAPs) should be displayed continuously on
the monitor screen. Either systolic or MAP can be used to
determine adequacy of pressure, although a MAP of greater
than 70 mm Hg is considered a more accurate descriptor
of normal tissue perfusion on the whole. Reasons for this
include the finding that, as the arterial pressure wave tra­
verses proximally to distal, the systolic pressure gradually
increases and the diastolic pressure decreases; the MAP
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 replacement. Care
must be taken to ensure that the diminished waveform is
not true hypotension, which can be determined using a
manual or cycling sphygmomanometer. Exaggerated wave­
forms with elevated systolic pressure and additional peaks
in the waveform (generally only two are found) may be
a phenomenon known 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 normal systolic blood pressure
values with evidence of catheter whipping as unexceptional
because the effect generally overestimates pressures. Again,
use of MAP as the principal guideline for the assessment
of blood pressure is optimal, as effects of catheter whip
or other problems with intraarterial monitoring are then
diminished.
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. Arterial blood
oxygen saturation measurement is also required, but con­
tinuous mixed venous saturation monitoring or the techni­
cal equivalent is optional. Equipment to measure weight
and body temperature should be standard. Oxygen avail­
ability with at least two vacuum pumps must be present for
each bed.
Ventilator 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 modes,
as well as high-frequency ventilators that are oscillatory
and/or percussive in design. An emergency cardiac cart
containing advanced cardiac life support (ACLS) medica­
tions and a battery-powered electrocardiograph/defibrillator
must be present in the unit. Infusion pumps to deliver con­
tinuous medications and intravenous/intraarterial fluids
must also be readily available. A laboratory providing blood
gas analysis, hematology, and blood chemistry should be
located on site. Point-of-care blood analysis for glucose,
arterial blood gas, and basic chemistries is strongly
advised.9,10 Microbiologic support to complete frequent,
routine bacterial and fungal cultures and sensitivities must
also be present, as well as virology.
Available specialty equipment should include various
sizes of fiberoptic bronchoscopes for the diagnosis and treat­
ment of pulmonary disorders, as well as personnel compe­
tent with these techniques. Fiberoptic gastroscopes and
colonoscopes for gastrointestinal complications are also
necessary for diagnosis, bleeding control, decompression,
and difficult feeding access. For renal support, equipment to
provide intermittent and/or continuous renal replacement
should be present. Portable radiographic equipment for
standard chest/abdominal/extremity radiographs must be
immediately available. Equipment for computed tomogra­
phy (CT), fluoroscopy, and angiography should be available.
Indirect calorimeters to measure metabolic rate are strongly
advised. Overhead warmers and central heating with indi­
vidualized ambient temperature controls must be available
for each room as a specialized requirement.8
Hemodynamic Monitoring in the
Burn Intensive Care Unit
Most burned patients follow an anticipated course of
recovery, which is monitored in the BICU by measuring
physiologic 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 neces­
sary from the unit’s standard care protocol as the patient
is following the anticipated course. At other times this is
not the case, and procedural or pharmacologic interven­
tion 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.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
331
significantly diminished except in special circumstances,
such as unexpected response to treatment, as in volume
replacement for oliguria. Even in this condition, new tech­
nology based on arterial waveform analysis gives an esti­
mate of cardiac output and end-diastolic volume, which
generally gives enough information to guide appropriate
therapy.19 However, in the appropriate patients, pulmonary
artery catheters may still play a valuable role.
Arterial Waveform Analysis
Multiple devices have been developed over the past decade
using arterial waveform analysis to continuously measure
cardiac output as well as to estimate preload. Stroke volume
variation provides a good estimate of the fluid responsive­
ness of shock with only arterial access.20 The transpulmo­
nary thermodilution technique provides an even more
complete hemodynamic dataset without the use of a pul­
monary artery catheter. Using only a central line and
central arterial line, thermodilution allows monitoring of
preload with global end-diastolic volume index, intratho­
racic blood volume, continuous cardiac output, and extra­
vascular lung water index. Numerous studies have shown
that these volumetric indices represent preload more pre­
cisely than urine output or cardiac filling pressures.21 In a
study involving 54 burned children, Herndon et al. deter­
mined pulse index continuous cardiac output (PiCCO) to be
the superior measurement for cardiac parameters to trans­
thoracic echocardiography and an objective cardiovascular
monitor to guide goal-directed fluid resuscitation.22
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 hemody­
namic function, it stands to reason that it could be used to
monitor 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 and showed that intravascular volume and cardiac
contractility are significantly diminished the first day after
burn in spite of high-volume resuscitation.23
Echocardiography has also been studied as a means to
supplement urine output monitoring. Investigators in
China examined whether esophageal Doppler monitoring
of heart function might be an improvement by studying 21
patients with massive burns (79 ± 8% TBSA burned) who
were resuscitated with a goal of 1.0 mL/kg per hour. 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.24 Held et al. evalu­
ated 11 adult burn patients with a mean TBSA of 37% and
found that changes in volume status on echocardiography
preceded changes in urine output and vital signs, and they
were able to titrate inotropes and vasopressors in elderly
patients.25
Complications associated with arterial catheters include
distal ischemia associated with vasospasm and thromboem­
bolism, catheter infection, and arterial damage/pseudo-
aneurysm during insertion and removal. Although these
complications are uncommon, the results can be devastat­
ing. Physical evidence of ischemia in the distal hand or foot
should prompt immediate removal of the catheter and ele­
vation of the extremity. If improvement in ischemic symp­
toms is not seen promptly (within an hour), angiography
and intervention must be considered. Should thromboem­
bolism 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.
Consideration for anticoagulation must be made while bal­
ancing the risk of hemorrhage from open wounds versus
the benefit of tissue salvage.
Evidence of catheter infection hallmarked by purulence
and surrounding erythema should instigate removal of the
catheter, which often will 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 pseudo-aneurysm is encountered after arterial
catheterization and removal without signs of distal ische­
mia, injection of thrombin14 or compression with a vascu­
lar ultrasound device until no further flow is seen in the
pseudo-aneurysm will often alleviate the problem without
operative intervention.15
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
BICUs. By measuring the back pressure through the distal
catheter tip “wedged” into an end-pulmonary branch, an
estimate 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 BICUs under
conditions 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 surgical ICUs showed an increase in mortal­
ity 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 evaluation of the use of pulmonary
artery catheters under all conditions.16 This was followed
by a clinical trial in the United Kingdom demonstrating
no benefit from the use of pulmonary artery catheters in
a general ICU setting.17 A more recent evaluation of the
usefulness of these devices has demonstrated that, with
proper training and in the appropriate setting, they can
provide data not available through other modalities.18 Over
the past years, the use of pulmonary artery catheters has

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
332
metabolism is lactic acid. Under ischemic conditions, plasma
lactate concentration will increase, leading to a decrease in
pH. Measurement of lactate is commonly performed to
determine the adequacy of generalized 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.34 Later in the course, however, lactate concen­
trations must be used with some caution because elevated
levels do not necessarily indicate ischemia. Under hyper­
metabolic conditions common in the severely burned, pyru­
vate dehydrogenase activity is sufficiently inefficient 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 sought.
Multisystem Organ Failure
MOF is largely a creation of our success in critical care
enabling previously moribund patients to survive long
enough for organ failure to develop. Often particular organ
systems are allowed to fail to maintain overall patient sur­
vival (e.g., performing an excision and grafting procedure
that leads to renal failure to remove a septic burn which
would otherwise be lethal). The topic of MOF is more thor­
oughly covered in Chapter 30, but we will briefly summa­
rize it here.
HUMORAL MEDIATORS
Humoral inflammatory factors elaborated from the burn
wound and the resultant immune, adrenal, and sympa­
thetic activation mediate the development of SIRS.
A number of theories have been developed to explain the
progression to MOF (Box 32.4). In the infection theory, as
organisms proliferate out of control, endotoxins and exo­
toxins are released that cause the initiation of a cascade of
inflammatory mediators through activation of pathogen-
activated molecular pathway (PAMP) receptors, such as
Toll-like receptors 2, 4, and 9,35 as well as the recruitment
of inflammatory cells. These pathways can result in organ
damage and progression toward MOF if unchecked.
MOF can also be initiated by inflammation from the pres­
ence of necrotic tissue, and open wounds can incite a
similar inflammatory mediator response to that seen with
endotoxins. Evidence suggests that this response is due to
activation of the cytokine cascade through damage-
associated molecular pathways (DAMPs), which might be
These results call into question the validity of urine
output as the primary measure of the adequacy of resusci­
tation. A similar study by investigators in Sweden probing
the role of cardiac function, as measured by echocardiog­
raphy, and myocyte damage, as measured by troponin
abundance in the serum, showed that half of their patients
had myocardial damage during resuscitation universally
associated with some temporary cardiac wall motion abnor­
mality. However systolic function was not adversely
affected.26 Bedside echocardiographic equipment and skills
are increasingly common in BICUs and are an increasingly
common means of hemodynamic monitoring in critical
care.27 However the intermittent nature of this procedural
assessment allows it to only serve as a useful adjunct to add
clarity to a difficult clinical scenario and prevents echocar­
diography from supplanting continuous monitoring modal­
ities, such as thermodilution or waveform analysis. We look
forward to further work regarding the optimal method of
assessment of resuscitation; for the present, however, urine
output remains the standard, and other measures are useful
adjuncts.
Laboratory Estimates of Perfusion
Mixed venous saturation is the gold standard for the mea­
surement of total tissue perfusion but has fallen out of favor
because it requires a pulmonary artery catheter.28 As such,
peripheral surrogates, such as base deficit and serum
lactate, have become the standard values followed to
monitor shock. These can be measured in minutes using
point-of-care techniques and rapid guide interventions.
The base deficit is a value calculated using the Henderson-
Hasselbalch equation based on the relationship between
pH, pCO2, and serum bicarbonate:
pH
HCO
pCO
=
+
−
6 1
0 03
3
2
.
log(
) (
)( .
)
It 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.29 The same can
be said for the use of base deficit in resuscitation of burned
patients.30,31 These studies showed a correlation between
higher base deficit and increased mortality, and some have
suggested that this value is a better monitor of resuscitation
than the time-honored monitors of urine output and arte­
rial blood pressure.32 Recent studies of burned patients
showed the base deficit was higher in nonsurvivors during
resuscitation, although the authors could not identify a spe­
cific boundary for the effect.33,34 Despite its utility as an
indicator of shock, base deficit remains a nonspecific indica­
tor of metabolic acidosis and may be elevated with many
confounding conditions other than shock, including hyper­
chloremia, uremia, and alcohol, cocaine, and methamphet­
amine use. Interpretation can be difficult under these
circumstances.
Lactate is another common measure used to determine
the adequacy of tissue perfusion. Under acute low-flow con­
ditions, cells transition from primarily aerobic metabolism
to anaerobic metabolism for energy production (i.e., ade­
nosine triphosphate [ATP]). A by-product of anaerobic
Box 32.4  Theories for the Development of
Multiple Organ Failure
■ Infectious causes
■ Macrophage theory
■ Microcirculatory hypothesis
■ Endothelial–leukocyte interactions
■ Gut hypothesis
■ Two-hit theory

