Điều Trị Bỏng Toàn Diện (Bản Expert Consult)

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237.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
50. Silverberg R, et al. A survey of the prevalence and application of
chest physical therapy in U.S. burn centers. J Burn Care Rehabil.
1995;16(2 Pt 1):154-159.
51. Koga T, et al. Pulmonary hyperinflation and respiratory distress
following solvent aspiration in a patient with asthma:
expectoration of bronchial casts and clinical improvement with
high-frequency chest wall oscillation. Respir Care. 2004;49(11):
1335-1338.
52. McCall JE, Cahill TJ. Respiratory care of the burn patient. J Burn
Care Rehabil. 2005;26(3):200-206.
53. Cox CS, Jr., et al. Heparin improves oxygenation and minimizes
barotrauma after severe smoke inhalation in an ovine model. Surg
Gynecol Obstet. 1993;176(4):339-349.
54. Desai MH, et al. Reduction in mortality in pediatric patients with
inhalation injury with aerosolized heparin/N-acetylcystine
correction of acetylcystine therapy. J Burn Care Rehabil. 1998;
19(3):210-212.
55. Fu Z, et al. The influence of N-acetyl-L-cysteine on pulmonary
injury and oxygen stress after smoke inhalation injury. Zhonghua
Shao Shang Za Zhi. 2002;18(3):152-154.
56. Sheridan RL. Airway management and respiratory care of the
burn patient. Int Anesthesiol Clin. 2000;38(3):129-145.
57. Dries DJ. Key questions in ventilator management of the
burn-injured patient (first of two parts). J Burn Care Res.
2009;30(1):128-138.
58. Dries DJ. Key questions in ventilator management of the
burn-injured patient (second of two parts). J Burn Care Res.
2009;30(2):211-220.
59. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory
distress syndrome. The Acute Respiratory Distress Syndrome
Network. N Engl J Med. 2000;342(18):1301-1308.
60. Peck MD, Koppelman T. Low-tidal-volume ventilation as a
strategy to reduce ventilator-associated injury in ALI and ARDS.
J Burn Care Res. 2009;30(1):172-175.
61. Sheridan RL, et al. Permissive hypercapnia as a ventilatory strategy
in burned children: effect on barotrauma, pneumonia, and
mortality. J Trauma. 1995;39(5):854-859.
62. Allan PF, et al. High-frequency percussive ventilation revisited.
J Burn Care Res. 2010;31(4):510-520.
63. Cortiella J, Mlcak R, Herndon D. High frequency percussive
ventilation in pediatric patients with inhalation injury. J Burn
Care Rehabil. 1999;20(3):232-235.
64. Mlcak R, et al. Lung compliance, airway resistance, and work of
breathing in children after inhalation injury. J Burn Care Rehabil.
1997;18(6):531-534.
65. Mlcak RP. Airway pressure release ventilation. J Burn Care Res.
2009;30(1):176-177.
66. Dart BWT, et al. Preliminary experience with airway pressure
release ventilation in a trauma/surgical intensive care unit.
J Trauma. 2005;59(1):71-76.
67. Thompson JT, et al. Successful management of adult smoke
inhalation with extracorporeal membrane oxygenation. J Burn
Care Rehabil. 2005;26(1):62-66.
68. Pierre EJ, et al. Extracorporeal membrane oxygenation in the
treatment of respiratory failure in pediatric patients with burns.
J Burn Care Rehabil. 1998;19(2):131-134.
69. Eckhauser FE, et al. Tracheostomy complicating massive burn
injury. A plea for conservatism. Am J Surg. 1974;127(4):418-423.
70. Coln CE, Purdue GF, Hunt JL. Tracheostomy in the young
pediatric burn patient. Arch Surg. 1998;133(5):537-539;
discussion 539-540.
71. Palmieri TL, Jackson W, Greenhalgh DG. Benefits of early
tracheostomy in severely burned children. Crit Care Med.
2002;30(4):922-924.
72. Saffle JR, Morris SE, Edelman L. Early tracheostomy does not
improve outcome in burn patients. J Burn Care Rehabil.
2002;23(6):431-438.
73. Palmieri TL. Long term outcomes after inhalation injury. J Burn
Care Res. 2009;30(1):201-203.
74. Park GY, et al. Prolonged airway and systemic inflammatory
reactions after smoke inhalation. Chest. 2003;123(2):475-480.
75. Mlcak R, et al. Lung function following thermal injury in
children–an 8-year follow up. Burns. 1998;24(3):213-216.
76. McElroy K, et al. Exercise stress testing for the pediatric patient
with burns: a preliminary report. J Burn Care Rehabil. 1992;13(2
Pt 1):236-238.
77. Desai MH, et al. Does inhalation injury limit exercise endurance
in children convalescing from thermal injury? J Burn Care Rehabil.
1993;14(1):12-16.
78. Bourbeau J, et al. Combined smoke inhalation and body surface
burns injury does not necessarily imply long-term respiratory
health consequences. Eur Respir J. 1996;9(7):1470-1474.
79. Casper JK, et al. Laryngeal and phonatory status after burn/
inhalation injury: a long term follow-up study. J Burn Care
Rehabil. 2002;23(4):235-243.
80. Traber MG, et al. α-Tocopherol adipose tissue stores are depleted
after burn injury in pediatric patients. Am J Clin Nutr.
2010;92(6):1378-1384.
81. Nguyen TT, et al. Free radical activity and loss of plasma
antioxidants, vitamin E, and sulfhydryl groups in patients with
burns: the 1993 Moyer Award. J Burn Care Rehabil. 1993;14:
602-609.
82. Rehberg S, et al. The role of nitric oxide and reactive
nitrogen species in experimental ARDS. Front Biosci (Schol Ed).
2010;2:18-29.
83. Hamahata A, et al. gamma-Tocopherol nebulization by a lipid
aerosolization device improves pulmonary function in sheep
with burn and smoke inhalation injury. Free Radic Biol Med.
2008;45(4):425-433.
84. Morita N, et al. Vitamin E attenuates acute lung injury in sheep
with burn and smoke inhalation injury. Redox Rep. 2006;11(2):
61-70.
85. Lange M, et al. Beneficial effects of concomitant neuronal and
inducible nitric oxide synthase inhibition in ovine burn and
inhalation injury. Shock. 2011;35(6):626-631.
86. Enkhbaatar P, et al. The inducible nitric oxide synthase inhibitor
BBS-2 prevents acute lung injury in sheep after burn and smoke
inhalation injury. Am J Respir Crit Care Med. 2003;167(7):
1021-1026.
87. Shimoda K, et al. Effect of poly(ADP ribose) synthetase inhibition
on burn and smoke inhalation injury in sheep. Am J Physiol Lung
Cell Mol Physiol. 2003;285(1):L240-L249.
88. Enkhbaatar P, et al. Inhibition of neuronal nitric oxide synthase
by 7-nitroindazole attenuates acute lung injury in an ovine
model. Am J Physiol Regul Integr Comp Physiol. 2003;285(2):
R366-R372.
89. Enkhbaatar P, et al. Inducible nitric oxide synthase dimerization
inhibitor prevents cardiovascular and renal morbidity in sheep
with combined burn and smoke inhalation injury. Am J Physiol
Heart Circ Physiol. 2003;285(6):H2430-H2436.
90. Lange M, et al. Beneficial Pulmonary Effects of a
Metalloporphyrinic Peroxynitrite Decomposition Catalyst in Burn
and Smoke Inhalation Injury. Am J Physiol Lung Cell Mol Physiol.
2011;300(2):L167-L175.
91. Szabo C. Hydrogen sulphide and its therapeutic potential. Nat
Rev Drug Discov. 2007;6(11):917-935.
92. Esechie A, et al. Beneficial effect of a hydrogen sulphide donor
(sodium sulphide) in an ovine model of burn- and smoke-
induced acute lung injury. Br J Pharmacol. 2009;158(6):
1442-1453.
93. Esechie A, et al. Protective effect of hydrogen sulfide in a murine
model of acute lung injury induced by combined burn and
smoke inhalation. Clin Sci (Lond). 2008;115(3):91-97.
94. Mlcak R, et al. Lung function following thermal injury in
children–an 8-year follow up. Burns. 1998;24:213-216.

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95. Sousse LE, et al. Acute lung injury-induced collagen deposition is
associated with elevated asymmetric dimethylarginine and
arginase activity. Shock. 2011;35(3):282-288.
96. Enkhbaatar P, Herndon DN, Traber DL. Use of nebulized heparin
in the treatment of smoke inhalation injury. J Burn Care Res.
2009;30(1):159-162.
97. Palmieri TL, et al. Studies of inhaled agents in inhalation injury.
J Burn Care Res. 2009;30(1):169-171.
98. Palmieri TL, et al. Inhalation injury in children: a 10 year
experience at Shriners Hospitals for Children. J Burn Care Res.
2009;30(1):206-208.
99. Traber DL, et al. Tocopherol as treatment for lung injury
associated with burn and smoke inhalation. J Burn Care Res.
2009;30(1):164-165.