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
333
■ Sufficient goal-directed fluid resuscitation
■ Early burn excision and grafting
■ Aggressive antimicrobial and source control of sepsis
■ Aggressive and sufficient nutritional support
■ Active warming
■ Aggressive physical, occupational, and respiratory
therapy
■ Aggressive and continuous support of organ failures
Sufficient fluid resuscitation of an acute burn wound is
thoroughly covered in Chapter 9 on fluid resuscitation.
Various formulas to predict fluid requirement, balances
between crystalloid versus colloid, and resuscitation end­
points have been advocated. Early in resuscitation it is criti­
cal to provide sufficient volume to maintain preload and
perfusion in the setting of fluid losses into burn edema and
distributive shock while avoiding over-resuscitation, with
the resultant costs such as heart failure, liver failure, and
compartment syndromes.46
Early burn excision and grafting has been discussed
thoroughly in Chapter 12 on operative management. The
overriding principle is to remove inflammatory and dis­
eased burned tissue to break the hyperinflammatory state
underlying burn shock. Early grafting reduces the inflam­
matory load on the patient, fluid loss, heat loss, the area
susceptible to infection, and the total length of critical care.
Collectively it reduces the exposure time available for MOF
to occur.
Furthermore, the blood loss associated with large-scale
early excision often results in a functional plasma
exchange.47 Plasma exchange has been shown to be effec­
tive in reducing burn resuscitation, ostensibly by removing
the inflammatory and oxidative humoral mediators under­
lying burn shock. Klein et al. reviewed 44 plasma exchanges
in patients reaching twice Parkland with albumin or fresh
frozen plasma and found a 40% reduction in fluid resuscita­
tion.48 In a plasma exchange protocol triggered at 1.2 times
Parkland, Neff et al. found a 24% increase in MAP, 400%
increase in urine output, and 25% reduction in resuscita­
tion rate, with a reduction in lactic acid as well.49 In 37
patients undergoing plasma exchange with a mean TBSA
of 48.6%, hourly fluid, base deficit, lactate, and hematocrit
all improved and were associated with decreased resuscita­
tion volume and increased urine output.48 Collectively these
data support the notion that plasma exchange improves
burn shock; however there are thus far no studies directly
linking plasma exchange resulting from intraoperative
blood loss with improvements in burn outcome demon­
strated in early burn excision.
Chapter 11 on infection control well defines the criti­
cal nature of early surgical source control and appropriate
antimicrobials, but generally emphasizes that meticulous
aseptic technique, excision of infected or devitalized tissue,
coverage with viable grafts, topical antimicrobials, culture
surveillance, and systemic antimicrobials when appropri­
ate are critical components.50 Similarly, Chapters 28 and
29 on nutrition support and hypermetabolism, respec­
tively, effectively discuss the critical need for enteral
feeding and nutritional support, physical therapy, and
the requirement to keep patients warm. The remainder
of this chapter is directed toward organ-specific critical
care support.
antigens associated with liberated mitochondria from our
own cells.37 Four of these cytokines, tumor necrosis factor-α
(TNF-α), interleukin-1β (IL-1β), IL-6, and IL-8, are most
strongly associated with sepsis and MOF in burns.36 The
primary support of this theory is that many patients,
including those burned, can develop MOF without identi­
fied infection. Regardless, it is known that a cascade of sys­
temic events is set in motion, either by invasive organisms
or from open wounds, that initiates SIRS and may progress
to MOF, thus supporting early burn excision and grafting.
Another theory implicates prolonged tissue hypoxia and
the subsequent generation of toxic free radicals during
reperfusion as the primary mediator of end-organ damage.
As discussed in Chapter 8 on burn edema, this free radical
damage can be ameliorated with high-dose intravenous
vitamin C during resuscitation.38 From in vitro models and
in vivo animal models, we know tissues that were in shock
initially and subsequently reperfused produce oxygen free
radicals known to damage a number of cellular metabolism
processes. It was found that free radical scavengers, such as
superoxide dismutase, improve survival in animal models,
but these results have not yet been established in humans.42
Endogenous natural antioxidants, such as vitamins C and
E, are low in burned patients, suggesting that therapeutic
interventions may be beneficial.43
The final two theories revolve around the role of the gut
in the generation of organ failure and the “two-hit” theory
of MOF. For years, investigators have implicated the gut as
the “engine” of organ failure, which is associated with loss
of gut barrier function and translocation of enteric bacteria
and/or their toxic metabolites. Bacterial translocation has
been shown to occur after burn in patients.45 No studies
have clearly shown whether bacterial translocation is the
cause of SIRS/MOF, probably because investigators have as
yet been unable to control bacterial translocation effectively
during shock in humans; thus, a cause-and-effect relation­
ship cannot be established. The “two-hit” theory ascribes a
summation of insults to the development of MOF. Each of
the insults alone is inadequate to cause the response, but
one or more can “prime” the inflammatory response system
just described, such that another normally insignificant
injury causes the release of toxic mediators ending in MOF.
It is likely that some part of all of these theories is a cause
for MOF in burned patients; probably the relative contribu­
tion is unique in each patient. Therefore a single solution is
unlikely, and this should be kept in mind when devising
strategies to improve care and outcomes.
COURSE OF ORGAN FAILURE
Generally, MOF will begin in the renal and/or pulmonary
systems and progress in a systematic fashion through the
liver, gut, hematologic system, and central nervous system.
The development of MOF does not inevitably lead to mortal­
ity, however. Efforts to support failed organs until they
recover are justified.
Critical Care Interventions
Critical care of a burn patient in the modern era is predi­
cated upon seven key factors:

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
334
narcotics.51 Interventions required for the patient to heal,
such as physical therapy or wound care, will create a certain
amount of pain that cannot be fully alleviated without pre­
venting the patient’s progress.54 The burn team must assess
the patient’s pain management and use their experience to
carefully balance short-term analgesia with long-term
recovery and function.
Additional analgesics of short duration should be used
for painful procedures, such as extensive wound care or
staple removal. Often additional narcotics, such as fentanyl
or additional morphine, are sufficient. For more extensive
procedures ketamine is a safe, effective, and recommended
agent. Several large series support ketamine use in nurse-
driven protocols. In a series of 522 painful procedures in
pediatric burn patients, only 2.9% required intervention
such as airway repositioning, zero intubations in lengths
from 1 to 105 minutes and weights from 2 to 111 kilo­
grams.55 A meta-analysis of 8282 ketamine sedations from
32 ED studies demonstrated no intubations. There was a
0.8% rate of transient apnea and 0.3% rate of laryngo­
spasm; however all were resolved with positioning and/or
bag valve masking.56 In these studies, trained nurses typi­
cally performed the sedation. Ketamine has a favorable
safety profile relative to benzodiazepine and narcotics due
to its lack of respiratory depression and its cardiovascular
stimulating effects.54 Care should be taken to prevent emer­
gence delirium in adult patients.
Sedation in the BICU is more complicated, requiring the
balance of short-term sedative goals and apparent patient
comfort with the intermediate costs of delirium and
decreased therapy participation, as well as with long-term
neuropsychiatric costs. The first goal is to minimize seda­
tion administered, which is accomplished best with the use
of a sedation scale and avoiding continuous benzodiazepine
infusions. The use of the Richmond Agitation Sedation
Scale has been shown to decrease mean duration of ventila­
tor and sedation consumption.57
Benzodiazepines have reduced utility due to increased
delirium and length of mechanical ventilation. Propofol,
ketamine, and remifentanil have been increasingly used as
alternatives to the formerly standard benzodiazepine-based
therapies.58 When compared directly to midazolam, patients
sedated with the α-adrenergic agonist dexmedetomidine
have required less sedation and have less hypotension. This
sedative can be considered more effective, as well as being
less of a risk in terms of hypotension.59 Benzodiazepines are
associated with an increased risk of agitation and delirium,
and benzodiazepine and propofol are associated with more
ventilator-associated events than dexmedetomidine. Dex­
medetomidine is associated with less time to extubation and
higher rates of bradycardia, but this is generally well toler­
ated in burn patients due to their hyperdynamic state and
tachycardia.60 The less expensive oral equivalent, clonidine,
is a common adjuvant to sedation working on a similar
α-adrenergic mechanism as dexmedetomidine; it is cur­
rently under meta-analysis for that role.61 Ketamine infu­
sion has been shown to be safe and effective in continuous
BICU sedation as well.62
Psychiatric and psychological care is a critical compo­
nent of BICU care. Standard psychological therapies and
interventions are important factors of burn care.63 The
critical care team can help prevent delirium and PTSD by
TOXICOLOGICAL BURN CRITICAL CARE
Many toxins can affect the burn-injured patient, particu­
larly with occupational injuries. Specific therapies for all
toxins are beyond the scope of this chapter and require
appropriate decontamination, antidotes, and consultation
with material data safety sheets and poison control centers
for known exposures if beyond the burn physician’s comfort.
However the most common toxins are cyanide and carbon
monoxide.51 Cyanide can be elaborated from the combus­
tion of various plastics, and significant exposure can result
from smoke inhalation. Mounting evidence indicates that
cyanide toxicity is clinically significant in inhalation inju­
ries, being found at clinically significant levels in up to 76%
of inhalation injury patients. Few clinical labs return blood
cyanide labs in a clinically useful time scale, so surrogate
markers of less than 15% TBSA with smoke inhalation,
Glasgow Coma Scale (GCS) under 14, abnormal hemody­
namics, and/or a lactate level of greater than 10 are known
sensitive indicators of cyanide toxicity of greater than
1.0 mg/L. In these cases, empiric therapy is recommended
with hydroxycobalamin.52 It is the first-line antidote for
cyanide toxicity and has a very mild side effect profile of
transient hypertension, bradycardia, and urine discolor­
ation. Hydroxycobalamin is also a nitric oxide scavenger
and effectively reduces the hypotension often seen in burn
shock.52
As a common product of combustion, carbon monox­
ide (CO) should be considered in any inhalation injury,
enclosed fire, or patient with altered mental status. Patients
with carboxyhemoglobin (COHb) levels above 25% should
be mechanically ventilated on 100% FIO2, which reduces
the half-life from 4 hours to 1 hour. There are rare indica­
tions for hyperbaric oxygen (HBO) because it can reduce
the CO half-life to 15 minutes, particularly in the setting
of pregnancy or seizures. HBO is only indicated in the burn
setting if it can be immediately employed in conjunction
with definitive burn care in specialized centers. For cases
where instituting HBO unnecessarily delays burn care,
mechanical ventilation can bring COHb to safe levels prior
to HBO’s institution, and appropriate burn care should take
precedence.53
NEUROLOGICAL BURN CRITICAL CARE
The main aspects of neurologic management of burn
patients are pain control, sedation, delirium management,
and management of acute stress disorder or posttraumatic
stress disorder (PTSD). Furthermore there can be a need for
seizure treatment or prophylaxis, management of the trau­
matic brain injury, or drug and alcohol withdraw protocols,
which can occur concomitantly with the burn injury and
are beyond the purview of this chapter. An important com­
ponent of neurological care is early mobilization; physical/
occupational therapy should be performed unless firmly
contraindicated.13
Pain control is the most common neurologic intervention
in the burn patient. Basal pain management with narcotics
such as morphine is administered as needed to maintain
comfort, while taking care to avoid oversedation that can
prevent achieving physical therapeutic goals. Methadone
can help by providing basal pain coverage and weaning of

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
335
transpulmonary thermodilution. These measures can be
used to optimize preload, balancing vascular volume
loading and cardiac performance against interstitial and
pulmonary edema.
Cardiac Contractility
The force with which the heart contracts is referred to as
cardiac contractility. It is directly related to the number of
fibers contracting, their preload and afterload. Contractility
is diminished in patients with low preload or high afterload,
in coronary artery disease with loss of myocardium from
infarction and ischemia, in burned patients during the
acute resuscitation due to myocardial depressant factor, in
septic shock with Takotsobu cardiomyopathy, or in severely
malnourished patients. Calculating the left ventricular
stroke work from pulmonary artery catheter-derived values
provides the best estimate of cardiac contractility and can
be determined with the following formula:
LVSW
SV MAP
PCWP
=
−
×
(
)
.
0 0136
where LVSW is left ventricular stroke work, SV is the stroke
volume (cardiac index ÷ heart rate), and PCWP is pulmo­
nary capillary wedge pressure. In current practice, the
contractility is usually tracked with arterial waveform con­
tinuous cardiac output monitoring or echocardiography.
Afterload
Afterload is the force impeding or opposing ventricular con­
traction and, in conjunction with cardiac output, creates
blood pressure. This force is equivalent to the tension devel­
oped across the wall of the ventricle during systole. Clini­
cally afterload is measured by arterial resistance as an
estimate of arterial compliance. Arterial resistance is
avoiding benzodiazepine, minimizing sedation, treating
pain first, limiting sleep disturbances, encouraging mobil­
ity, reorientation, and avoiding prolonged infusion of seda­
tives.64 Despite our best efforts, many patients in the BICU
experience delirium and agitation. Haloperidol remains in
use in critical agitation and delirium settings and has docu­
mented safety in pediatric and adult burn populations.65
Atypical antipsychotics have gained a substantial role in
basal coverage of delirium and agitation and are safe and
effective. The BICU team must remember to discontinue
these medications when patient are no longer delirious;
84.2% of patients started in the BICU continued use after
discharge from BICU, and 28.6% continued following dis­
charge from the hospital.66
CARDIOVASCULAR BURN CRITICAL CARE
Treatment of cardiovascular responses after burn requires
an understanding of cardiovascular physiology and the
effects of treatment. One of the hallmarks of serious illness
is the direct link between cardiac performance and patient
performance. Cardiac compensation to burn injury is
hyperdynamic to meet hypermetabolic needs, maintain per­
fusion of injured vascular beds, and compensate for the
vasoplegia associated with burn shock. As such, patients
often require supraphysiologic cardiac output to compen­
sate for their systemic pathology.67 The four determinants
of cardiac function and hence tissue perfusion are:
■ Ventricular preload or end-diastolic muscle fiber length
■ Myocardial contractility or strength of the heart
muscle
■ Ventricular afterload, or the degree of resistance
against which the heart must pump
■ Heart rate and rhythm
A thorough comprehension of the effects of each of these
components on heart function is necessary to initiate effec­
tive treatments for burned patients with cardiovascular
abnormalities.
Preload
Preload is the force that stretches the cardiac muscle prior
to contraction. This force is composed of the volume that
fills the heart from venous return. Due to the molecular
arrangement of actin and myosin in muscle, the more the
incoming venous volume stretches the muscle, the further
it will contract. This is best demonstrated on a Frank–
Starling curve (Fig. 32.1), first described by Otto Frank in a
frog heart preparation in 1884; Ernest Starling extended
this observation to the mammalian heart in 1914. The rela­
tionship demonstrated in the Frank–Starling curve justifies
the use of preload augmentation by volume resuscitation to
increase cardiac performance. However when the end-
diastolic volume becomes excessive, cardiac function can
decrease; probably the muscle fibers overstretch and pull
the contractile fibers past each other, thereby reducing the
contact required for contractile force. The preload neces­
sary to reduce cardiac function in experimental settings is
in excess of 60 mm Hg, which is rarely encountered in
patients.
Preload is estimated clinically by central venous pressure,
pulmonary artery wedge pressure, echocardiography, or
Volume
Pressure
Frank–Starling curve
Fig. 32.1  Frank–Starling curve. The solid line depicts the pressure–
volume relationship of the heart, showing that as pressure to the heart
(preload) increases, the volume pumped by the heart increases. Imme­
diately after burn, contractility diminishes, shifting the curve down­
ward (dashed line). It still must be noted that, with this change, the
volume pumped by the heart still increases with increased pressure
(preload), validating the use of increased atrial pressure as a means of
increasing cardiac output after severe burn.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
336
Excessive volume administration may lead to significant
interstitial edema and volume overload, with the develop­
ment of peripheral and pulmonary edema. These changes
can lead to conversion of partial-thickness burns to full-
thickness injuries in the periphery and cause significant
respiratory problems, liver failure, and compartment syn­
drome. Once hemodynamics are restored, fluid overload
can be treated with spontaneous diuresis, pharmacologic
diuresis, dialysis, or even therapeutic phlebotomy if
required.
Hemodynamic Therapy: Inotropes and Vasopressors. 
If preload optimization is insufficient to improve hemody­
namics, patients may require inotropes to increase cardiac
output and/or vasopressors to increase afterload. Inotrope
classes include phosphodiesterase inhibitors, digoxin, and
adrenergic agonists. Phosphodiesterase inhibitors like mil­
rinone increase contractility and decrease afterload without
increasing myocardial oxygen demand by raising intracel­
lular cyclic adenosine monophosphate (cAMP) levels to
increase myocyte calcium (Ca2+) levels. Digoxin increases
contractility and decreases heart rate without increasing
myocardial oxygen demand by inhibiting the sodium/
potassium (Na+/K+) pump and increasing intracellular Ca2+.
Dobutamine is a commonly used inotrope with effects
limited to β-adrenergic stimulation, thereby increasing CO
and causing vasodilation. Dobutamine can be associated
with increased heart rate and does increase myocardial
oxygen demand. The associated vasodilation may be useful
in perfusing peripheral vascular beds, as in threatened skin.
The data support dobutamine reducing extravascular lung
water and decreasing SVR index with increasing cardiac
index and urine output, despite the global end-diastolic
volume index (GEDI) being unchanged.70
Catecholamines, the most commonly used medication to
augment blood pressure, are considered “inoconstrictors”
because they have both inotropic and vasoconstrictive
properties. One caveat regarding the use of these inocon­
strictors is that myocardial oxygen consumption increases,
which may affect the ischemic areas of the heart. However
the hypotension being treated by the catecholamines will
also compromise myocardial oxygen delivery substantially,
so this consideration should not preclude their use by an
experienced critical care burn physician. Epinephrine is the
catecholamine of choice because it provides a greater pro­
portion of its increase in blood pressure from inotropy
rather than vasoconstriction. However norepinephrine is
the preferred pressor in septic shock; its greater reliance on
vasoconstriction versus inotropy can compromise dermal
vascular beds critical to wound healing and survival in a
burn patient, particularly in the setting of inadequate
preload. Dopamine has generally fallen out of favor due to
tachyphylaxis and tachycardias.71 Therefore we consider
epinephrine the preferred catecholamine.
Pure vasoconstrictors have a very limited role in burn
care because concomitant inotropic support is advisable
due to the patient’s hyperdynamic state. Agents with
primary effects on the α-adrenergic receptor can be used to
induce vasoconstriction and increase blood pressure. Nor­
epinephrine is often considered in this group, although
40% of its increase in blood pressure is due to α-mediated
vasoconstriction, whereas 60% is from increased CO.72,73
measured as the difference between inflow pressure (mean
arterial) and outflow pressure (venous) divided by the flow
rate (cardiac output):
SVR
MAP
CVP CO
=
−
(
)
where SVR is systemic vascular resistance, CVP is central
venous pressure, and CO is cardiac output. Pulmonary
artery catheters, arterial waveform analysis, or echocar­
diography calculates this value.
Heart Rate and Rhythm
For the heart to function properly, the electrical conduction
system must be intact to provide rhythmic efficient contrac­
tions to develop sufficient force to propel blood through the
circulatory system. For example, if the heart rate approaches
200 beats/min, the heart will have insufficient time to fill
completely, thereby reducing myocardial fiber stretch and
heart function. Also, if frequent premature ventricular con­
tractions are present, the heart will not perform optimally,
for similar reasons. Heart rate and rhythm are monitored
continuously as routine in every critically ill patient using
electrocardiography. A combination of sympathetic and
adrenergic tone, combined with high atrial stretch, can pre­
dispose burn patients to atrial arrhythmias, such as atrial
fibrillation (AF). Judicious fluid and electrolyte manage­
ment, β-blockade, rate control, and the appropriate use of
antiarrhythmics are cornerstones of treatment. An impor­
tant note: mortality is higher in BICU patients after develop­
ing AF.68
Effects of Burn on Cardiac Performance
Severe burns affect cardiac performance in a plethora of
ways. The first is to reduce preload to the heart through
volume loss into burned and nonburned tissues. It is for this
reason that volumes predicted by resuscitation formulas
must be used to maintain blood pressure and hemodynam­
ics. In addition, severe burn induces myocardial depression
characterized by a decrease in tension development, and
velocities of contraction and relaxation. CO is then reduced.
These effects are most evident early in the course of injury
during resuscitation; however they are followed shortly
thereafter by a hyperdynamic phase of increased CO, pri­
marily caused by a decrease in afterload through vasodi­
lation and an increase in heart rate.
Hemodynamic Therapy: Preload Augmentation. 
When hypotension or other signs of inadequate cardiac
function (i.e., decreased urine output) are encountered, the
usual response is to augment preload by increasing intra­
vascular volume. This is a sound physiologic approach
based on the Frank–Starling principle and should be the
first therapy for any patient in shock. Intravascular volume
can be increased using either crystalloids or colloids to
increase the CVP and PCWP to a value between 10 and
20 mm Hg. Preload goals can also be stroke volume varia­
tion below 12% or global end-diastolic volume index
between 680 and 800 mL/m2.69 The adequacy of this
therapy can be monitored by the restoration of arterial
blood pressure, a decrease in tachycardia, and a urine
output of greater than 0.5 mL/kg per hour.
Some caution must be exercised when augmenting
preload for hemodynamic benefit in burned patients.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
337
thermoregulation. A nonspecific β-blocker, propranolol,
has been used to reduce heart rate and myocardial work
in severe burns.80 Propranolol administration also reduces
peripheral lipolysis81 and muscle catabolism,82 which are
additional benefits. Wurzer et al. demonstrated that pro­
pranolol reduced cardiogenic stress by reducing cardiac
index and MAP in severely burned, injured children without
reducing peripheral oxygen delivery or increasing lactic aci­
dosis events or organ dysfunction.83 Further trials are in
progress to define the benefits of β-blockade as well as its
interaction with other anabolic medications such as oxan­
drolone. Regardless β-blockade is becoming an increasingly
standard component of burn care.
PULMONARY BURN CRITICAL CARE
Lungs can be injured from inhalation injury, infection,
inflammatory mediators, heart failure, or a sequela of criti­
cal care interventions, such as fluid overload or ventilator
injury. Minor pathology can be treated with supplemental
oxygen, diuresis, bronchodilators, or mucolytics. However
mechanical ventilation is an essential treatment to manage
pulmonary failure.
Mechanical ventilation in the severely burned generally
occurs for three reasons: airway control during the resusci­
tative phase, airway management for smoke inhalation,
and support during acute respiratory distress syndrome
(ARDS). The first indication is for airway control early in the
course, with the development of massive whole-body edema
associated with the great resuscitative volumes required to
maintain euvolemia. In this situation, the need for mechan­
ical ventilation is not due to lung failure per se, but rather
to maintain the airway until the whole-body edema is
resolved. Once this occurs, usually 2–3 days into the course,
extubation can be accomplished with minimal sequela.
Ventilator management during this phase is routine. The
second indication is airway management early in the course
of smoke inhalation, which is a direct toxic injury to the
airways and alveoli resulting in mucosal sloughing, loss of
mucociliary escalator function, airway narrowing and
edema, loss of surfactant, weakening of cartilaginous
support of the airways, and fibrinous exudation into the
airways.53 Chapter 16 on inhalation injury comprehen­
sively covers this issue. The third indication is the develop­
ment of hypoxemia or hypercarbia due to a high
alveolar-arterial (A-a) gradient, shunting, ventilation/
perfusion (VQ) mismatching, poor compliance, or high
resistance. Severe burns are known to be associated with
hypoxemia and the development of ARDS. The clinical
manifestations are dyspnea, severe hypoxemia, and
decreased lung compliance, with radiographic evidence of
diffuse bilateral pulmonary infiltrates.
Indications for Intubation
Intubation entails passing an endotracheal tube from either
the nose or the mouth through the pharynx and into the
trachea. This tube is subsequently connected to a mechani­
cal ventilator to induce inspiration and passive exhalation.
In burned patients indications for intubation are, in general,
to improve oxygenation and ventilation or to maintain a
compromised airway, such as in a severe inhalation injury
or obtunded patient (Table 32.1).
Phenylephrine is a pure α-agonist, and can decrease CO and
perfusion.72,73 These agents are effective in septic shock or
neurogenic shock to increase vascular tone.74 However, in
burned patients, it is believed that these agents will cause
vasoconstriction of the skin and splanchnic circulation,
thereby redistributing blood flow. This can cause grafts to
fail and conversion of partial-thickness skin injuries to full-
thickness, as well as resulting in ischemic injury to the gut.
Additionally norepinephrine in both physiologic and phar­
macologic doses suppressed wound macrophage efficiency
in a cAMP-mediated manner via the adrenergic receptor.
This may be part of the benefit provided by β-blockers.75 The
physiology of catecholamines was discussed in Chapter 23
on hormonal, adrenal, and sympathetic responses to burn
injury.
Another pure vasoconstrictive agent used with great
popularity is vasopressin. A very potent vasoconstrictor, it
is mediated through its own receptor independent of the
adrenergic receptors. Levels of vasopressin have been
shown to be low in septic shock, and physiologic replace­
ment at 0.02–0.044 U/kg per minute without titration is
used in some burn units to increase MAP to good effect.
Some investigators found that the use of vasopressin in this
setting increased blood pressure, decreased heart rate, and
spared norepinephrine dosing when used concomitantly.76
In these physiologic replacement doses, there is believed to
be minimal effect on splanchnic or dermal flow. Although
there was a trend toward reduced renal failure with the
administration of vasopressin, the VANISH trial failed to
conclusively demonstrate reduced renal failure rates in
septic patients treated with vasopressin compared to nor­
epinephrine.74 In an animal model, Li et al. found that
adding a small physiologic dose of vasopressin to norepi­
nephrine improved mitochondrial function and all mea­
sures of hemodynamics, as well as tissue and splanchnic
perfusion.77 In a series studying 30 septic burn patients
treated with vasopressin plus norepinephrine, reduction of
total norepinephrine dosing was shown. However one
patient died from upper gastrointestinal necrosis; this
patient presented with increased peripheral ischemia and
donor site conversion, as well as skin graft failure. These
data again support concerns regarding the use of pure
vasoconstrictive agents when treating burn patients.76
Very rarely methylene blue, as a pure vasoconstrictor,
may prove beneficial in treating refractory vasoplegia. It is
a potent nitric oxide synthase inhibitor and, in case reports,
has been shown to successfully reverse refractory vasople­
gia following severe burn and thus should be in the
armamentarium.78,79
Use of vasopressors and ionotropes in burn patients is an
indispensible component of burn care. Balancing risks and
benefit profiles of various medications in an individual
patient’s physiology is the purview of an experienced,
trained burn critical care surgeon.
Effects of β-Blockade on Cardiac Performance After
Severe Burn
One response to severe burn is a dramatic increase in
catecholamine production; this has been linked to a
number of metabolic abnormalities including increased
resting energy expenditure, muscle catabolism, and altered