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©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00020-5
Respiratory care
Ronald P. Mlcak, Sachin D. Hegde, David N. Herndon
Introduction
The multitude of respiratory complications caused by smoke
inhalation, thermal burns, and their treatment epitomize the
clinical challenges which confront respiratory care practi­
tioners. Smoke inhalation injury and its sequelae impose
demands upon the respiratory care practitioners who play a
central role in its clinical management. These demands may
range from intubation and resuscitation of victims in the
emergency room to assistance with diagnostic broncho­
scopies, to performance of pulmonary function studies,
monitoring of arterial blood gases, airway maintenance,
chest physiotherapy, and mechanical ventilator manage­
ment.1 Additional demands are placed upon the respiratory
care practitioner in the rehabilitation phase in determining
disability or limitations diagnosed by pulmonary function
studies or cardiopulmonary stress testing. In some countries
outside the United States, the duties of the respiratory care
practitioner are augmented by a combination of physicians,
nurses, and physiotherapists. It is imperative that a well-
organized, protocol-driven approach to respiratory care of
the burn patient be utilized so that improvements can be
made, and the morbidity and mortality associated with inha­
lation injury can be reduced (Box 20.1). This chapter pro­
vides an overview of the common hands-on approaches
to the treatment of inhalation injury, with emphasis on
mucociliary clearance techniques, pharmacologic adjuncts,
mechanical ventilation, infection control, and the late com­
plications associated with inhalation injury.
Bronchial hygiene therapy
Airway clearance techniques are an essential component of
respiratory management of patients with smoke inhalation.
Bronchial hygiene therapy is a term used to describe several
of the modalities intended to accomplish this goal. Thera­
peutic coughing, chest physiotherapy, early ambulation,
airway suctioning, therapeutic bronchoscopy, and pharma­
cologic agents have been effective in the removal of retained
secretions.
Therapeutic coughing
Therapeutic coughing functions to promote airway clearance
of excess mucus and fibrin cast in the tracheal bronchial tree.
The impairment of the cough mechanism will result in
retained secretions, bronchial obstruction, atelectasis, and/
or pneumonia. A cough may be either a reflex or a voluntary
action. The mechanisms of a cough include:
•
a deep inspiration;
•
the closure of the glottis;
•
contraction of the muscles of the chest wall, abdomen,
and pelvic floor;
•
opening of the glottis; and
•
a rapid expulsive exhalation phase.
During a cough, alveolar, pleural, and subglottic pressures
may rise as much as 200 cmH2O. A failure of the cough
mechanism may be due to an impairment of any step in the
sequences described. When this occurs, it is necessary to
perform techniques which are used to improve the cough.
Series of three coughs
The patient is asked to start a small breath and small cough,
then a bigger breath and harder cough, and finally a really
deep breath and hard cough. This technique is especially
effective for postoperative patients who tend to splint
from pain.2
Tracheal tickle
The therapist places the index and middle finger flat in the
sternal notch and gently massages inward in a circular
fashion over the trachea. This is most effective in obtunded
patients or in patients coming out of anesthesia.2
Cough stimulation
Patients with artificial airways cannot cough normally since
a tube is either between the vocal cords (endotracheal) or
below the cords (tracheostomy). Adequate pressure cannot
be built up without approximation of the cords. These
patients may have a cough stimulated by inflating the cuff
on the tube, giving a large, rapid inspiration by a manual
resuscitation bag, holding the breath for 1–2 s, and rapidly
allowing the bag to release and exhalation to ensue. This
technique is normally performed by two persons and is
made more effective by one therapist performing vibration
and chest compressions from the time of the inspiratory
hold, all during exhalation.2 Cough and deep breathing exer­
cises are encouraged every 2 h to aid in removing retained
secretions.
CHAPTER 20 
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IN THIS CHAPTER
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Total Burn Care
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240
Box 20.1  Inhalation injury treatment protocol
•
Titrate humidified oxygen to maintain SaO2s >90%
•
Cough, deep breath exercises every 2 h
•
Turn patient side to side every 2 h
•
Chest physiotherapy every 4 h
•
Aerosolize 3 cc of 20% N-acetylcysteine every 4 h with a
bronchodilator
•
Alternate aerosolizing 5000 units of heparin with 3 cc of normal
saline every 4 h
•
Nasotracheal suctioning as needed
•
Early ambulation on postoperative day 5
•
Sputum cultures for intubated patients every M-W-F
•
Pulmonary function studies prior to discharge and at outpatient
visits
•
Patient/family education regarding inhalation injury.
The protocol is continued for 7 days.
Figure 20.1  Patient positioning for secretion mobilization.
Figure 20.2  Chest physiotherapy techniques.
Chest physiotherapy
Chest physiotherapy has come to mean gravity-assisted
bronchial drainage with chest percussion and vibrations.
Studies have shown that a combination of techniques are
effective in secretion removal.3–6
Bronchial drainage/positioning
Bronchial drainage/positioning is a therapeutic modality
that uses gravity-assisted positioning designed to improve
pulmonary hygiene in patients with inhalation injury or
retained secretions. There are 12 basic positions in which
patients can be placed for postural drainage. Due to skin
grafts, donor sites, and the use of air fluid beds, clinical judg­
ment dictates that most of these positions are not practical.
In fact, positioning in the Trendelenburg and various other
positions may acutely worsen hypoxemia. Evidence has
shown that a patient’s arterial oxygenation may fall during
positioning.7 To accomplish the same goal it is common
practice, in intensive care units, to turn patients side to side
every 2 h so as to aid in mobilizing secretions (Fig. 20.1).
Percussion
Percussion aids in the removal of secretions from the tra­
cheal bronchial tree. Percussion is done by cupping the hand
so as to allow a cushion of air to come between the percus­
sor’s hand and the patient. If this is done properly, a popping
sound will be heard when the patient is percussed. There
should be a towel between the patient and the percussor’s
hand in order to prevent irritation of the skin.8 Percussion
is applied over the surface landmarks of the bronchial seg­
ments that are being drained. The hands rhythmically and
alternately strike the chest wall. Incisions, skin grafts, and
bony prominences should be avoided during percussion
(Fig. 20.2).
Vibration/shaking
Vibration/shaking is a shaking movement used to move
loosened secretions to larger airways so that they can be
coughed up or removed by suctioning. Vibration involves
rapid shaking of the chest wall during exhalation. The per­
cussor vibrates the thoracic cage by placing both hands over
the percussed areas and vibrating into the patient, isometri­
cally contracting or tensing the muscles of their arms and
shoulders. Mechanical vibrations have been reported to
produce good clinical results. Gentle mechanical vibration
may be indicated for patients who cannot tolerate manual
percussion (Fig. 20.3). Chest physiotherapy techniques
should be used every 2–4 h for patients with retained secre­
tions. Therapy should continue until breath sounds improve.
Early ambulation
Early ambulation is another effective means of preventing
respiratory complications. Patients routinely should be
helped out of bed on postoperative day 5 and encouraged
to ambulate and sit in a chair. With appropriate use of anal­
gesics, even patients on continuous ventilatory support can
be helped out of bed and into a chair (Fig. 20.4). The rocking
chair (Fig. 20.5) has several beneficial effects:
•
the patient can breathe with regions of the lungs which
are normally hyperventilated;
•
muscular strength and tone are preserved;
•
contractions are prevented and exercise tolerance is
maintained.9