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
338
and tidal volume at 6 mL/kg ideal body weight initially. In
a normal patient, Vmin is 100 cc/kg per minute, but with the
high CO2 production seen in burn patients the needed
minute ventilation can increase two- to fourfold. Adjust­
ments can then be made in minute ventilation to optimize
PaCO2, which is usually 40 mm Hg but can be higher in
patients with pre-existing chronic obstructive pulmonary
disease (COPD) or smoking habits.87 When making these
adjustments, it should be noted that the respiratory rate
cannot be increased above 40 breaths/min in those who are
not neonates, and tidal volume should be minimized to
avert ventilator-induced lung injury (VILI).
As respiratory rates increase in an attempt to increase
minute ventilation while complying with low tidal volumes,
the fraction of dead space can also increase, further imped­
ing ventilator function. In these cases, decreasing the
minute ventilation will increase CO2 elimination. Dead
space ventilation–perfusion abnormalities can be moni­
tored with volumetric capnography performed bedside to
measure physiological and alveolar dead space.88 This can
be a useful adjunct for ventilator management. Volumetric
capnography accounts for total CO2 exhaled, unlike late
expiratory end-tidal CO2 (EtCO2) monitoring, which assumes
an A-a gradient of only 2–3 mm Hg, inappropriate in many
critical care patients. EtCO2 monitoring has utility in moni­
toring trends or in the setting of a low gradient, as seen in
traumatic head injuries. However in critically ill burn
patients, the A-a gradient can be in a state of flux, calling
into question values received from the EtCO2 monitor and
making volumetric capnography more appealing. Factors
affecting the A-a gradient include CO, airway dead space,
airway resistance, and metabolic rate; each of these may
change in a severely burned patient, particularly those with
inhalation injury. For these reasons, EtCO2 monitoring is
ill-advised in burned patients for the estimation of PaCO2.
Serial blood gas examination is a more reliable monitor.
The ARDSnet studies have well documented that ventila­
tory injuries to the lung can induce ARDS and have an
appreciable effect on morbidity and mortality. Volutrauma
occurs when an excess of volume over-distends the lungs,
injuring compliant alveoli. Volumes are preferentially
directed to compliant and uninjured alveoli because non­
compliant alveoli have too long a time-constant to accept
the volume. As healthy alveoli are sequentially injured, a
positive feedback is established, and the injury continues to
worsen. This is the principle underlying low tidal volume
(LTV) ventilation. Use of positive end expiratory pressure
(PEEP) can facilitate maintaining more compliant alveoli
and reduce atelectotrauma by reducing alveolar collapse as
well as preserving the lung in a more compliant portion of
the pressure volume loop.89 Furthermore having more
nitrogen in the ventilated gas maintains a stenting function
because it is not absorbed out of the airways as is oxygen.90
When plateau airway pressures are greater than 30 mm Hg
the ventilated lung is relatively noncompliant, indicative of
ARDS or pulmonary edema, which subject the lung to baro­
trauma similarly. In this situation, “permissive hypercap­
nia” is a strategy that can be used to reduce barotrauma.
This strategy seeks to limit peak and plateau airway pres­
sures by reducing tidal volumes to allow for respiratory aci­
dosis (PaCO2 >45 mm Hg, arterial pH <7.30). This strategy
was used to some extent in the trial investigating the
It is important to intubate appropriate patients prior to
respiratory arrest. It should be considered, however, that in
a large study series more than 33% of burn patients were
extubated within 1 day of intubation for transfer to a burn
center without reintubation. These patients were subjected
to risk without reward, and loss of an endotracheal tube in
a heavily sedated or paralyzed patient is potentially fatal.84
Securing an endotracheal tube (ETT) to a burned and/or
edematous face can be challenging. In a large survey of
burn centers, ETTs were reported secured with linen non­
adhesive tape in 59% of cases, manufactured devices in
48%, and orthodontically in 24%.85 Our center has used
nasal intubation with a septal tie for 20 years without acci­
dental extubation or septic sinusitis.
Tracheotomy can provide a long-term durable airway
with less patient discomfort. In a survey of American burn
centers, the average tracheostomy was performed at 2
weeks; however there is a consensus that there are indica­
tions for earlier tracheostomy.85 Interestingly, however, in a
study of 600 adult medical ICU patients, Terragni et al.
found that early tracheotomy did not result in significant
improvement in ventilator-associated pneumonia, although
the duration of ventilator-assisted respiration was reduced,
as was ICU time.86
Pulmonary Physiology
There has been a proliferation of management strategies for
pulmonary failure with an alphabet soup of ventilator
modes. However the physiology of human lungs remains
constant regardless of the proliferation of devices. Main­
taining a broad physiologic view allows optimal matching
of the ventilator’s actions to the patient’s needs. Lungs have
three main functions:
■ Ventilation
■ Oxygenation
■ Expectoration
Ventilation.  Ventilation allows the elimination of carbon
dioxide (CO2), as measured on arterial blood gas by the
PaCO2. The ventilator accomplishes this with minute venti­
lation (Vmin) minus dead space ventilation (Vd). In general,
PaCO2 varies inversely with Vmin, so this value must be con­
sidered when making ventilator adjustments to alter PaCO2.
Vmin is equal to tidal volume multiplied by respiratory rate.
Therefore, PaCO2 can be adjusted downward by increasing
either tidal volume or respiratory rate. In general, the respi­
ratory rate should be set between 10 and 20 breaths/min
Table 32.1  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

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
339
VQ mismatching occurs as deoxygenated blood is shunted
through poorly ventilated lungs and hypoxic vasoconstric­
tion becomes dysregulated in the pulmonary vasculature.
This is treated first by improving the aeration of the lung
using pulmonary toileting, recruitment maneuvers, and
open lung techniques to aerate long time constant aveoli.97
Furthermore inhaled pulmonary vasodilators, such as
nitric oxide or prostaglandins, can vasodilate aerated beds
and improve VQ matching.98 Finally prone positioning can
also improve VQ matching, as well as posterior aeration.99
In a survey of American burn centers, ARDS was managed
through fluid restriction/diureses and enteral nutrition, as
well as by neuromuscular blockade. In severe ARDS, prone
positioning was used in 33% of centers and extracorporeal
membrane oxygenation (ECMO) in 18%.85
Oxygen is principally delivered to tissues on hemoglobin,
so, in general, a PaO2 value of 60 mm Hg is considered suf­
ficient because it equates to a saturation of approximately
92%. Pulse oximetry effectively measures oxygenation and
can be used to guide ventilator management. Falsely mea­
suring methemoglobin and carboxyhemoglobin as oxygen-
saturated hemoglobin, which is common initially in patients
with smoke inhalation injury, highlights the shortcoming
of this technique. Otherwise this is a very accurate method
to determine the oxygen content in arterial blood because
97% of oxygen is carried to the tissues via hemoglobin. This
assertion has been corroborated by in vitro studies showing
the accuracy of pulse oximetry to within 2–3% of oxyhe­
moglobin levels.100 The major limitations of this technique
lie in its insensitivity to changes in pulmonary gas exchange.
Because of the shape of the oxyhemoglobin dissociation
curve, when the SaO2 exceeds 90% and the PaO2 is greater
than 60 mm Hg, the curve is flat, and changes in PaO2 can
move considerably with little variation in SaO2. Regardless
it is presumed that an SaO2 value of greater than 92% is
indicative of adequate oxygenation. That the oxygenation
saturation measurement is a continuous direct measure
immediately available whereas blood gas measurement of
PaO2 is intermittent is an advantage that should not be
overlooked.
A commonly used parameter to assess the adequacy of
oxygenation is the ratio of PaO2 to FIO2 (P/F ratio). It is an
easily calculated surrogate for the A-a gradient.101 As such,
the P/F ratio is one of the criteria utilized to diagnose ARDS
in the Berlin definition (Table 32.2). ARDS is defined as
bilateral opacities not explained by effusion, collapse of
nodules occurring within 1 week of a clinical insult not
fully explained by cardiac failure, or fluid overload associ­
ated with a P/F ratio of less than 300. ARDS is stratified to
mild, with a P/F between 200 and 300; moderate, between
100 and 200; and severe, below 100.101
However, not incorporating MAP, a key determinant in
oxygenation, is a major flaw when utilizing the P/F ratio.
Thus two patients on two different levels of ventilator
support (one on minimal PEEP, the other on maximal) are
indistinguishable based on this parameter, although they
are clearly disparate when using the A-a gradient. To
account for this variable, the oxygenation index (OI) may be
used:102
Oxygenation index OI
Mean airway pressure
mmH O
iO
a
(
)
(
)
)
(
=
×
2
2
F
P O2
efficacy of pressure-limited ventilation on improving out­
comes in critically ill ventilated patients.91
LTV ventilation has been shown in the ARDSnet trials to
be protective against ARDS, but it can also compromise ven­
tilatory function and CO2 elimination. Burn patients repre­
sent unique challenges in mechanical ventilation and ARDS
given the reduced compliance due to eschar, chest wall and
pulmonary edema due to resuscitation, the unique physiol­
ogy from inhalation injury, and the increased CO2 produc­
tion due to hypermetabolic response. Furthermore the work
of breathing progressively increases at lower tidal volumes.92
LTV protocols have been proved ineffective in the burn pop­
ulation: 33% of burn patients failed to meet oxygenation
and ventilation requirements, increasing to approximately
67% in inhalation patients.85
Sousse et al. analyzed pulmonary outcomes in 932
burned pediatric patients with inhalation injury over 28
years, stratifying for tidal volume. Their findings, starkly
divergent from ADRSnet predictions, demonstrated high
tidal volume (15 +/− 3 mL/kg) was associated with signifi­
cantly decreased ventilator days, maximum PEEP, and sig­
nificantly increased maximum peak inspiratory pressure;
ARDS was significantly decreased, but pneumothorax
increased. They concluded that high tidal volumes might
interrupt the sequences of events leading to lung injury
following inhalation injury.93
Another school of thought holds that surrogate markers,
such as airway pressures, should be used to avoid ARDS. By
this logic, when tidal volumes were lowered, patients with
more compliant lungs did poorly, whereas patients with less
compliant lungs did well.94 Regardless, lung-protective
strategies are notoriously difficult to institute in the burn
population, and some lung injury often must be accepted to
assure overall patient survival.
Oxygenation.  Like the adequacy of ventilation, oxy­
genation has been classically determined using the PaO2
in arterial blood. Arterial oxygenation is calculated using
three factors: mean alveolar pressure of oxygen (MAP-O2),
the A-a gradient, and VQ mismatching. MAP-O2, as deter­
mined by the ventilator, is the area beneath the pressure/
time curve multiplied by the fraction of inspired oxygen
(FIO2). Increasing the FiO2 has limited ability to improve
oxygenation because FIO2 in excess of 60 is considered
pulmonary toxic for prolonged time courses.95 However
increasing MAP-O2 profoundly improves oxygenation,
often quite safely. This can be accomplished by increasing
the PEEP or the inspiratory time during which the airways
are maintained at inspiratory pressure for longer, thereby
enlarging the area under the curve. However as more time
is maintained in inspiration, less is available for exhalation
and ventilation. Thus hypercarbia and acidosis can limit
the maintenance of high MAP-O2.96 These implications
will be discussed in further detail in the ventilator mode
section.
The A-a gradient is a function of the diffusion membrane
separating air from blood. This is affected by pulmonary
edema. A-a gradient issues are best managed by reducing
pulmonary edema with diuresis, improving cardiac perfor­
mance using inotropes, and allowing time for the lungs to
heal their diffusion membrane by repopulating the type-1
pneumocytes.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
340
Mechanical Ventilation
Mechanical ventilation is an essential component of burn
pulmonary critical care. Mechanical ventilatory support
allows life to be sustained with lungs that would otherwise
inexorably lead to death. It is important that the use of
mechanical ventilation provide the minimal interruption to
burn care, including both wound care and physical therapy.
The safety of mobilization of mechanically ventilated
patients is well documented, including out-of-bed mobiliza­
tion of intubated patients (Fig. 32.2).13
The principal clinical difference between mechanical
ventilation and spontaneous ventilation is the effect of
positive pressure, as opposed to normal physiologic nega­
tive pressure. The use of positive pressure improves ventila­
tion by recruiting alveoli and increasing functional residual
capacity (i.e., the number and volume of open alveoli at
the end of expiration), thus improving VQ mismatch and
reducing shunting of blood past nonventilated lung areas
(Fig. 32.3). Positive pressure ventilation also allows main­
tenance of higher MAP-O2 to overcome high A-a gradi­
ents. Adverse effects of positive-pressure ventilation lie
in its propensity to produce trauma to the airways (baro­
trauma) and its effects on intrathoracic pressure, which can
impede venous return to the heart, thus reducing cardiac
output.
In a survey of American burn centers, pressure support
ventilation and volume assist control were the most
common starting ventilator modes for all burn patients;
however 53% of centers report using an open lung tech­
nique such as high-frequency percussive ventilation
(HFPV), high-frequency oscillation ventilation (HFOV), or
airway pressure release ventilation (APRV) in the setting of
inhalation injury.85
When oxygenation begins to decline, initial maneuvers
are to increase the FIO2 to greater than 40%, possibly to
100%. Concentrations of oxygen greater than 60% are con­
sidered toxic to airway epithelium over the course of hours;
other means to increase oxygenation should be employed.95
As discussed earlier, treating hypoxia is first accomplished
by increasing the MAP-O2 by raising the level of PEEP incre­
mentally until the desired level of oxygenation is reached
while keeping the FIO2 to less than 60%. Once a level of
15–20 mm Hg of PEEP is reached, other means of increas­
ing MAP-O2 will need to be employed. These consist of ven­
tilator modes, including inverse ratio ventilation, HFOV,
HFPV, and APRV.
After MAP-O2 is maximized, therapies are directed at
improving VQ mismatching with inhaled nitric oxide or
prone positioning. ECMO has been used with success in
burn patients when the lungs are too injured to perform
life-sustaining gas exchange. This must be done with
caution given the need for anticoagulation and the limita­
tion imposed in the ability to mobilize the patient, both of
which can compromise other critical aspects of burn
care.107
Ventilator Modes.  Regardless of the mode (Fig. 32.4), the
basic pulmonary physiology principles balancing ventila­
tion, oxygenation, and expectoration against VILI lung
injury are the purview of a skilled burn surgeon and respi­
ratory therapist.
This parameter is particularly helpful in determining a
patient’s oxygenation status in relation to the level of ven­
tilator support: the higher the number, the worse the level
of oxygenation. Generally, an OI of greater than 20 should
be a cause for concern.
Expectoration.  The final aspect of pulmonary physiology
necessary for consideration in pulmonary critical care is
expectoration. The injured lung must clear its secretions,
damaged mucosa, pathogens, and aspirated material. In the
case of an inhalation injury, there is the transudate of
fibrinous material and sloughing of injured mucosa that
must be cleared in the setting of a compromised mucocili­
ary escalator. Chest physiotherapy, mucolytics, suctioning,
and particular ventilator modes aid in the expectoration of
the lungs.103
A commonly used technique to treat inhalation injury is
the combination of nebulized heparin and N-acetylcysteine
with albuterol and pulmonary toileting.104 The goal is that
the heparin will prevent coagulation of the transudated
plasma, which comes through the injured pulmonary capil­
laries. The N-acetylcysteine serves as a mucolytic agent and
allows expectoration, along with the sloughed mucosa,
during physiotherapy and suctioning.
In a meta-analysis of five studies comprising 286 patients,
inhaled heparin was found to reduce ventilator days and
resulted in more patients alive at day 28 with lower lung
injury scores, although methodological issues were noted.105
However, in a follow-up analysis of those studies, individual
patient data provided no convincing evidence regarding
any benefit of heparin nebulization in intubated and venti­
lated ICU patients, although none of these patients had
inhalation burn injuries.105 In a review of inhalation-
injured patients, Kashefi found a nebulized heparin and
N-acetylcysteine/albuterol protocol did not reduce mortal­
ity or duration of mechanical ventilation, but did increase
pneumonia rates.106 Conversely Sood and Waldroth more
recently published a case-control study of 72 inhalation-
injured patients and found that a 7-day course of nebulized
heparin with N-acetylcysteine and albuterol decreased
mean ventilator days from 14 to 7 and increased ventilator-
free days. There was no change in mortality, pneumonia
rates, or bleeding in their study. In this series of inhalation-
injured patients, nebulized heparin was found to be safe and
effective.104 This efficacy is consistent with our own clinical
experience.
Table 32.2  Berlin Definition—ARDS
Onset within one week of onset of injury or illness
Bilateral lung opacities not explained by effusion, atelectasis, or
nodules
Respiratory failure without cardiac failure or fluid overload
Diminished oxygenation
Mild
200 < P/F < 300
Moderate
100 < P/F < 200
Severe
P/F < 100
P/F = partial pressure arterial oxygen/fraction of inspired oxygen