Respiratory care
241
Airway suctioning
Airway suctioning is another method of clearing an airway.
Normal bronchial hygiene is usually accomplished by the
mucociliary escalator process. When these methods are not
effective in maintaining a clear airway, tracheobronchial suc­
tioning is indicated.10–13 Nasotracheal suctioning is intended
to remove from the trachea accumulated secretions and
other foreign material which cannot be removed by the
patient’s spontaneous cough or less-invasive procedures.
Nasotracheal suctioning has been used to avoid intubation
which was solely intended for the removal of secretions.
Nasotracheal suctioning refers to the insertion of a suction
catheter through the nasal passages and pharynx into the
trachea in order to aspirate secretions or foreign material.
The first step in this process is to hyperoxygenate the patient
with 100% oxygen. The patient should be positioned in the
Fowler’s position and the catheter slowly advanced through
the nares to a point just above the larynx. The therapist or
nurse then listens for air sounds at the proximal end of the
catheter. When airflow is felt to be strongest and respiratory
sounds are loudest, the tip of the catheter is immediately
above the epiglottis. On inspiration, the catheter is advanced
into the trachea. After the vocal cords have been passed, a
few deep breaths are allowed and the patient is reoxygen­
ated. Suction is begun while the catheter is slowly withdrawn
from the trachea. The patient should not be suctioned for
more than 15 s without being reoxygenated. Suctioning is
not without potential hazards.14,15 Complications include
irritation of the nasotracheal mucosa with bleeding, abrupt
drops in PO2, vagal stimulation, and bradycardia. Preoxy­
genating and limiting suction time have been shown to
decrease or eliminate the fall in the PO2.12–14 Sputum cultures
should be performed for microbiological identification
when they are clinically indicated. Patients on mechanical
ventilation should have sputum cultures performed once
per week.
Therapeutic bronchoscopy
When all other techniques fail to remove secretions, the use
of the fiberoptic bronchoscope has proven to be of benefit.
In addition to its diagnostic functions, bronchoscopy
retains important therapeutic applications. Copious secre­
tions encountered in patients with inhalation injury may
require repeated bronchoscopic procedures when more con­
servative methods are unsuccessful. The modern fiberoptic
bronchoscope is small in diameter, flexible, and has a steer­
able tip that can be maneuvered into the fourth- or fifth-
order bronchi for examination or specimen removal.
Pharmacologic adjuncts
Bronchodilators
Bronchodilators can be helpful in some cases. Inhalation
injury to the lower airways results in a chemical tracheobron­
chitis which can produce wheezing and bronchospasms.
This is especially true for patients with preexisting reactive
airway diseases. Most drugs used in the management of
bronchospasms are believed to act on the biochemical
mechanism which controls bronchial muscle tone. Aero­
solized sympathomimetics are effective in two ways: they
Figure 20.3  Gentle mechanical chest vibrations.
Figure 20.4  Early ambulation.
Figure 20.5  Patient up out of bed, secretions being mobilized by rocking,
and chest physiotherapy techniques.

Total Burn Care
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242
smoke or by one or more of the compounds in the arachi­
donic cascade.22 Animal studies have shown an increased P/F
ratio, decreased peak inspiratory pressures, and a decreased
amount of fibrin cast formation with heparin/acetylcysteine
combinations.23 In a retrospective review, Desai et al. have
shown that the use of heparin/N-acetylcysteine is effective in
pediatric patients with inhalation injury.24 Results indicate a
significant decrease in the reintubation rates, incidence of
atelectasis, and improved mortality for patients treated with
heparin/N-acetylcysteine therapy. Therefore a standard treat­
ment for patients with inhalation injury might include
5000–10 000 units of heparin and 3 mL normal saline
nebulized every 4 h, alternating with 3–5 mL of 20% acetyl­
cysteine for 7 days. This insures that the patient receives an
aerosolized treatment every 2 h. Baseline and daily clotting
studies are recommended for the entire length of the aero­
solized treatments.
A prospective randomized study on the use of nebulized
heparin for the treatment of inhalation injury is necessary
to validify the continued used of this mode of therapy. A
multicenter study is being developed that will evaluate the
effectiveness of therapy and answer some of the questions
regarding the mechanism of action, safety, and affects on
lung function.
Patient/family education
Burn care involves utilizing a family-centered care approach.
Therefore the patient and family should be informed about
the extent of the lung injury and the various treatment
options available based upon evidence-based medicine or
best practice.
Mechanical ventilation
Over the past 30 years, and especially over the past decade,
there has been an increase in new ventilatory techniques
which present alternatives for the treatment of patients with
smoke inhalation. Unfortunately, although the number of
options available to the clinician has appeared to increase
exponentially, well-controlled clinical trials defining the
specific role for each of the modes of ventilation and com­
paring them to other modes of ventilation have not been
forthcoming. Based upon current available data, the recom­
mendations from the American College of Chest Physicians
consensus conference on mechanical ventilation generally
serve as guidelines.25 The general consensus concludes:
•
The clinician should choose a ventilator mode that has
been shown to be capable of supporting oxygenation
and ventilation and that the clinician has experience in
using.
•
An acceptable oxygen saturation should be targeted.
•
Based primarily on animal data, a plateau pressure of
greater than 35 cmH2O is cause for concern. With
clinical conditions that are associated with a decreased
chest wall compliance, plateau pressures greater than
35 cmH2O may be acceptable.
•
To accomplish the goal of limiting plateau pressures,
PCO2 values should be permitted to rise (permissive
hypercapnia) unless other contraindications exist that
demand a more normal PCO2 or pH.
result in bronchial muscle relaxation and they stimulate
mucociliary clearance. The newer bronchodilators are more
effective and have fewer side-effects than the older genera­
tion drugs. Some of the newer compounds used in the
United States are worthy of note. First, metaproterenol is
available in cartridge inhalers, as a liquid to be aerosolized,
as an oral medication in tablets, or as a syrup. The recom­
mended oral dose is 10–20 mg every 6–8 h; as an inhaled
bronchodilator, 1–2 puffs every 3–4 h. Its duration of action
as an inhaled bronchodilator is 1–5 h.16
Albuterol can also be administered orally, parenterally,
and by aerosol. Albuterol is available in a metered cartridge
inhaler and its standard dose is 1–2 puffs three to four times
daily. Aerosolized albuterol has a duration of action of
approximately 4–6 h.17
Racemic epinephrine is used as an aerosolized topical
vasoconstrictor, bronchodilator, and secretion bond breaker.
The vasoconstrictive action of racemic epinephrine is useful
in reducing mucosal and submucosal edema within the
walls of the pulmonary airways. A secondary bronchodilator
action serves to reduce potential spasm of the smooth
muscles of the terminal bronchioles. Water, employed as a
diluent for racemic epinephrine, serves to lower both adhe­
sive and cohesive forces of the retained endobronchial secre­
tions, thus serving as a bond-breaking vehicle. Racemic
epinephrine has also been used for the treatment of post-
extubation stridor.18 Its mode of action is thought to be
related to the vasoconstrictive activity, with the resultant
decrease in mucosal edema. Aerosolized treatments may be
given every 2 h as long as the heart rate is not increased.
Hypertonic saline offers a theoretically more effective form
of mucokinetic therapy. The deposition of hypertonic drop­
lets on the respiratory mucosa results in the osmotic attrac­
tion of fluids from the mucosal blood vessels and tissues
into the airway. Thus a ‘bronchorrhea’ is induced, and the
watery solution helps to dilute down the respiratory tract
secretions and to increase their bulk, thereby augmenting
expectoration. Furthermore, there is evidence that hyper­
tonic saline has a direct effect on the mucoprotein DNA
complexes, and by reducing the cohesive intramolecular
forces, the salt helps reduce the viscous properties of the
mucoid fluid.19 Excessive use of hypertonic saline is not
recommended because irritation can occur in the respiratory
tract, absorption can occur, and burn patients who cannot
tolerate the sodium load may develop edema.
Finally, aerosolized acetylcysteine is a powerful mucolytic
agent in use in respiratory care. Acetylcysteine contains a
thiol group; the free sulfhydryl radical of this group is a
strong reducing agent which ruptures the disulfide bonds
that serve to give stability to the mucoprotein network of
molecules in mucus. Agents that break down these disulfide
bonds produce the most effective mucolysis.20 Acetylcysteine
is an irritant to the respiratory tract. It can cause mucosal
changes, and it may induce bronchospasm. For this reason,
patients are evaluated for signs of bronchospasm, and a
bronchodilator may be added if necessary. Acetylcysteine has
proven to be effective in combination with aerosolized
heparin for the treatment of inhalation injury in animal
studies.21
Heparin/acetylcysteine combinations have been used as
scavengers for the oxygen free radicals produced when alveo­
lar macrophages are activated either directly by chemicals in