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
341
Endotracheal tubea
Intubation
RESPIRATORY
CONSIDERATIONS
IN-BED
EXERCISES
OUT-OF-BED
EXERCISES
Tracheostomy tube
Respiratory parameters
Fraction of inspired oxygen
Percutaneous oxygen saturation
Respiratory rate
Ventilation
Mode HFOV
PEEP
Ventilator dysynchronyc
Prone positioningd
Rescue therapies
Nitric oxide
Prostacyclin
≤ 0.6
≤ 30 bpm
≤ 10 cmH2O
> 10 cmH2O
> 30 bpm
> 0.6
≥ 90%
< 90%b
Fig. 32.2  Respiratory considerations for in-bed and out-of-bed exercises. Green circle indicates low risk for adverse event. Yellow triangle indicates
potential risk and consequences of an adverse event but may be outweighed the potential benefits of mobilization. Red octagon indicates a significant
potential risk of an adverse event, and mobilization should only be carried out with specific consideration by senior staff nurse or physical therapist.
(From Hodgson CL, Stiller K, Needham DM, et al. Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated
critically ill adults. Crit Care. 2014;18[6]:658.)

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
342
Volume-control mode delivers a preset tidal volume regard­
less of patient effort and is typically used only under general
anesthesia due to ventilator–patient dyssynchrony; it takes
all respiratory control away from the patient (Fig. 32.5).
Assist-control mode differs by allowing the patient to demand
additional breaths with a ventilator-preset minimum rate.
All breaths are delivered at a prescribed volume, irrespective
of any patient attempts for a larger or smaller breath. Some
patients find this mode uncomfortable due to the inability
to control their volume and require greater sedation than
they would under other modes.
Volume-cycled ventilation delivers a set volume of air
regardless of pressure required. In the case of poor lung
compliance, such as ARDS, this mode could lead to exces­
sive ventilator pressures and significant airway injury. For
this reason, time-cycled pressure control ventilation was devel­
oped; this delivers inspiration at a given flow rate to a preset
pressure. The breath is terminated at a set cycle time, not
on the basis of volume of flow, as with volume-controlled
ventilation. Therefore pressure control has the advantage
of limiting inspiratory pressure despite changes in compli­
ance. It has the disadvantage of a variable tidal volume
during dynamic changes in lung compliance, which can
lead to inadequate or excessive minute ventilation if compli­
ance respectively worsens or improves.
Aerated alveoli
Collapsed alveoli
Aerated alveoli
Fig. 32.3  A schematic of intrapulmonary shunting. Blood comes into
the lung and then divides into capillaries and passes close to alveoli,
where gas exchange occurs. In the case of alveolar collapse, the passing
blood does not undergo gas exchange and thus returns to the pulmo­
nary vein unchanged (low oxygen concentration, blue color). This then
mixes with oxygenated blood from the aerated alveoli (high oxygen
concentration, red color) to return to the heart and the periphery. In
effect, more collapsed lung equates to less oxygenation through this
process.
C
B
A
Fig. 32.4  Photographs of different ventilators commonly used in
burn units in the United States. (A) The most commonly used is the
servo type ventilator, which can be set to give volume- or pressure-
regulated breaths with or without pressure support or positive end
expiratory pressure (PEEP). The I:E ratios can also be reversed. (B) The
second type is the volumetric diffusive respiration (VDR) ventilator,
which delivers high-frequency percussive ventilation (HFPV) or as
continuous positive airway pressure (CPAP). (C) The third type is the
airway pressure release ventilation (APRV) ventilator, which can be
set to all the servo settings as well as APRV.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
343
[IN]
Time
[LIM]
Vol.
[CYC]
Vol.
Pressure
[IN]
Press.
[LIM]
Vol.
[CYC]
Vol.
[IN]
Time
[LIM]
Vol.
[CYC]
Vol.
A
B
C
Fig. 32.5  Airway pressure curves illustrating the three mechanical functions: IN, initiation of the cycle; LIM, the preset limit (i.e., pressure or volume)
imposed on the positive pressure cycle; CYC, the function (i.e., time or volume) ending the cycle. Each mechanical function is governed by one of four
physical factors: volume, pressure, flow, and time. (A) A time-initiated, volume-limited mode. (B) A pressure-initiated (sub-baseline pressure produced
by the patient’s effort to breathe), volume-limited mode. (C) A time-initiated, volume-limited, time-cycled mode that extends inspiration beyond the
time that the volume is delivered. A plateau is reached after flow has stopped but before the ventilator cycles into exhalation. (From Shapiro BA, Lacmak
RM, Care RD, et al. Clinical application of respiratory care. St. Louis, MO: Mosby Year Book; 1991.)
+10
+3
–3
0
+10
+3
–3
0
+10
+3
–3
0
+10
+3
–3
0
Control
mode
Assist
control mode
IMV
mode
SIMV
mode
Fig. 32.6  Airway pressure tracings of four volume-cycled modes. The
thick solid lines represent ventilator breaths. The thick dotted lines are
spontaneous breaths. The thin dotted lines illustrate the spontaneous
breathing pattern in the absence of ventilator breaths. IMV, intermit­
tent mandatory ventilation; SIMV, synchronized intermittent manda­
tory ventilation. (From Shapiro BA, Lacmak RM, Care RD, et al. Clinical
application of respiratory care. St. Louis, MO: Mosby Year Book; 1991.)
IN
EX
To patient
[IN]
Pressure
[LIM]
Pressure
[CYC]
Flow
Fig. 32.7  Schematic illustration of pressure support ventilation. IN, ini­
tiation by spontaneous breath; LIM limit (pressure); CYC, cycle (derived
from decreasing inspiratory flow); EX, expiration. (From Shapiro BA,
Lacmak RM, Care RD, et al. Clinical application of respiratory care. St. Louis,
MO: Mosby Year Book; 1991.)
Intermittent mandatory ventilation (IMV) allows spontane­
ous ventilation interspersed with volume-cycled or time-
cycled pressure control mechanical ventilation. The addition
of synchronization, in synchronized intermittent manda­
tory ventilation (SIMV), avoids placing a mechanical breath
on top of a spontaneous patient breath, greatly improving
this mode. It was hoped that maintaining some patient
work in breathing would preserve respiratory strength
while mechanical ventilation was required and that this
mode would support weaning to progressively increasing
patient effort while reducing mechanical support, although
outcome data did not support a role in weaning (Fig. 32.6).
Pressure-support ventilation (also known as continuous
positive airway pressure [CPAP]) is a patient-triggered
pressure-limited flow-cycled ventilatory mode (Fig. 32.7).
Each pressure support breath is triggered by patient
negative-pressure effort and allows the patient to control
his or her minute ventilation. This is a very comfortable
mode for patients and effective for weaning; however it is
not compatible with decreased respiratory drive. Care must
be taken to ensure the patient does not develop progressive
atelectasis with resultant decreases in compliance.
Inverse ratio ventilation (IRV) increases the MAP-O2
thereby improving oxygenation in the setting of high A-a
gradients. Conventional ventilation uses the time of inspira­
tion and expiration at a ratio of 1 : 4 or 1 : 2, providing the
greater time for expiration, as it is generally a passive
process. IRV reverses this to give a longer inspiratory time
(1 : 1 or 2 : 1) by using rapid inspiratory flow rates and decel­
erating flow patterns during the inspiratory phase. The pro­
longed inspiratory pressure increases MAP-O2 dramatically
to drive oxygen across a large diffusion membrane. Simi­
larly to PEEP, this prolonged pressure recruits alveoli with
long time constants. In severe lung disease, ventilation in
the lung is unequal due to peribronchial narrowing. Thus
some underventilated alveoli are actually open but unable
to efficiently exchange gases, thereby increasing the intra­
pulmonary shunt and reducing arterial oxygenation. IRV
can improve on this by selective air-trapping (intrinsic

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
344
employed.110 A randomized prospective trial in adult
patients with ARDS demonstrated that HFOV resulted in
brief improvements in oxygenation, although mortality
and complication rates were not different.111 One center
reported early success in reversing profound hypoxemia in
burned patients with ARDS while facilitating early excision
and grafting with intraoperative use.112 However this same
group recently showed that, in burned patients with inhala­
tion injury, this method often failed secondary to hypercap­
nia rather than hypoxia.113 HFOV appears to be effective in
improving oxygenation in burned patients with inhalation
injury, but the data without inhalation injury are murkier.
In the recent OSCILLATE and OSCAR trials in unburned
populations, no benefit and potential harm with HFOV was
found.85
HFPV is a pressure-limited, time-cycled mode of ventila­
tion delivering subtidal pressure-limited breaths at a high
frequency (400–800 beats/min) superimposed on a con­
ventional inspiratory and expiratory pressure-controlled
cycle (10–30 breaths/min). The purported advantages are
mobilizing airway secretions, casts permitting better expec­
toration and pulmonary toilet, and providing adequate gas
exchange at lower airway pressures. First reported in 1989,
HFPV has been tested primarily in burned patients with
inhalation injury.114 In this study, HFPV was used as a
salvage therapy in one group of burned patients with inha­
lation injury and as the primary therapy in another.
Improvements in oxygenation and a lower rate of pneumo­
nia were observed. A subsequent study documented
improvements in mortality in burned patients with inhala­
tion injury treated with HFPV compared to historical con­
trols.115 Other outcomes in this study were significant
decreases in the work of breathing and lower inspiratory
pressures in addition to improvements in oxygenation and
the pneumonia rate. This method of ventilation is advo­
cated in the treatment of inhalation injury because it facili­
tates expectoration, particularly compared to HFOV.
In severely burned ventilated patients, a randomized con­
trolled trial tested the effects of a low tidal volume conven­
tional ventilator strategy against an HFPV ventilator
strategy. This study found differences in improved oxygen­
ation early in the course but no differences in mortality or
other outcomes. However it demonstrated the need for ven­
tilator “rescue” in only the HFPV group, defined as the need
for changing ventilator modes due to inadequate oxygen­
ation or ventilation despite maximizing the mode. Thus the
data support HFPV in this population (e.g., less rescue indi­
cated).116 At a minimum, these data show HFPV as a useful
tool in the burned patient population.
Nitric oxide (NO) is used to improve VQ mismatch in the
setting of refractory hypoxemia. It is a short-lived gaseous
product of endothelial cells that is a powerful local vasodila­
tor. As a gas, this product can be delivered through the
endotracheal tube to areas of ventilated lung where it can
provide localized pulmonary vasodilation. Thus areas of
ventilated lung can receive more blood flow to reduce intra­
pulmonary shunting and improve oxygenation. This com­
pound has been used extensively to beneficial effect in
neonates and children with hypoxemic respiratory failure.
It has also been used in ventilated burned children to
improve oxygenation.98 Although NO therapy has received
considerable attention as a potential therapeutic option in
PEEP) in these compromised air spaces. This can be done in
either a volume-cycled or time-cycled pressure ventilation
mode, but pressure-controlled ventilation is most com­
monly used to reduce peak airway pressures. Some studies
show no benefit of IRV compared to conventional volume
ventilation in terms of oxygenation.108 These studies dem­
onstrate some slight improvements in ventilation (PaCO2).
Furthermore this mode is not well tolerated by patients
because they are unable to spontaneously breathe and thus
tend to require heavy sedation. For these reasons, IRV
cannot be recommended except in the setting of ARDS
refractory to other therapies.
APRV delivers continuous positive airway pressure with
a time-cycled pressure-release phase (to allow for expira­
tion). Similar to IRV, it maintains high pressures within the
airways for most of the respiratory cycle, thus allowing for
very high MAP-O2 to overcome high A-a gradients, recruit­
ment of long time constant alveoli, and improved VQ
matching. Unlike IRV, the patient can breathe spontane­
ously over the high and low pressures enabling greater
patient comfort and synchrony, minimal sedation, and aug­
mented minute ventilation. These characteristics allow for
an open lung with extensive alveolar recruitment and
thereby improved VQ mismatching.109 This mode is best uti­
lized in patients permitted to breathe spontaneously with
negative pressure induced by diaphragmatic contraction,
which aids in lung recruitment of areas previously atelec­
tatic. This contrasts conventional positive-pressure ventila­
tion, where positive pressure within the bronchus through
the volume of air distributes preferentially down the path
of least resistance to areas of the lung already well aerated,
predisposing them to over-distension and barotrauma. The­
oretically APRV is the ideal lung-protective strategy.
APRV gained popularity in the late 1990s and is becom­
ing the preferred mode of ventilation in many centers, par­
ticularly in the setting of inhalation injuries. This open lung
technique allows effective expectoration during the “dump”
exhalation phases. Small prospective trials suggest APRV
associates with fewer ventilator days, improved gas
exchange, decreased atelectasis, improved hemodynamic
performance, and decreased sedative administration com­
pared to conventional modes in nonburned populations.97
Some recent data in trauma patients refute this, although
that paper suffered from a significant lack of statistical
power.109 Nonetheless this mode is being increasingly used
in burn units around the world, but no prospective trials
have yet been reported.
HFOV maximizes MAP-O2 by maintaining airways at
MAP-O2 and delivering subtidal, high-frequency oscillatory
breaths otherwise described as “CPAP with a wiggle.” It is
believed to maintain open alveoli by recruiting collapsed
portions of diseased lung and applying the equivalent of
CPAP used during conventional ventilation and driving
oxygen into the blood with a high A-a gradient. HFOV
maintains a maximal MAP-O2 with a limited peak pressure
while there is neither opening nor closing of alveoli. Thus
this is a “lung-protective” mode preventing atelectotrauma,
volutrauma, and barotrauma. Ventilation and CO2 elimina­
tion are achieved via eddy currents mixing the air through­
out the ventilator circuit, but poor CO2 elimination is a
major limitation of HFOV.96 Because there is no exhalation,
expectoration is minimal unless special maneuvers are