Respiratory care
243
•
It is sometimes poorly tolerated in awake, nonsedated
subjects and can require sedation to insure synchrony
of patient and machine.
•
It can cause respiratory alkalosis.
•
It may worsen air trapping with patients with chronic
obstructed lung disease.24
Synchronized intermittent mandatory ventilation
Synchronized intermittent mandatory ventilation (SIMV)
combines a preset number of ventilator-delivered manda­
tory breaths of present tidal volume with the facility for
intermittent patient-generated spontaneous breaths.34,35
Advantages are as follows:
•
The patient is able to perform a variable amount of
respiratory work and yet there is the security of a preset
mandatory level of ventilation.
•
SIMV allows for a variation in level of partial
ventilatory support from near total ventilatory support
to spontaneous breathing.
•
It can be used as a weaning tool.
Disadvantages are:
•
Hyperventilation with respiratory alkalosis.
•
Excessive work of breathing due to the presence of a
poorly responsive demand valve, suboptimal ventilatory
circuits, or inappropriate flow delivery could occur.
•
In each case, extra work is imposed on the patient
during spontaneous breaths.
Pressure control mode
In pressure-controlled ventilation all breaths are time- or
patient-triggered, pressure-limited, and time-cycled. The
ventilator provides a constant pressure of air to the patient
during inspiration. The length of inspiration, the pressure
level, and the back-up rate are set by the operator. Tidal
volume is based upon the compliance and resistance of the
patient’s lungs, the ventilator system, as well as on the preset
pressure. Pressure control ventilation has become a fre­
quently used mode of ventilation for the treatment of ARDS.
Pressure support ventilation
Pressure support ventilation (PSV) is a pressure-targeted,
flow-cycled, mode of ventilation in which each breath must
be patient-triggered. It is used both as a mode of ventilation
during stable ventilatory support periods and as a weaning
method.35–39 It is primarily designed to assist spontaneous
breathing and therefore the patient must have an intact res­
piratory drive.
Advantages are:
•
It is generally regarded as a comfortable mode of
ventilation for most patients.
•
Pressure support reduces the work of breathing.
•
It can be used to overcome the airway resistance caused
by the endotracheal tube.
•
Pressure support may be useful in patients who are
difficult to wean.
Disadvantages are:
•
The tidal volume is not controlled and is dependent on
respiratory mechanics, cycling frequency, and synchrony
between the patient and ventilator.
•
Positive end-expiratory pressure (PEEP) is useful in
supporting oxygenation. An appropriate level of PEEP
may be helpful in preventing lung damage. The level of
PEEP required should be established by empirical trials
and reevaluated on a regular basis.
•
Large tidal volumes (8–10 mL/kg) with PEEP may be
needed to improve oxygenation if the use of protective
ventilatory strategies becomes ineffective. Peak flow
rates should be adjusted as needed to satisfy patient
inspiratory needs.25 Care must be taken to avoid the
consequences of utilizing high ventilator pressures if
large tidal volumes are required.
Animal studies performed showed a reduction in ventilator-
induced injury with a reduction in plateau pressures to
35 cm of water by increasing positive end-expiratory pres­
sure (PEEP) and decreasing tidal volume.26 A number of
clinical trials have been conducted to support this treatment
strategy.27–29 A meta-analysis of these trials was conducted by
the Cochrane Anesthesia Review Group in 2007.30 It showed
a reduction in mortality and duration of mechanical ventila­
tion with the use of plateau pressure at <31 cm water and
tidal volume at <7 mL/kg body weight. In light of this evi­
dence, the tidal volumes used when initiating mechanical
ventilation should be 6–8 mL/kg of predicted body weight.
If the patient becomes obstructed with fibrin cast and
presents with an acute increase in PCO2 and decrease in
PaO2, the clinician should first provide aggressive pulmo­
nary toilet, then consider changing over to volume ventila­
tion with higher tidal volumes. If ventilation continues to
worsen, tidal volumes of 8–10 mL/kg may be needed to
provide adequate mechanical ventilation.
Modes of ventilation
Control mode
In the control mode of ventilation, the ventilator cycles auto­
matically at a rate selected by the operator. The adjustment
is usually made by a knob calibrated in breaths/min. The
ventilator will cycle regardless of the patient need or desire
for a breath, but guarantees a minimum level of minute
ventilation in the anemic, sedated, or paralyzed patient. The
control mode of ventilation is often utilized in patients with
ARDS because of the high peak pressures needed to achieve
adequate chest expansion. The major disadvantage with this
mode is that the patient cannot cycle the ventilator and thus
the minute ventilation must be set appropriately.
Assist-control mode
In the assist-control mode of ventilation, in which every
breath is supported by the ventilator, a back-up control rate
is set; however, the patient may choose any rate above the
set rate. Using this mode of ventilation, the tidal volume,
inspiratory flow rate, flow waveform, sensitivity, and control
rate are set.31–33 Advantages are that assist-control ventilation
combines the security of controlled ventilation with the pos­
sibility of synchronizing the breathing pattern of the patient
and ventilator, and it ensures ventilatory support during each
breath. Disadvantages are as follows:
•
Excessive patient work occurs in case of inadequate
peak flow or sensitivity settings, especially if the
ventilator drive of the patient is increased.31–33

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20.1). The pulsatile flow (PIP) rate should set at 20 cmH2O.
The pulse frequency (high rate) should be set between 500
and 600. The low respiratory rate should be set at about
15–20. Oscillatory PEEP levels should be initially set at
about 3 cmH2O, and demand PEEP set on 2 cmH2O. Venti­
lator settings are adjusted based upon the patient’s clinical
condition and blood gas values. To improve oxygenation,
the ventilator can be set up in a more diffusive mode
(increased pulse frequency) and, to eliminate carbon dioxide,
the ventilator can be set up in a more convective mode
(decreased pulse frequency). With this mode of ventilation,
subtidal volumes are delivered in a progressive stepwise
fashion until a preset oscillatory equilibrium is reached and
exhalation is passive.
Clinicians must be familiar with the technique used and
its possible limitations. There must be adequate humidifica­
tion of the respiratory gases or severe necrotizing tracheo­
bronchitis can occur. Special delivery devices for providing
adequate humidification during HFV are required. It is not
clear when and how it should be used following inhalation
injury.52 Its efficacy in comparison to other modes of ventila­
tion needs to be assessed. As the methodology to HFPV
evolves, it is anticipated that HFPV will play a larger role
in the care of select mechanical ventilation-dependent
populations.53
Pressure control inverse ratio ventilation
Pressure control inverse ratio ventilation (PCIRV) is the use
of pressure ventilation with an inspiratory/expiratory (I:E)
ratio greater than 1 : 1. The rationale behind this is to main­
tain a high mean airway pressure and to hold peak alveolar
pressure within a safe range. The second theoretical concept
underlying PCIRV is the prolongation of inspiration to allow
for recruitment of lung units with a long time constant. Deep
sedation and/or paralysis is nearly always required with this
mode of ventilation. At this time there is no conclusive sci­
entific data comparing PCIRV to conventional mechanical
ventilation in patients with inhalation injury.
Airway pressure release ventilation
Airway pressure release ventilation (APRV) is a pressure-
regulated mode of ventilatory support that allows for time-
cycled decreases in pressure to facilitate CO2 elimination.
This mode allows spontaneous breathing while limiting
airway pressures and may therefore limit the amount of
•
Pressure support may be poorly tolerated in some
patients with high airway resistances because of the
preset high initial flow rates.
Alternate modes of ventilation
During the last decade, a new concept has emerged regarding
acute lung injury. In severe cases of ARDS, only a small part
of the lung parenchyma remains accessible to gas delivered
by mechanical ventilation.40,41 As a consequence, tidal
volumes of 10 mL/kg or more may over expand and injure
the remaining normally aerated lung parenchyma and could
worsen the prognosis of severe acute respiratory failure by
extending non-specific alveolar damage. High airway pres­
sures may result in over distension and local hyperventila­
tion of more compliant parts of the diseased lung. Over
distension of lungs in animals has produced diffuse alveolar
damage.42–44 This is the reason why alternative modes of
ventilation, all based on a reduction of end-inspiratory
airway pressures and/or tidal volumes delivered to the
patient, have been developed and are used by many clini­
cians caring for patients with severe forms of acute or chronic
respiratory failure. Five alternative modes of ventilation:
high-frequency ventilation (HFV); high-frequency percussive
ventilation (HFPV); pressure control inverse ratio ventilation
(PCIRV); airway pressure release ventilation (APRV), and
volumetric diffusive ventilation (VDR), will be discussed.
High-frequency ventilation
High-frequency ventilation (HFV) is the administration of
small tidal volumes of 1–3 mL/kg at high frequencies of
100–3000 cpm.45 Because it is a mode of ventilation based
on a marked reduction in tidal volumes and airway pres­
sures, it has the greatest potential for reducing pulmonary
barotraumas. There are a number of different types of high-
frequency ventilation techniques. The two most common are
high-frequency jet ventilation (HFJV) and high-frequency
percussive ventilation (HFPV).
High-frequency jet ventilation is the only high-frequency
mode routinely used to ventilate patients with ARDS, mainly
in Europe.25 Comparative data concerning the advantages of
HFJV over conventional ventilation are limited. There is no
agreement, however, that HFJV is better than conventional
mechanical ventilation in ARDS.46
High-frequency percussive ventilation is a relatively new
technique that has shown some promise in the ventilation
of patients with inhalation injury.47–49 The term HFPV refers
to ventilation utilizing the VDR ventilator. Clinical studies
indicate that this mode of ventilation may aid in reducing
pulmonary barotrauma.47,48 In a retrospective study, Cortiella
et al. have shown a decreased incidence of pneumonia,
peak inspiratory pressure, and an improved P/F ratio in
children ventilated with the use of HFPV as compared with
controls.50
In the first prospective randomized study on HFPV, Mlcak
et al. have shown a significant decrease in the peak inspira­
tory pressures needed to ventilate pediatric patients with
inhalation injury.51 No significant differences were found for
incidence of pneumonia, P/F ratios, or mortality.
Based upon clinical experience, the following guidelines
are given for initial set-up of the HFPV in children (Table
Table 20.1  High-frequency percussive ventilation
set-up guidelines
Variable
Settings
Pulsatile flow rate (PIP)
20 cmH2O
Pulse frequency (high rate)
500–600
Low respiratory rate
15–20
I:E ratio
1 : 1 or 2 : 1
Oscillatory PEEP
3 cmH2O
Demand PEEP
2 cmH2O

Respiratory care
245
concern regarding the development of barotrauma and
ventilator-induced lung injury increases.55,56 The clinician
must always look at the patient to insure adequate chest
expansion with the setting of the tidal volume. Expired tidal
volumes should be measured for accuracy at the connection
between the patient’s wye and the artificial airway. This
insures that the volume selected reaches the patient and is
not lost in the compressible volume of the ventilator tubing.
The range of tidal volumes will vary depending on the
disease process, with some diseases requiring maximum
tidal volumes and others needing less. Severe interstitial dis­
eases such as pneumonia and ARDS may require a tidal
volume of 8–10 mL/kg to adequately inflate the lungs and
improve gas exchange if protective ventilatory strategies
become inadequate. However, the acceptable range of
6–8 mL/kg allows the clinician to make more precise adjust­
ments in volume, as needed by the patient.
Respiratory rate
Setting of the mandatory ventilator respiratory rate is depend­
ent on the mode of ventilation selected, the delivered tidal
volume, dead space to tidal volume ratio, metabolic rate,
targeted PCO2 levels, and level of spontaneous ventilation.
With adults, set mandatory rate normally varies between 4
and 20 breaths/min, with most clinically stable patients
requiring mandatory rates in the 8–12 range.57 In patients
with inhalation injury, mandatory rates exceeding 20 per
minute may be necessary, depending on the desired expired
volume and targeted PCO2. It is important to have targeted
arterial blood gas values set to aid the clinical team in proper
management (Table 20.3) Along with the PCO2, pH, and
patient comfort; the primary variable controlling the selec­
tion of the respiratory rate is the development of air trapping
and auto PEEP.58
The respiratory rates of children and infants all need to be
set substantially higher than those of adults. For pediatrics,
the respiratory rate can be set from 12 to 45, depending on
the disease state and the level of targeted PCO2 one wishes
to achieve. Slower respiratory rates are useful in the patient
with obstructed airways because slower rates allow more
time for exhalation and emptying of hyperinflated areas.
Arterial blood gases should be checked after the patient
has been on the ventilator for approximately 20 min and the
respiratory rate adjusted accordingly.
Flow rates
The selection of peak inspiratory flow rate during volume
ventilation is primarily determined by the level of spontan­
eous inspiratory effort. In patients triggering volume breaths,
patient effort, work of breathing, and patient ventilator
sedatives or neuromuscular blocking agents needed. APRV is
a protective ventilator strategy that uses inverse ratio ventila­
tion at two levels of PEEP. Several limited studies have sug­
gested that APRV may be beneficial for the treatment of burn
patients who develop ARDS. Evidence-based recommenda­
tions to use this mode of ventilation await outcome studies.
Volumetric diffusive ventilation
The volumetric diffusive ventilator (VDR) is a pneumatically
powered, pressure limited ventilator that stacks oscillatory
breaths to a selected peak airway pressure by means of a
sliding venturi called a ‘phasitron’. After inspiration, exhala­
tion is passive and ends at a selected level of oscillatory
CPAP.54 Studies comparing VDR to high volume strategies
have shown VDR improves gas exchange, decreases peak
pressures and lowers mortality. However, there is a need to
compare VDR to the low tidal volume ventilation being
practiced more recently. Usage of the VDR requires special
training; the other disadvantages are the inability to monitor
tidal and minute volumes and the requirement of humidi­
fied air and nebulized saline to prevent airway desiccation.
Typical ventilator settings required
A large multicentered study by the NHLBI evaluated the use
of volume ventilation with low versus high tidal volume on
ARDS. This study documented a decreased incidence of mor­
tality in patients with ARDS who were ventilated with small
tidal volumes.27 Based upon this study, it has become clini­
cally accepted practice to use small tidal volumes when ini­
tially setting up mechanical ventilation (Table 20.2).
Tidal volumes
In volume-cycled ventilation, a machine-delivered tidal
volume is set to be consistent with adequate gas exchange
and patient comfort. The tidal volume selected for burned
patients normally varies between 6 and 8 mL/kg of predicted
body weight. Numerous factors, such as lung/thorax compli­
ance, system resistance, compressible volume loss, oxyge­
nation, ventilation, and barotrauma, are considered when
volumes are selected.51 Of critical importance is the avoid­
ance of over distension. This can generally be accomplished
by insuring that peak airway and alveolar pressures do not
exceed a maximum target. Many would agree that a peak
alveolar pressure greater than 35 cmH2O in adults raises
Table 20.2  Traditional mechanical ventilation guidelines
in children
Variable
Settings
Tidal volumes
6–8 mL/kg
Respiratory rate
12–45 breaths/min
Plateau pressures
<30 cmH2O
I:E ratio
1 : 1–1 : 3
Flow rate
40–100 L/min
PEEP
7.5 cmH2O
Table 20.3  Arterial blood gas goals
Variable
Goal
pH
7.25–7.45
PO2
55–80 mmHg or SaO2 of 88–95%
PCO2
35–55 mmHg (permissive hypercapnia can be used
as long as pH > 7.25)

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246
intubation holds the larynx constantly open, which leads to
alveolar collapse and a reduction in the functional residual
capacity.
Optimal PEEP is the level of end-expiratory pressure that
results in the lowering of intrapulmonary shunting, signifi­
cant improvement in arterial oxygenation, and only a small
change in cardiac output, arteriovenous oxygen content dif­
ferences, or mixed venous oxygen tension.
In order to decide the ideal PEEP for patients with ALI or
ARDS, the ARDS Network performed a multicenter, rand­
omized, prospective clinical trial.62 ALI or ARDS patients
were treated with 6 mL/kg predicted body weight tidal
volumes, and randomized to either low (5 cm H2O up to
24) or high (12 cm H2O up to 24) PEEP. The trial showed
no effect of higher levels of PEEP on duration of mechanical
ventilation, duration of non-pulmonary organ failure, and
in-hospital mortality.
Extubation criteria
Standard extubation criteria include a wide variety of physio­
logic indices that have been proposed to guide the process
of discontinuing ventilatory support. Traditional indices
include:
•
PaO2/FiO2 ratio of greater than 250
•
Maximum inspiratory pressure of greater than
60 cmH2O
•
Vital capacity of at least 15–20 mL/kg
•
Tidal volume of at least 5–7 mL/kg
•
Maximum voluntary ventilation of at least twice the
minute volume63–66
•
An audible leak around the endotracheal tube must be
present.
In general, these indices evaluate a patient’s ability to
sustain spontaneous ventilation. They do not assess a
patient’s ability to protect the upper airway. For this reason,
traditional indices often fail to reflect the true clinical picture
of a patient with an inhalation injury. For a complete evalu­
ation prior to extubation, bronchoscopic examination will
aid in determining if the airway edema has decreased enough
to attempt extubation. Prior to a scheduled extubation it is
recommended that reintubation equipment be set up and
that the person doing the extubation be experienced in emer­
gency intubations.
If the patient demonstrates signs of inspiratory stridor, the
use of racemic epinephrine by aerosol has been effective in
reducing the mucosal edema and may prevent the patient
from being reintubated.
Infection control of respiratory equipment
Infections are the leading cause of mortality in burned
patients. Pneumonia has become one of the most frequent
life-threatening infections and is an important determinant
of survival.65 The majority of pneumonias are nosocomial,
occurring in the burned patient after 72 h of hospitalization,
and are often associated with either an inhalation injury or
endotracheal intubation with exposure to respiratory care
equipment, or both.67–72 One of the most important risk
factors predisposing to pneumonia in burned patients is
synchrony depend on the selection of peak inspiratory
flow.32 Peak inspiratory flows should ideally match patient
peak inspiratory demands. This normally requires peak flows
to be set at 40–100 L/min, depending on expired volume
and the inspiratory demand.25
Inspiratory/expiratory (I:E) ratio
The time allowed for the inspiratory and expiratory phases
of mechanical ventilation is commonly referred to as the
inspiratory/expiratory (I:E) ratio. The inspiratory part of
the ratio includes the time to deliver the tidal volume before
the exhalation valve opens and exhalation begins. The expir­
atory part of the ratio includes the time necessary for the
tidal volume to exit through the exhalation valve before the
next inspiration begins. The inspiratory time should be long
enough to deliver the tidal volume at flow rates that will not
result in turbulence and high peak airway pressures. The
usual I:E ratio is 1 : 1–1 : 3.59
In severe lung disease, it is acceptable to prolong the
inspiratory time to allow for better distribution of gas and
enhance oxygen diffusion. When a longer inspiratory time
is required, careful attention should be given to sufficient
expiration to avoid stacking of breaths and impeding venous
return. Prolonged inspiratory time creates a more laminar
flow, which helps to keep the peak pressures lower. Fast
inspiratory times are tolerated in patients with severe airway
obstruction. The fast inspiratory time allows for a longer
expiratory phase, which may help to decrease the amount of
overinflation.
Inspired oxygen concentration
As a starting point, and until the level of hypoxemia is deter­
mined, a patient placed on a ventilator should receive an
oxygen concentration of 100%. The concentration should be
systematically lowered as soon as arterial blood gases dictate.
In general, as a result of the concerns regarding the effects
of high oxygen concentration on lung injury, the lowest
acceptable oxygen level should be selected as soon as pos­
sible. In patients who are difficult to oxygenate, oxygen con­
centrations can be minimized by optimizing PEEP and mean
airway pressures and selecting a minimally acceptable oxygen
saturation.60
Positive end-expiratory pressure
Positive end-expiratory pressure (PEEP) is applied to recruit
lung volumes, elevate mean airway pressure, and improve
oxygenation.61 The level of PEEP used varies with the disease
process. PEEP levels should start at 8–10 cmH2O and be
increased in 2.5-cm increments. Increasing levels of PEEP, in
conjunction with a prolonged inspiratory time, aids in oxy­
genation and allows for the safe level of oxygen to be used.
The use of pressure–volume curves to determine the best
PEEP level has been recommended to aid in overstretching
the alveoli. This technique has certain limitations and is dif­
ficult to perform in the clinical setting. The use of PEEP trials
can determine the best PEEP without causing a decrease in
cardiac output.
Usually a minimum of 8 cmH2O of PEEP will be indi­
cated for use during mechanical ventilation since tracheal