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
345
pressure support or intermittently with t-tube or PSV trials)
will be successful (Fig. 32.8).
The standard of care has shifted to perform protocolized
daily sedation interruptions, spontaneous breathing trials,
and assessment from extubation. This protocol has been
shown to decrease ventilator days and mortality in random­
ized controlled trials (RCTs). An RCT has demonstrated one
life saved for every seven patients treated with a spontane­
ous breathing trial protocol.121 There is an argument that
decreased sedation applied in these protocols increases self-
extubation, which was found in the study. However the
reintubation rate was not different, indicating that patients
who were able to self-extubate tended to not require further
intubation. Thus, in this study, self-extubation was a good
weaning parameter.121
Monitoring of Mechanical Ventilation.  For patients on
mechanical ventilation, sedatives and paralytics for the
endotracheal tube or other conditions often impair the
normal physiologic regulation of ventilation and oxygen­
ation. For these reasons, monitoring of ventilation and oxy­
genation by the clinician is required utilizing serial
examination, chest X-ray, blood gas analysis, continuous
SaO2, and, preferably, EtCO2.
LIMITING VENTILATOR-INDUCED LUNG INJURY.  Mechanical
ventilatory support is employed to provide supraphysiologic
conditions to injured lungs otherwise unable to sustain life.
Ultimately ventilator weaning is predicated on these lungs
healing sufficiently to allow them to again sustain the
patient’s life without the supraphysiologic conditions the
ventilator creates, such as positive pressure. Care must be
taken to balance the systemic needs of the patient for gas
exchange with the injurious nature of mechanical
severe pulmonary disease, no reports to date have docu­
mented improved mortality or other clinical outcomes in
spite of improvements in oxygenation. Inhaled prostaglandins
have a similar effect via an alternate mechanism. Some
centers prefer using prostaglandins due to cost. Epopros­
tenol has been shown to be noninferior to inhaled nitric
oxide with regards to ventilator-free days in ARDS.117
Inhaled NO and aerosolized epoprostenol consistently
improve oxygenation but have not yet been demonstrated
to impact survival ventilator-free days or attenuation of
disease severity. 118 Epoprostenol has also been successfully
used in cases of inhalation injury with a nebulized heparin
protocol.119
Weaning From Mechanical Ventilation.  Regardless of
the mode of ventilation, almost all patients surviving the
initial insult will eventually need to be weaned off the ven­
tilator. Clinicians continue to debate the advantages of
weaning patients with various forms of mechanical ventila­
tion. Some prefer using pressure support ventilation (PSV)
with or without SIMV because of the ease with which the
level can gradually be reduced. Others advocate that inter­
mittent trials with abrupt cessation of ventilator support
while also maintaining endotracheal intubation (“t-tube
trials”) result in more rapid weaning.120 Between weaning
trials it is important to provide sufficient support to re­
recruit alveoli and prevent progressive atelectasis and the
resultant loss of compliance, all of which make weaning
more difficult. Weaning from ventilation depends on the
rate at which the patient recovers from the condition re­
quiring mechanical ventilation and the aggression of the
clinician driving the weaning process. In practice, either
method of weaning from the ventilator (gradually with
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
Duration of weaning (days)
Probability of success in weaning
Intermittent trials
Once-daily trial
Pressure support ventilation
Intermittent mandatory ventilation
8
9
10
11
12
13
Fig. 32.8  The probability of successful weaning with intermittent mandatory ventilation, pressure support ventilation, intermittent trials of spontane­
ous breathing, and once-daily trials of spontaneous breathing (Kaplan–Meier curves). After adjustments for baseline characteristics (Cox proportional
hazards model), the rate of successful weaning with a once-daily trial of spontaneous breathing was 2.83 times higher than that with intermittent
mandatory ventilation (P< 0.006) and 2.05 times higher than that with pressure support ventilation (P < 0.04). (From Esteban A, Frutos F, Tobin MJ, et al.
A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. The N Engl J Med.
1995;332(6):345-350.)

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
346
It stands to reason that pressure-limited ventilation strat­
egies (either conventional or high frequency) might be of
benefit in burned patients in sufficiently powered studies.
One outcome that should certainly be accounted for is the
need for adjunctive therapies (rescue treatments), as implied
earlier. Given current data, the best balance is struck by an
experienced physician with a firm understanding of pulmo­
nary physiology continuously weighing the systemic needs
of the patient against the capabilities of available interven­
tions and their potential pulmonary harm.
Epidemiology, Pathophysiology, and Treatment of
ARDS.  ARDS occurs as a result of injury to the lung,
which can be direct through smoke inhalation or pneumo­
nia or indirect through mediators associated with sepsis
(Table 32.3). Until recently, most studies of ARDS reported
mortality rates between 40% and 60%. Now, in trauma
patients, the most recent mortality rate for ARDS was 14%;
in addition, the incidence of ARDS fell by 50% in a matched
patient population.127 Thus we conclude that the incidence
has gone down. What changed is the method of manage­
ment, indicating that reducing the risk of further harm is
the most effective treatment for this condition.
ARDS occurs because of damage to the endothelium and
lung epithelium. It is speculated that the products of inflam­
mation, such as cytokines, endotoxin, complement, and
coagulation system products, induce the changes charac­
teristic of ARDS.122 The acute phase of ARDS is marked by
an influx of protein-rich edema fluid into the air spaces as
a consequence of increased permeability of the alveolar–
capillary barrier (Fig. 32.9). The importance of endothelial
injury and increased vascular permeability leading to the
formation of pulmonary edema is well established. Epithe­
lial injury is also of great importance. In fact, the degree of
alveolar epithelial injury is an important predictor of
outcome.
Neutrophils play a role in the pathogenesis of ARDS. His­
tologic studies of lung specimens obtained early in the
course demonstrate marked accumulation of neutrophils
in the alveolar fluid. However it must be stated that ARDS
develops in patients with profound neutropenia, and some
animal models of ARDS are neutrophil independent, imply­
ing that neutrophils may be nothing more than bystanders
in the inflammatory process.128
The effects of ventilator injury on the development and
progression of ARDS are now firmly established. Previous
ventilation in a supraphysiologic manner. VILI is the result
of injurious ventilator settings that lead to a combination
of barotrauma, volutrauma, atelectrauma (repeated
opening and closing of alveoli), and chemotrauma (para­
crine inflammatory effects). VILI is a common complication
of mechanical ventilation and results in pneumothorax,
pneumomediastinum, subcutaneous emphysema, intersti­
tial emphysema, or pneumatoceles.122
In a volume-cycled mode, large tidal volumes, along with
elevated peak and plateau pressures, have been implicated
in inducing VILI. It is conceivable that limiting airway pres­
sures may reduce morbidity. Early reports showed no clear
benefit of pressure-limited ventilation, which was demon­
strated by giving lower tidal volumes more frequently to
maintain minute ventilation and accepting a higher PaCO2
value and lower arterial pH.123
This “permissive hypercapnia” is a compromise in the
acceptance of a recoverable compensated systemic pathol­
ogy to allow less injurious ventilation and hopefully permit
the lungs to heal.91 Criticism of these trials rests in their low
enrollment and lack of power to show differences. As an
answer to this critique, a large multicenter trial documented
improved survival and increased ventilator-free days during
the first 28 days in the ICU in patients with ARDS treated
with low tidal volumes (6 mL/kg predicted body weight)
versus traditional tidal volumes (12 mL/kg predicted body
weight). In fact, the data safety committee halted the study
early because the benefits incurred to the treated group
were so clinically significant.124 Suspected reasons for the
improvements seen in this trial contrary to prior trials
was the number of subjects enrolled as well as the defined
protocol to limit both tidal volumes (volutrauma) and
plateau pressures of less than 30 cm H2O (barotrauma).
Interestingly, this trial demonstrated decreased inflam­
matory markers, specifically IL-6, in the low tidal volume
arm, suggesting a third possible mechanism of benefit
(chemotrauma).
Theoretically the low tidal volume strategy subscribes to
the theory of ARDS, which dictates that small healthy
regions of lung exist adjacent to diseased and collapsed
areas. In the conventionally treated group, higher tidal
volumes and pressure are distributed only to open healthy
alveoli; therefore the barotrauma of high pressures is deliv­
ered to this “healthy” lung, thereby increasing the damage
there and worsening outcomes.125
In burned patients, decreased chest wall compliance,
presence of smoke inhalation injury to the upper airways,
and massive fluid administration coupled with increased
CO2 production due to hypermetabolism are just a few vari­
ables that make effective gas exchange challenging while
optimally minimizing VILI. Prospective trials comparing
modes of ventilation to minimize VILI are lacking in burn
literature, making it difficult to ascertain which approach is
best suited to this population. In 61 burned patients, one
study showed no statistically significant differences between
a pressure-limited strategy and a conventional strategy for
mortality, pulmonary complications, or incidence of pneu­
mothoraces.126 In the trial comparing HFPV (a pressure-
limited strategy) to an ARDSnet-based conventional
strategy, a lower incidence of barotrauma was seen in the
HFPV group. However there was no difference in inflamma­
tory markers between the two modalities.116
Table 32.3  ARDS Risk Factors
Direct
Indirect
Pneumonia
Nonpulmonary sepsis
Aspiration of gastric contents
Major injury
Inhalation injury
Pancreatitis
Pulmonary contusion
Severe burns
Pulmonary vasculitis
Noncardiogenic shock
Drowning
Drug overdose
Transfusion-related acute
lung injury

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
347
and ARDS develop in burned patients, a scenario not unlike
that in other types of patients who develop ARDS, such as
after abdominal sepsis or multiple blunt trauma. While
smoke inhalation is understandably associated with the
development of ARDS, this affiliation is related to the
inflammation corresponding to the injury in addition to
that rendered by the burn wound. In fact, it was shown that
the degree of inhalation injury was not associated with the
development of ARDS in burned patients.132 It may be,
then, that smoke inhalation and ARDS are actually two
distinct conditions that are related. Indeed, the preponder­
ance of pathology in smoke inhalation is to the airways
beginning proximally and decreasing in effect as you move
more distally into the lung away from the source of smoke.
Conversely the preponderance of damage in ARDS is alveo­
lar, beginning distally and decreasing as it proceeds
proximally.
Treatment of ARDS.  Until the healing processes just
described can be accomplished, the treatment of ARDS is
largely supportive. A careful search for potential underlying
causes should ensue, including attention to possibly treat­
able sources such as unexcised or open burn wounds, inva­
sive burn wound infection, intraabdominal infections,
pneumonia, line sepsis, or cholangitis, to name a few. Treat­
ment of the inciting cause of ARDS and careful ventilator
management aimed to limit further VILI while maintaining
life-sustaining gas exchange are the core of ARDS treat­
ment protocol. An improved understanding of the patho­
genesis of ARDS has led to the assessment of several novel
treatment strategies, including changes in mechanical ven­
tilation strategies, fluid management, surfactant therapy,
NO treatments, and antiinflammatory strategies.
The most appropriate method of mechanical ventilation
for ARDS has been controversial for some time, although
the picture is becoming clearer; the ARDSnet study pro­
vided much of this clarity.124 They reported a 22% decline
in mortality in patients with ARDS treated with tidal
volumes of 6 mL/kg compared to those treated with con­
ventional volumes of 12 mL/kg. In this study, peak airway
pressures could not exceed 30 cm H2O in the lower tidal
volume group, and a detailed protocol was used to adjust
the FIO2 and PEEP. These results differed from those of
smaller previous studies showing no improvement with
pressure-limited ventilation. Potential reasons for the dis­
crepancy between the National Institutes of Health (NIH)
study and the others are as follows: the NIH study had the
lowest tidal volume of the three studies and respiratory aci­
dosis was allowed in the NIH study, with sodium bicarbon­
ate treatment if necessary to maintain homeostasis.
Furthermore the NIH study had more patients and so may
have been more sufficiently powered to show differences
between treatment groups.
The implementation and utility of low tidal volume proto­
cols have been limited, likely due to the unique pathology of
burn patients with hypermetabolism requiring greater gas
exchange and inhalation injury requiring greater airway
support and expectoration. In one study, one-third of burn
patients failed to meet oxygenation and ventilation require­
ments when treated with low tidal volumes, and two-thirds
failed when there was an inhalation injury.85 Counter to
the ARDSnet data, in a review of 28 years of 932 burned
studies focused on the potentially damaging effects of high
oxygen concentrations on lung epithelium and a prolonged
FIO2 of greater than 60% should be avoided.129 Evidence
suggests that mechanical ventilation at high pressures
injures the lung,124 causing increased pulmonary edema in
the uninjured lung and enhanced edema in the injured
lung.130 Alveolar overdistension and cyclic opening and
closing of alveoli associated with high ventilator pressures
are also potentially damaging to the lung. High FIO2 may
predispose to this atelectrauma by displacing nitrogen from
the alveoli. Nitrogen is then not absorbed and can serve as
a stent maintaining airway patency.90
After the development of ARDS, some patients have a
rapid recovery over a few days. Others progress to fibrotic
lung injury; the alveolar space fills with mesenchymal cells,
extracellular proteins, and new blood vessels. The finding of
fibrosis on histologic analysis correlates with increased
mortality.131
In nonfatal cases of ARDS, the lung heals by the prolif­
eration of type II epithelial cells, which begin to cover the
denuded basement membrane and differentiate into type I
epithelial cells, restoring normal alveolar architecture, and
increasing the fluid transport capacity of the alveolar epi­
thelium. Alveolar edema is resolved by active transport of
sodium from the distal airspace into the interstitium by
intact alveoli. Soluble protein is removed primarily by diffu­
sion between alveolar cells, while insoluble protein is elimi­
nated by endocytosis and transcytosis by alveolar epithelial
cells and phagocytosis by macrophages.
The severely burned are unique among patients who
develop ARDS. Direct injury to the lung from smoke inhala­
tion can cause respiratory insufficiency and relative hypoxia
due to increased capillary permeability and interstitial
edema increasing the A-a gradient, while ciliary dysfunc­
tion embarrasses expectoration. A few days later, the
damaged and necrotic respiratory mucosa begin to slough,
causing bronchial plugging and atelectasis, further worsen­
ing the clinical condition. However it is not typically until
4–8 days into the course of injury that severe hypoxemia
Severe burn ±
smoke inhalation
Hypoxemia
Time
Day 0
Day 5
Day 7
Decreased lung
compliance
Lung infiltrates
on CXR
Fig. 32.9  Typical timeline for progression to acute respiratory distress
syndrome (ARDS). Patients are typically intubated for airway compro­
mise and operative intervention. At day 4 or 5 after severe burn, oxy­
genation will deteriorate, requiring higher inspired concentrations of
oxygen. These measures will soon fail with the introduction of
decreased lung compliance requiring higher inspired airway pressures.
Only then will infiltrates begin to appear on the chest X-ray.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
348
minimize VQ mismatch, mechanical circulatory support
must be considered. ECMO can be employed either in a
venovenous method to only supplement gas exchange or in
an arteriovenous method to also supplement cardiac func­
tion. Its use has the benefit of maximizing gas exchange
while allowing total lung rest without need for further inju­
rious ventilation techniques. There has been limited experi­
ence globally and no large trials to document any benefit to
date. In a small series investigating ECMO, 60% of burned
patients in the series survived and had significant improve­
ments within 96 hours of ECMO administration.137 This
intervention must be regarded with great trepidation, given
the need for anticoagulation and that cannulation prevents
standard burn care and rehabilitation. This therapy can be
life-saving, but it should be considered carefully and utilized
only in the appropriate candidate. Often it is preferable to
balance an injurious but survivable ventilation strategy
with the other burn care needs of the patient.
Last, glucocorticoids have been used in the treatment
of ARDS because of the inflammatory nature of the
disease. There have been several trials with contradic­
tory and equivocal data. To add fuel to the fire, the most
recent large trial of glucocorticoid treatment of early severe
ARDS showed an improvement in ventilator days and MOF
scores.138 Others have shown the benefit of glucocorti­
coids when used to good effect in the later fibroproliferative
phases of the disease.139 It is probable that some population
with ARDS exists in which glucocorticoid treatment is of
benefit, but we do not think it is burns. This type of therapy
may be treacherous in burned patients at risk for invasive
burn wound infection but might be considered upon com­
plete burn wound closure. If steroids are used, high-dose
vitamin A can be tried to ameliorate the wound-healing
complications.140
GASTROINTESTINAL SYSTEM BURN
CRITICAL CARE
Pathophysiologic Changes in the Gut After Burn
The gut, including the stomach, intestines, liver, and pan­
creas, plays six critical roles after burn injury: absorption of
nutrients, mucosal barrier to invasive microbes, elimina­
tion of hydrophobic wastes, clearance of lactate, produc­
tion of acute-phase proteins and coagulation factors, and
an endocrine function able to drive toward anabolism. The
gastrointestinal response to burn injury is highlighted by
mucosal atrophy, changes in digestive absorption, and
increased intestinal permeability. Changes in gut blood flow
are related to changes in permeability. Intestinal blood flow
was shown to decrease in nonresuscitated animals, a
change associated with increased gut permeability at 5
hours post burn.141 This effect was abolished at 24 hours.
Systolic hypotension has been shown to occur in the imme­
diate hours after burn in animals with a 40% TBSA full-
thickness injury.
Clinical Changes in the Gut After Burn
Given these changes in the gut from burn, it is common­
place to observe some evidence of gut dysfunction after
burn, as evidenced by feeding intolerance and mucosal
ulceration and bleeding, particularly in the stomach and
pediatric patients with inhalation injury and stratify­
ing for tidal volume, high tidal volume (15 +/− 3 mL/kg)
was associated with significantly fewer ventilator days.
This effect could reflect an interruption of events leading
to lung injury following inhalation injury but could also
evince the capacity of pediatric lungs to heal given their
preserved stem cell function and ability to form airways
de novo.93
PEEP has clearly been shown to benefit patients with
ARDS; however the optimum level has been contentious.
The best effects of PEEP are to increase functional residual
capacity or the number of open alveoli at the end of expira­
tion, as well as increase MAP-O2 and thus oxygenation.
However the use of prophylactic PEEP therapy in patients
at risk for ARDS showed no benefit for the treatment group
compared to controls.89
A study of PEEP therapy aimed at raising the level of
PEEP above the lower inflection point on pressure–volume
curves, thereby preventing alveolar closure, in conjunction
with low tidal volumes and pressure-controlled IRV showed
improved mortality compared to a control group managed
with conventional ventilation.133 Drawbacks to this study
were the unusually high mortality (71%) in the control
group; improvements in mortality for the treatment group
compared to controls could only be determined at hospital
day 28, which was not appreciated at hospital discharge.
Inhaled NO and prostaglandins are potent pulmonary
vasodilators with effects localized to ventilated areas of the
lung, thus directing more blood to the functional areas of
the lung. The conceivable result, then, is to diminish the
fraction of blood shunted through the lungs without oxy­
genation, thereby improving pulmonary venous oxygen­
ation and reducing VQ mismatching. Observational studies
suggest that inhaled NO might be beneficial in the treat­
ment of ARDS by improving oxygenation without increased
ventilatory pressures and reducing barotrauma. However
randomized trials testing this hypothesis have, as of yet,
been disappointing. In the most recent large study, inhaled
NO therapy did not reduce mortality or the duration of
mechanical ventilation. Improvements in oxygenation were
seen, but the effects were not sustained.134 The reported
experience with this modality in burns is only anecdotal.
Prone positioning is another modality commonly used in
BICUs for refractory hypoxemia, aimed to reduce VQ mis­
match. This is based on the rationale that dependent areas
of the lung in ARDS have the most blood flow and the most
edema, thereby leading to a greater mismatch of blood flow
and aerated lung and a greater shunting of blood past
unaerated areas; hence blood returns to the heart unoxy­
genated. By placing the patient in the prone position for a
prescribed period, the previously aerated lung now receives
a greater portion of blood flow as directed by gravity. This
approach almost always results in improved oxygenation,
but, as with NO, has not been shown to be of benefit for
mortality in prospective trials.135 However two recent meta-
analyses have demonstrated significant mortality benefit in
those with severe hypoxemia.99,136 Thus it appears that in
certain subpopulations VQ mismatch therapies may be con­
sidered after carefully balancing risk versus benefit.
Ultimately if the lungs are too injured to provide the suf­
ficient gas exchange required to maintain life, even with the
support of mechanical ventilation and techniques aimed to

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
349
injured patients and is more thoroughly discussed in Chap­
ters 30 and 31 on MOF and the liver, respectively. It is
related to ICU common causes such as preexisting cirrhosis,
drug toxicity, or viral activation, but also to burn-specific
issues such as hepatic steatosis, right heart failure, and/or
fluid overload. High central venous pressures (CVPs) com­
promise the pressure gradient from the portal system that
provides 75% of the oxygen delivery to the liver, thus creat­
ing an ischemic injury.147 Treatment is to first remove hepa­
totoxic medications and reduce CVP to improve hepatic
perfusion, then begin symptomatic treatment including
monitoring and treating elevated ICP; treating hemody­
namic failure, respiratory failure, and hypoglycemia; and
replacing clotting factors.148
Pancreatitis also occurs, though rarely subsequent to
burn injury. Its etiology tends to be ischemic in nature, with
an incidence of 0.17% demonstrated in a pediatric series.
It is associated with elevated mortality and thus should be
taken seriously. It is diagnosed with elevated amylase or
lipase in conjunction with abdominal pain, feeding intol­
erance, or radiographic signs. Treatment is feeding distal
to the ligament of Trietz and, should this fail to abate
the pancreatitis, bowel rest is advisable with parenteral
feedings.149
RENAL BURN CRITICAL CARE
Pathophysiology
Acute kidney injury (AKI) is a potentially lethal complica­
tion of burns. Of note, AKI has supplanted the prior term
(acute renal failure [ARF]). Despite substantial technical
developments in dialysis to replace the function of the
kidneys, mortality meets or exceeds 50% for all critically ill
patients who develop ARF.150 Interestingly mortality associ­
ated with AKI undergoing hemodialysis for frank renal
failure in the critically ill has not improved significantly in
more than 40 years. The same can be said for renal failure
requiring dialysis, specifically in the severely burned. The
cause of death in these critically ill patients was not uremia
because of advances in dialysis, but primarily sepsis and
cardiovascular and pulmonary dysfunction.151
With the advent of early aggressive resuscitation after
burn, the incidence of renal failure coincident with the
initial phases of recovery has diminished significantly in the
severely burned. However another period of risk for the
development of renal failure 2–14 days after resuscitation
is still present and is likely related to the development of
sepsis.152 Transient hypotension, nephrotoxic medications
such as antibiotics, hypovolemia from insensible fluid losses,
and rhabdomyolysis are all also significant etiologies of AKI
in the BICU.153
AKI, usually in the form of acute tubular necrosis (ATN),
is characterized by deterioration of renal function over a
period of hours to days, resulting in the failure of the kidney
to excrete nitrogenous waste products and maintain fluid
and electrolyte homeostasis. It may be caused by a number
of factors interfering with glomerular filtration and tubular
resorption. In burned patients, the causes can be generally
narrowed to renal hypoperfusion, nephrotoxic insults from
pharmacologic treatments (e.g., aminoglycosides or intra­
venous contrast agents), or sepsis.153 Ischemic renal failure
duodenum.5 Enteral feeding is an important means of pro­
viding nutrition to burned patients and has led to a decrease
in mortality, but on occasion the gut will not cooperate.
Reduced motility and ileus are common, as is diarrhea, at
times requiring parenteral nutrition to meet caloric needs.
At present there is no specific treatment for burn-induced
ileus, but early enteral feeding prevents some of these
potential complications.
The best management for the gut and the patient in total
is sufficient enteral nutrition. Ascertaining the amount and
type of nutrition is the subject of Chapter 28 on nutritional
support. It is worth noting here that feeding the gut pro­
motes mucosal barrier function, nourishes the patient, and
promotes bile flow, elimination of hydrophobic wastes, and
an anabolic hormonal release from the gut and pan­
creas.142,143 In determining the amount to feed, measure­
ment of resting energy expenditure is superior to equations
used to estimate caloric needs, such as the World Health
Organization (WHO), Schodield-HW, and Harris-Benedict
equations and, as such, should be used to calculate feeding
goals.144
Stress ulceration of the stomach and duodenum, on the
other hand, can be prevented effectively with antacid
therapy. In the 1970s, stress ulceration leading to life-
threatening hemorrhage was common. The mechanism of
injury corresponds to an imbalance between protective
factors, such as mucus production, protective prostaglan­
din output, and bicarbonate secretion, and injurious factors,
such as decreased blood flow and acid production. Gastric
ulcers developed in the watershed zones between capillary
beds, which are worsened by gastric acid-induced injury.
With today’s use of standard critical care techniques,
including gastric acid suppression and expeditious wound
closure, upper gastrointestinal bleeding is relatively rare.
When it occurs, treatment is congruent with standard
upper gastrointestinal bleeding protocols through identifi­
cation of the bleeding source and control with local tech­
niques or surgery when required.
Abdominal compartment syndrome has proved a signifi­
cant risk. This is associated with massive volume resuscita­
tion, inducing generalized edema in a relatively limited
abdominal compartment. It eventuates in decreased gut
blood flow and renal blood flow causing oliguria and bowel
ischemia.145 The tragedy is that the early sign of this condi­
tion is low urine output, which is commonly addressed by
more intravenous fluid, which only worsens the case. The
associated physical finding is abdominal distension. An esti­
mate of intraabdominal pressure can be obtained by pres­
sure monitoring of the bladder; pressures of greater than
30 torr are concerning and should instigate further inves­
tigation. Treatments are aimed at reducing intraabdominal
pressures through drainage, sedation, and paralysis, or
decompressive laparotomy if needed.146 Unfortunately
those with burns of greater than 40% TBSA are at highest
risk for abdominal compartment syndrome and have a mor­
tality rate approaching 100% when treated with decom­
pressive laparotomy.87 Therefore the best treatment for this
condition is prevention through judicious resuscitation, as
discussed in Chapters 8 and 9 on burn edema and resuscita­
tion, respectively.
The liver also plays a critical role in the recovery from
burn injury. Acute liver failure is a rare occurrence in burn