Respiratory care
247
strict, respiratory, or enteric isolation and before entering
intensive care units. The most commonly used agents are
70% isopropyl alcohol, iodophors, and chlorhexidine. Scrub
regimens such as the povidone-iodine surgical scrub are
appropriate for these areas.84
Chemical agents for sterilization/disinfection
Disinfectants act to kill microorganisms by several methods:
•
oxidating microbial cells;
•
hydrolyzing;
•
combining with microbial proteins to form salts;
•
coagulating the proteins of microbial cells;
•
denaturing enzymes; or
•
modifying cell wall permeability.85
Aldehydes
Aldehydes contain some of the most commonly used anti­
microbials in respiratory care practice. These agents achieve
their antimicrobial action through the alkylation of enzymes.
The cidal action of glutaraldehyde is accomplished by dis­
ruption of the lipoproteins in the cell membrane and cyto­
plasm of vegetative bacterial forms. This reaction between
the chemical glutaraldehyde and cell proteins is dependent
on both time and contact. Items to be disinfected must be
free of material that would inhibit contact, and adequate
contact time is needed for the chemical reaction to be
complete.
Alkaline glutaraldehyde, buffered by a 0.3% bicarbonate
agent, is used as a 2% solution. Once activated with the
buffering agent, it is fully potent for approximately 14 days.
This solution is bactericidal, virucidal, and tuberculocidal
within 10 min and produces sterilization when applied
for 10–20 h. Equipment disinfected or sterilized with
glutaraldehyde should be thoroughly rinsed and dried prior
to use, because any residue would be irritating to mucous
membranes.
Glutaraldehyde solutions are commonly used for the cold
disinfection or sterilization of respiratory care equipment
and have a large degree of safety. These solutions can be used
to disinfect bronchoscopes as well as many of the current
respiratory supplies.
Alcohols
Alcohols, especially ethylene and isopropyl alcohol, are
perhaps the most commonly used disinfectants. Alcohols, as
a chemical family, have many desirable characteristics needed
in disinfectants. They are generally bactericidal and accom­
plish their bactericidal activity by damaging the cell wall
membrane. They also have the ability to denature proteins,
particularly enzymes called dehydrogenases. For alcohol to
coagulate microbial proteins, water must be present. For this
reason, 70% has been considered the critical dilution for
alcohol, with a rapid loss of bactericidal activity with dilu­
tions less than 50%. Both ethyl and isopropyl alcohols are
rapidly effective against vegetative bacteria and tubercle
bacilli but are not sporicidal.
To be sure that the current infection control practice is
effective in each institution, random microbiological cul­
tures should be done whenever a problem is suspected, or
endotracheal intubation.73,74 The incidence of pneumonia
developing is estimated to be five times higher for intubated
than nonintubated patients, and tracheostomy increases this
risk even higher.75 Exposure to respiratory care equipment
adds an increased risk of pneumonia above and beyond the
risk associated with endotracheal intubation.76,77 After the
use of nebulization equipment in respiratory care became
popular, several epidemics of nosocomial pneumonia were
reported.78 The risk of pneumonia from mechanical ventila­
tors was significant but decreased with a better under­standing
of the necessity to decontaminate respiratory equipment.79,80
Intubated patients receiving respiratory care may be at an
increased risk of pneumonia because of coincidental expo­
sure to other procedures such as suctioning and bronchos­
copy. Respiratory care equipment, if not properly cared for,
may provide a source of extraneous organisms that can con­
taminate the patient’s respiratory tract.
The potential role of respiratory care equipment in provid­
ing reservoirs for organisms that are capable of infecting the
lungs is well established. This problem, particularly pertain­
ing to reservoir devices and medications, has been recog­
nized for a number of years, and effective control strategies
have been developed. Most hospitals maintain a bacterio­
logical monitoring system, and significant contamination by
this route is not likely.81 Contamination of the compressed
gases used to operate respiratory care devices is uncommon,
principally because of the desiccation of gases and the inabil­
ity of most bacterial species to survive such harsh treatment.
Nebulization equipment delivers a fine-particle aerosol and,
if contaminated, the aerosol droplets may contain bacteria.
Humidification equipment provides water vapor but does
not deliver a large quantity of water in particulate form. In
fact, humidifiers generally remove bacteria from airstreams,
because the bacteria are physically trapped in the fluid phase
and are not vaporized.
Bag-mask units have been shown to allow the persistence
of infectious organisms and the subsequent infection of
other patients on whom the equipment has been later used.82
Ventilator circuits are inevitably contaminated by the
patient’s own respiratory tract flora during exhalation and
coughing, and the fluid that collects in this tubing is thereby
contaminated. However, the American Association for Res­
piratory Care evidence-based clinical practice guidelines
suggest that ventilator circuits should not be changed rou­
tinely for infection control purposes.83 The exact length of
time that circuits can be used safely is unknown.
Handwashing
Handwashing is generally considered the single most impor­
tant procedure for preventing nosocomial infections. Regard­
less of whatever benefits are accrued by cleaning or
sterilization, they are negated if the simple process of hand­
washing is overlooked. The recommended handwashing
procedures depend on the purpose of washing. In most situ­
ations, a vigorous brief washing with soap under a strong
running water is adequate to remove transient flora. Gener­
ally, simple handwashing with soap is performed before and
after contact with patients and whenever the hands are
soiled.
Antimicrobial handwashing procedures are indicated
before all invasive procedures, during the care of patients in

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248
persistent severe respiratory symptoms, the severity of the
impairment should be documented and the patient evalu­
ated for a pulmonary rehabilitation program.
Conclusion
Inhalation injury and associated major burns provide a chal­
lenge for healthcare workers who provide direct hands-on
care. The technical and physiologic problems which compli­
cate the respiratory management of these patients require a
practical knowledge of the possible sources of nosocomial
infections. Patients with inhalation injury frequently require
the use of respiratory care equipment that, if not properly
cared for, can aid in the spread of infections. Important
priorities for reducing the risk of infections include: an
aggressive bronchial hygiene therapy program, the adher­
ence to established infection control practices, the use of
universal precautions during procedures, meticulous clean­
ing of respiratory care equipment, as well as routine epid­
emiologic surveillance of the established infection control
practices within each institution.
It is imperative that a well-organized protocol-driven
approach to respiratory care of the burn patient be utilized
so that further improvements can be made, and the mor­
bidity and mortality associated with inhalation injury be
reduced.
Further reading
Cartotto R. Use of high frequency oscillatory ventilation in inhalation
injury. J Burn Care Res. 2009;30(1):178-181.
Mlcak R, Desai MH, Herndon DN. A prospective randomized study
of high frequency percussive ventilation compared to conventional
mechanical ventilation in pediatric patients with inhalation injury.
J Burn Care Rehabil. 2000;21(1):S158.
Mlcak R, Desai MH, Robinson E, et al. Inhalation injury and lung
function in children – a decade later. J Burn Care Rehabil.
2000;21(1):S156.
Peck MD, Koppelman T. Low-tidal-volume ventilation as a strategy to
reduce ventilator-associated injury in ALI and ARDS. J Burn Care
Res. 2009;30(1):172-175.
The Acute Respiratory Distress Syndrome Network. Ventilation with
lower tidal volumes as compared with traditional tidal volumes
for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med. 2000;342(18):1301-1308.
to test the reliability of the disinfection or sterilization
techniques.
Late complications of inhalation injury
Tracheal stenosis
Tracheal complications are commonly seen and consist of
tracheitis, tracheal ulcerations, and granuloma formation.
The location of the stenosis is almost invariably subglottic
and occurs at the site of the cuff of the endotracheal or tra­
cheostomy tube.86 Several problems arising after extubation
represent sequelae of laryngeal or tracheal injury incurred
during the period of incubation. While tracheal stenosis or
tracheomalacia are usually mild and asymptomatic, in some
patients they can present as severe fixed or dynamic upper
airway obstructions. These conditions can require surgical
correction. In the management of intubated patients, such
complications should be mostly preventable by meticulous
attention to the tracheostomy or endotracheal tube cuff.
Inflation of the cuff should be to the minimal pressure level
consistent with preventing a leak in the ventilator at end
inspiration.
Obstructive/restrictive disease
Chronic airway disease is a relatively rare reported sequel of
inhalation injury and its supportive treatment. Spirometry is
a useful screening tool for airway obstruction. Reports in the
literature for adults indicate that lung function returns to
normal after inhalation injury.87,88 However, Mlcak et al.
reported pulmonary function changes following inhalation
injury for up to 10 years post-injury in a group of severely
burned children.89 Fortunately, most pulmonary function
abnormalities will persist for only months following lung
parenchymal injury. In the great majority of cases, eventual
resolution of both symptoms and physiologic abnormalities
will occur. During the resolution phase, serial measurement
of airflow obstruction should be obtained.90 Desai et al.
demonstrated that physiologic insults that occur as a result
of thermal injury may limit exercise endurance in children.91
Data from exercise stress testing showed evidence of a respi­
ratory limitation to exercise. This was confirmed by a decrease
in the maximal heart rate, decrease in the maximal oxygen
consumption, and increased respiratory rate. In the cases of
Access the complete reference list online at

Respiratory care
248.e1
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20. Hirsh SR, Zastrow JE, Kory RC. Sputum liquification agents: a
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22. Desai MH, Mlcak R, Brown M, et al. Reduction of smoke injury
with DMSO and heparin treatment. Surg Form. 1985;36:103.
23. Desai MH, Brown M, Mlcak R, et al. Nebulization treatment of
smoke inhalation injury in sheep model with DMSO, heparin
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19(3):210-212.
25. Slutsky A. American College of Chest Physicians Consensus
Conference: mechanical ventilation. Chest. 1993;104:1833-1859.
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33. Ward ME, Corbeil C, Gibbons MW, et al. Optimization of
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inspiratory work due to endotracheal tubes. Chest. 1988;93:
499-505.
40. Brochard L, Rau F, Lorino H, et al. Inspiratory pressure support
compensates for the additional work of breathing caused by the
endotracheal tube. Anesthesiology. 1991;75:739-745.
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outcome? Intensive Care Med. 1990;9:239-250.
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total respiratory system in acute respiratory failure. Am Rev Respir
Dis. 1987;136:730-760.
43. Dreyfuss D, Soler P, Basset G, et al. High inflation pressures,
pulmonary edema, respective effects of high airway pressure,
high tidal volume and PEEP. Am Rev Respir Dis. 1988;137:
1159-1164.
44. Kolobow T, Moretti MP, Fumagalli R, et al. Severe impairment of
lung function induced by high peak airway pressure during
mechanical ventilation. Am Rev Respir Dis. 1987;135:312-315.
45. Froese AB, Bryan AC, High frequency ventilation. Am Rev Respir
Dis. 1987;135:1363-1374.
46. Fusciardi J, Rouby JJ, Barakat T, et al. Hemodynamic effects of
high frequency jet ventilation in patients with and without shock.
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47. Cioffi W, Graves T, McManus W, et al. High-frequency percussive
ventilation in patients with inhalation injury. J Trauma. 1989;29:
350-354.
48. Cioffi W, Rue LW III, Graves T, et al. Prophylactic use of high-
frequency percussive ventilation in patients with inhalation
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resistance, and work of breathing in children after inhalation
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50. Cortiella J, Mlcak R, Herndon DN. High frequency percussive
ventilation in pediatric patients with inhalation injury. J Burn
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51. Mlcak R, Desai MH, Herndon DN. A prospective randomized
study of high frequency percussive ventilation compared to
conventional mechanical ventilation in pediatric patients with
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52. Cartotto R. Use of high frequency oscillatory ventilation in
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55. Hickling KG, Henderson SJ, Jackson R. Low mortality associated
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65. Herndon DN, Lange F, Thompson P, et al. Pulmonary injury in
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burned patient. Burns. 1984;11:79.
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complications in burned patients. J Thorac Cardiovasc Surg.
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predisposing to Gram-negative bacillary necrotizing pneumonia.
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exercise endurance in children convalescing from thermal injury.
J Burn Care Rehabil. 1993;14:16-20.

The systemic inflammatory
response syndrome
Edward R. Sherwood, Daniel L. Traber
Introduction
Burn patients, with or without inhalation injuries, com­
monly exhibit a clinical picture that is largely produced by
systemic inflammation. The phrase ‘systemic inflammatory
response syndrome (SIRS)’ was introduced to designate the
signs and symptoms of this condition. SIRS has a continuum
of severity ranging from physiologic alterations such as tach­
ycardia, tachypnea, fever, and leukocytosis, to refractory
hypotension and, in its most severe form, shock and multi­
ple organ system dysfunction. In thermally injured patients
the most common cause of SIRS is tissue damage caused by
the burn itself. Sepsis, defined as SIRS in the presence of
infection, is also common in burn patients and is a signifi­
cant cause of morbidity and mortality. Starting from a local
infection at the burn wound, an infected catheter tip or
pulmonary infection, the spread of microbes and their toxins
can further potentiate systemic inflammation. Pathological
alterations of metabolic, cardiovascular, pulmonary, renal,
gastrointestinal, and coagulation systems occur as a result of
the hyperactive immune system. This chapter will review
current understanding of SIRS and the associated immuno­
logical, cardiovascular, and pulmonary dysfunction that
occurs following trauma and thermal injury.
Definition of SIRS
The phrase ‘systemic inflammatory response syndrome
(SIRS)’ was recommended by the American College of Chest
Physicians/Society for Critical Care Medicine (ACCP/SCCM)
consensus conference in 1992 to describe a systemic inflam­
matory process, independent of its cause.1 The proposal was
based on clinical and experimental results indicating that a
variety of conditions, both infectious and non-infectious
(i.e. burns, ischemia–reperfusion injury, multiple trauma,
pancreatitis), induce a similar host response. Two or more
of the following conditions must be present for the diagnosis
of SIRS to be made:
•
body temperature >38°C or <36°C;
•
heart rate >90 beats/min;
•
respiratory rate >20/min or PaCO2 <32 mmHg;
•
leukocyte count >12 000/µL, <4000/µ, or >10%
immature (band) forms.
All of these pathophysiologic changes must occur as an acute
alteration from baseline in the absence of other known
causes. This definition is very sensitive and non-specific, and
most of the SIRS criteria are also addressed in other scoring
systems of injury-induced physiologic derangement, such
as the Acute Physiology and Chronic Health Evaluation
(APACHE), Mortality Probability Model (MPM), and Sim­
plified Acute Physiology Severity (SAPS) systems. Several
investigators have criticized the definition of SIRS as being
too sensitive and encompassing the majority of ICU patients,
and certainly the vast majority of patients suffering extensive
thermal injury.2,3 The initial definition of SIRS also did not
address the continuum of disease severity as was defined
for sepsis. Criteria for the diagnosis of severe sepsis included
the additional derangements of organ dysfunction, hypo­
tension, and hypoperfusion. Evidence of hypoperfusion
included, but was not limited to, the presence of lactic aci­
dosis, oliguria, and altered mental status. Septic shock was
characterized by hypotension and hypoperfusion in patients
who were adequately volume resuscitated or required treat­
ment with catecholamines or other vasoactive drugs to
support cardiovascular function. Muckart and Bhagwangee,2
in an effort to define a continuum of severity for SIRS, later
proposed the categories of severe SIRS and SIRS-associated
shock. These conditions were defined by the same criteria as
severe sepsis and septic shock in the absence of demonstra­
ble infection. In its most severe form, SIRS can induce organ
injury and subsequent multiple organ dysfunction syndrome
(MODS).
Despite the limitations in the definitions of SIRS and
sepsis, most clinicians and investigators generally adopted
the SIRS concept. However, the initial definition and criteria
were not felt to be optimized. To address these issues, a
second consensus conference was assembled in 2001.4 The
goal of this conference was to revisit the previously defined
criteria for SIRS and sepsis as well as to determine whether
revision of these criteria was indicated. The consensus was
that the concepts of sepsis and SIRS are useful but the diag­
nostic criteria are overly sensitive and non-specific. The par­
ticipants added additional criteria that defined metabolic,
biochemical and functional alterations associated with SIRS
and sepsis. Among these were hyperglycemia, edema, ele­
vated plasma C-reactive protein concentration, coagulation
abnormalities, thrombocytopenia, ileus, and hyperbiliru­
binemia. The group further proposed a staging system for
sepsis and SIRS that could be used to stratify patients for
prediction of outcome. This staging system, termed PIRO,
defined several criteria, including the predisposition of
patients to a poor outcome as determined by premorbid
conditions and possible genetic factors. Other factors include
the severity and type of insult, the host response to injury
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00021-7
CHAPTER 21 
Access the complete reference list online at