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
350
conversion from an oliguric to a nonoliguric state improves
outcomes.
The initial care of patients with AKI is focused on revers­
ing the underlying cause and correcting fluid and electro­
lyte imbalances. Renal failure is heralded by a decrease in
urinary output. Volumes of urine of less than 1 mL/kg per
hour may indicate the onset of AKI. This failure may be due
to a prerenal cause, which is typically due to decreased
renal blood flow from hypoperfusion, or intrinsic renal
causes, which are associated with medications, rhabdomy­
olysis, or sepsis. Differentiation between these etiologies can
be made with laboratory examinations (Table 32.4). Prer­
enal etiologies are associated with concentrated urine
(urine osmolarity >400 mmol/kg), decreased urinary
sodium concentrations, and decreased fractional excretion
of sodium. Intrinsic renal causes will be associated with a
more dilute urine with higher sodium concentrations.
These tests should be performed before diuretics are admin­
istered because this treatment will increase urinary sodium
and decrease urine osmolality even in prerenal conditions.
In general, urine osmolarity and urinary sodium concen­
trations are primarily used for these determinations because
of the ease of measurement. In terms of clinical utility,
renal dysfunction is often a mixture of prerenal and intrin­
sic causes, making treatment decisions difficult.
Should these tests reveal a prerenal cause, volume opti­
mization should ensue to prevent further renal ischemia,
although in the fluid overloaded patient with heart failure
inotropes may be necessary. Physical examination and
invasive monitoring, if deemed appropriate, should guide
this volume replacement. The decision to administer or
remove fluids may prove difficult, however, because both
strategies have detrimental consequences if followed inap­
propriately. Although volume replacement is ineffective in
restoring renal function once tubular necrosis is estab­
lished, it remains the most effective prophylactic strategy,
and so is generally the place to start at the onset of renal
failure.
Owing to the wide variation in the definition of AKI,
reporting an accurate incidence, as well as resultant out­
comes, has been problematic. In an effort to resolve this
and standardize the classification of AKI, the Acute Dialysis
Quality Initiative (ADQI) developed and reported the Risk,
Injury, Failure, Loss of function, End-stage (RIFLE) renal
disease criteria.158 More recently, the Acute Kidney Injury
Network (AKIN) proposed a modified version of the RIFLE
system because of a number of identified limitations. These
revised criteria are intended to simplify the definition and
make it more clinically applicable. According to the AKIN
is the more common of the three causes and is induced by
hypoperfusion from an imbalance between vasoconstrictive
and vasodilatory factors acting on the small renal vessels
during low-flow states. Decreased flow to the renal cells
directly alters endothelial cell function, reducing the pro­
duction of and response to vasodilatory substances. The
renal medulla is the portion of the kidney most sensitive to
hypoxia, and the damage is initially to the renal tubular
cells. The outer medulla and proximal tubules have high
oxygen requirements, and the resulting ischemia causes
swelling of tubular and endothelial cells, with necrosis,
apoptosis, and inflammation evident on a histologic exami­
nation. These changes lead to further vascular congestion
and decreased blood flow, resulting in more cell loss and
further decrements in renal function. Characteristic tubular
casts can be seen on urine microscopy that is diagnostic for
ATN.
After the initiating event, tubular function and glomeru­
lar filtration rate (GFR) decrease to reduce urine produc­
tion. The progression of AKI is commonly divided into three
phases: initiation, maintenance, and recovery; it can be
oliguric (urine output <400 mL/day) or nonoliguric (urine
output >400 mL/day) in nature. Patients with nonoliguric
AKI have a better prognosis than oliguric AKI patients,
probably due in large measure to the decreased severity of
the insult and the fact that many have drug-associated
nephrotoxicity or interstitial nephritis.151
Once AKI is established, pharmacologic improvement of
renal blood flow will not reverse the injury. Agents such as
dopamine, which was commonly used in the past to dilate
renal arterioles and increase renal blood flow via dopamine
receptors, have been shown to be mostly ineffective.154
Recently the potent dopamine-1 receptor agonist fenoldo­
pam has garnered some interest as an agent to improve
renal perfusion and outcomes. A meta-analysis of random­
ized controlled trials demonstrated that low-dose fenoldo­
pam (0.03–0.09 µg/kg per minute) may be of benefit in
reducing the need for renal replacement therapy and hos­
pital mortality when used in septic patients with either
established AKI or at high risk for AKI in a mixed ICU popu­
lation.155 Its use in this setting has been reported in a non­
controlled study in burned patients, with improvement in
renal function (increased urine output and decreased serum
creatinine) and without any hypotension at the low dose.156
Further work will need to be done in the burn population
to fully determine its efficacy.
Diuretic therapies, such as mannitol and loop diuretics,
have been used extensively in patients with AKI to increase
urine flow and protect the kidney from further ischemic
damage. Mannitol can reduce cellular swelling in the proxi­
mal tubule and increase intratubular flow, thus potentially
decreasing intratubular obstruction and further renal dys­
function. Mannitol has been previously recommended
along with vigorous volume replacement and sodium bicar­
bonate for the treatment of early myoglobinuric acute
kidney injury. However recent evidence suggests a lack of
benefit and a need to reevaluate this practice.157 Loop
diuretics also increase intratubular flow rates and can
convert an oliguric state to a nonoliguric state, thereby
facilitating clinical management of renal failure. While
patients with nonoliguric AKI are generally easier to
manage from a volume standpoint, there is no evidence that
Table 32.4  Laboratory Tests to Distinguish Prerenal
from Intrinsic Renal Failure
Examination
Prerenal
Intrinsic Renal
Urine osmolality (mmol/kg)
>400
<400
Urinary sodium (mEq/dL)
<20
>40
FENa (%)*
<1
>2
*FENa, fractional excretion of sodium, calculated as (U/PNa/U/PCr) × 100,
where U is urinary concentration, and P is plasma concentration. Na is
sodium and Cr is creatinine.

32  •  Critical Care in the Severely Burned: Organ Support and Management of Complications
351
that the patient is volume overloaded. Reducing the volume
of fluid given can also alleviate volume overload in burned
patients. These patients have increased insensible losses
from the wounds that can be roughly calculated at
3750 mL/m2 TBSA wound plus 1500 mL/m2 TBSA total.
Reducing the infused volume of intravenous fluids and
enteral feedings below the expected insensate losses may
alleviate some of these problems.
However it is important to continue sufficient nutritional
delivery to the patient and balance this against the renal
function, utilizing diuretics and even dialysis to ensure an
excessive nutrient debt does not develop. Reducing potas­
sium administration in enteral feedings and giving oral
bicarbonate solutions can minimize electrolyte abnormali­
ties. Almost invariably, severely burned patients require
exogenous potassium because of the heightened aldoste­
rone response resulting in potassium wasting. Therefore
hyperkalemia is rare, even with some renal insufficiency.
Indeed, spironolactone is generally a wise adjuvant to loop
diuretics in burn patients due to this potassium wasting.
Intermittent dialysis remains a viable replacement
therapy for severe AKI in the hemodynamically normal ICU
patient, although this is changing. The indications for dialy­
sis are edema and volume overload, electrolyte abnormali­
ties not amenable to other treatments, or refractory acidosis.
In recent years, continuous renal replacement therapies
(CRRT) have emerged as another option for critically ill
patients with AKI. The advantages of continuous over
intermittent treatment include more precise fluid and meta­
bolic control, increased hemodynamic stability, and the
enhanced ability to remove injurious cytokines. Addition­
ally many BICU surgeons perform CRRT without use of
nephrologists or dialysis nurses, thus making the timely
application of CRRT practical as a component of burn criti­
cal care. Disadvantages constitute the need for heightened
surveillance, heavy resource and nursing utilization, and
slower overall clearance compared to intermittent dialysis.
Peritoneal dialysis (PD) is another option for AKI in
burned patients.163 Catheters can be placed at the bedside
with near-continuous exchanges to improve electrolyte and
volume overload problems. The capital required for this
treatment is minimal and surgeons unable to perform CRRT
can easily place a catheter and begin PD. Hypertonic solu­
tions are used to remove fluid volume, and the concentra­
tions of potassium and bicarbonate are modified to produce
the desired results. The dwell time is usually 30 min, fol­
lowed by 30 min of drainage. This treatment can be repeated
in cycles until the problem is resolved. For maintenance,
4–6 such cycles a day with prolonged dwell times (1 h) is
usually sufficient during the acute phase. This treatment is
known to be useful in burned patients but has not received
a significant amount of study.
HEMATOLOGIC BURN CRITICAL CARE
Burn patients are subject to major blood loss due to phle­
botomy and surgery. As such, they can suffer intravascular
hemolysis in burn wounds. They also suffer hematopoietic
suppression or modulation from inflammation and adren­
ergic causes. Coagulation factors and platelets can be con­
sumed, creating a consumptive coagulopathy. Resultantly
transfusion is a standard component of burn critical care.
criteria, stage 1 AKI is delineated by “an abrupt (within
48 hours) reduction of kidney function currently defined
as an absolute increase in serum creatinine of more than
or equal to 0.3 mg/dL, a percentage increase in serum cre­
atinine of more than or equal to 50% (1.5-fold from base­
line), or a reduction in urine output (documented oliguria
of less than 0.5 mL/kg per hour for more than 6 hours).”
Stages 2 and 3 are the same as RIFLE—Injury and Failure,
respectively.159
In burned patients, investigators showed that the inci­
dence and outcomes of greater than 20% TBSA burned
patients with AKI using RIFLE criteria was 24% (12% Risk,
8% Injury, and 5% Failure). Associated mortality was 14%,
which increased directly with each RIFLE class (7% normal,
13% Risk, 40% Injury, and 83% Failure). Renal dysfunction
occurred within 7 days in 55% of affected patients and
completely recovered in all survivors; pulmonary dysfunc­
tion was present in all. Sepsis was a possible aggravating
factor in acute kidney injury in 48%. They concluded that
AKI is common after severe burn, develops within days of
injury, and parallels other organ dysfunction.160 These data
confirm earlier studies showing that the development of
renal failure is associated with dismal outcomes. Minor dys­
function does not necessarily correlate to progression and
mortality, giving hope to therapies designed to maintain
renal function after severe burn.
Another study examined the incidence of renal dysfunc­
tion in burned patients, defined by serum creatinine levels
of greater than 1.4 mg/dL. Thirty-nine percent of patients
admitted to the BICU developed renal insufficiency, of which
33% underwent renal replacement therapy. Associated
mortality in those with renal insufficiency was 44%. Those
who developed renal insufficiency within 5 days of thermal
injury had a higher mortality than those with later onset.
Of interest, all survivors regained normal renal function
later in their course.153 The next study investigated early
markers of renal dysfunction and found that elevations in
urinary microalbumin and malondialdehyde (both three-
and fourfold) were present in all burn patients with even­
tual renal dysfunction.161 These may come to be indicators
of risk for injury that can be acted upon early to prevent
progression to more severe degrees of failure and thereby
improve outcomes.
The last study investigated the role of continuous veno­
venous hemofiltration (CVVH) in the treatment of renal
dysfunction after severe burn. Investigators compared a
population of patients treated with high-volume CVVH (at
least 50 mL/kg per hour) compared to nontreated historical
controls and found that both 28-day and mortality improved
by 50% with this therapy.162 A multicenter RCT comparing
early high-volume CVVH (70 mL/kg per hour) to standard
care is under way in this high-risk population (ClinicalTri­
als.gov Identifier: NCT01213914).
After ensuring adequate volume status, every effort
should be made to prevent other causes of renal injury. All
nephrotoxins should be discontinued or avoided. Hyperka­
lemia may develop and can be treated with resins, glucose
and insulin, and sodium bicarbonate in the presence of
metabolic acidosis. Medications eliminated through the
kidney should be adjusted. Once the diagnosis of AKI is
established, consideration can be given to diuretic therapy
or the early initiation of CVVH, especially if it is determined