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SIRS criteria had a mortality rate of 3%, compared to 6% in
those with two SIRS markers. Patients with three or four SIRS
criteria had mortality rates of 10% and 17%, respectively,
whereas those with culture-negative shock had a 46% death
rate. Haga et al.10 have shown that the persistence of SIRS for
more than 3 days in surgical patients is a harbinger of com­
plications and is associated with increased morbidity. Talmor
et al.7 reported that persistence of SIRS to the second post­
operative day in high-risk surgical patients correlated with
an increased incidence of MODS. Additional studies have
shown that persistence of SIRS criteria for more than 3 days
in trauma and burn patients is associated with worse
outcome.10–13 Therefore, three important factors appear to
determine the effect of SIRS on the host. The first is the sever­
ity of the initial inflammatory response. This response is
proportional to the severity of injury, and the presence of
shock or MODS within the first 24 hours after injury carries
a poor prognosis. The second determinant is the persistence
of SIRS beyond the first few days of injury. Specifically, pro­
longation of SIRS beyond the second day after severe trauma
or thermal injury is associated with an increased complica­
tion rate. Factors that appear to be important in reducing the
incidence of a prolonged inflammatory state include ade­
quate fluid resuscitation within the first 24 hours after injury,
aggressive excision of necrotic tissue and enteral feeding.11–13
A third factor is the adaptive capacity of the host. Results of
several studies have shown that extremes of age and the pres­
ence of coexisting disease will diminish the adaptive capacity
of the host and predict a worse prognosis for any given sever­
ity of injury.14,15
The initiating event
The crucial pathophysiologic event that precipitates systemic
inflammation is tissue damage. This can occur both as a
result of direct injury to tissues from mechanical or thermal
trauma and as a result of cellular injury induced by ischemia
and reperfusion. Injury results in the acute release of pro­
inflammatory cytokines such as tumor necrosis factor-α
(TNFα), interleukin (IL)-1 and IL-6. If injury is severe, such
as in extensive thermal injury, a profound release of cytokines
and non-cytokine mediators of inflammation occurs, result­
ing in the induction of a systemic inflammatory reaction
(Fig. 21.1). The ability of the host to adapt to this systemic
inflammatory response is dependent on the magnitude and
duration of the response as well as the adaptive capacity of
the host. If the insult and the host’s response to it are beyond
the adaptive capacity of the host, or if adequate resuscitation
is not promptly initiated, organ injury may ensue during the
early post-injury period. Factors that have been implicated
in the worsening or prolongation of SIRS include inadequate
resuscitation during the acute phase following thermal
injury, persistent or intermittent infection, ongoing tissue
necrosis, and translocation of bacteria or endotoxin across
the bowel.15,16
The actual mechanisms that initiate trauma-induced
inflammation at the cellular and molecular levels are becom­
ing increasingly understood. Two primary sensing systems
have been identified. Recent evidence has implicated the
ability of Toll-like receptors (TLR) to respond to endogenous
cellular factors that are produced or released following tissue
and the presence of organ dysfunction. The participants pro­
posed that this model could be used to generate more spe­
cific criteria for defining the SIRS phenomenon. Although
the validity of this approach remains to be established,
Rubulotta recently reported that the PIRO criteria have pre­
dictive value regarding mortality in septic patients.5 Never­
theless, the validity of the staging system remains to be fully
determined.
Another pitfall in the designation of SIRS is the difficulty
of applying the initial criteria to children. Some of the crite­
ria, particularly those for heart rate and respiratory rate, fall
within the normal physiologic range for young children. In
2002, a consensus conference was assembled to define crite­
ria for sepsis and SIRS in children.6 The participants defined
six age groups based on clinical and physiological character­
istics (Table 21.1). SIRS was defined as the presence of at least
two of the following four criteria, one of which must be
abnormal temperature or leukocyte count:
•
temperature >38.5°C or <36°C;
•
tachycardia, defined as mean heart rate >2 SD above
normal for age or for children <1 year,
•
bradycardia, defined as heart rate <10% of normal for
age;
•
mean respiratory rate >2 SD above normal for age or
requirement for mechanical ventilation;
•
leukocyte count elevated or depressed for age.
Severe sepsis was defined as sepsis plus one of the following:
cardiovascular dysfunction, acute respiratory distress syn­
drome or two or more organ dysfunctions (respiratory, renal,
neurologic, hematologic or hepatic).
The definition of septic shock is problematic in children
because children can maintain blood pressure until they
become severely ill. Therefore, hypotension is not a useful
criterion for diagnosing shock in children. This group pro­
posed criteria for septic shock that included the presence of
tachycardia in conjunction with signs of decreased periph­
eral perfusion, such as decreased capillary refill, decreased
peripheral pulses, decreased urine output, altered mental
status and cold/mottled extremities.6
Several studies have been conducted with the goal of deter­
mining the prognostic value of the SIRS designation. In the
acute setting, SIRS has been demonstrated in the majority of
critically injured patients and the intensity of the response
correlates directly with the severity of injury.3,7 The presence
of SIRS within the first 24 hours after severe injury has not
served as a reliable predictor of mortality in trauma or burn
patients.3,7 However, the presence of shock is an important
predictor of poor outcome, particularly when associated
with MODS.2 In addition, the presence of more than two of
the SIRS criteria in the setting of acute injury has correlated
with increased morbidity and mortality.8,9 A study by Rangel-
Frausto et al.9 showed that trauma patients who did not meet
Table 21.1  Pediatric age groups for SIRS criteria
Newborn 0 day to 1 week
Neonate 1 week to 1 month
Infant 1 month to 1 year
Toddler or preschool 2 to 5 years
School age 6 to12 years
Adolescent 13 to 18 years

The systemic inflammatory response syndrome
251
Figure 21.1  Pathogenesis of the systemic inflammatory response
syndrome (SIRS) and counter anti-inflammatory response syndrome (CARS).
Tissue injury induces production of proinflammatory mediators resulting in
SIRS. A compensatory anti-inflammatory response (CARS) may also be
mounted through the production of anti-inflammatory mediators such as
IL-10 and TGFβ. In many cases SIRS and CARS may coexist. (From Cotran R,
Kumar V, Collins T, eds. Robbins pathologic basis of disease, 6th edn. Philadelphia: WB
Saunders; 1999: 75)
Early MODS
IL-6
SIRS
SIRS
CARS
CARS
TNFα
IL-10
TNFβ
Late
Infection
Normal
Anti-inflammatory
Inflammatory
Injury
Figure 21.2  Toll-like receptor signaling. Toll-like receptors (TLR) are membrane-associated receptors that recognize microbial products and endogenous
products released during tissue injury, allowing the host to recognize the presence of microbes or tissue injury. TLR activation initiates intracellular signaling
pathways that facilitate transcription of proinflammatory gene products. (From Kawai and Akira, Cell Death and Differentiation 13: 816, 2006)
Triacyl
lipopeptide
TLR1 TLR2
Inflammatory
cytokines
Inflammatory
cytokines
Type I IFN
Inflammatory
cytokines
Inflammatory
cytokines
Type I IFN
Inflammatory
cytokines
TLR2 TLR6
TLR3
TLR4
TLR7/8
TLR9
TLR5
TLR11
Adapters
TIRAP
MyD88
MyD88
MyD88
Trif
TIRAP
TIRAP
MyD88
MyD88
MyD88
MyD88
Trif
TRAM
Imidazoquinolines
ssRNA
Diacyl
lipopeptide
CpG DNA
Hemozoin
Profilin-like protein
Uropathogenic
bacteria
LPS
dsRNA
Flagellin
trauma (Fig. 21.2). TLR are expressed by leukocytes and
some parenchymal cells. They allow the host to sense the
presence of microbes and initiate an innate immune
response. However, recent studies indicate that TLR have
the ability to respond to endogenous ligands as well. Among
the proposed endogenous TLR ligands are heat shock pro­
teins (recognized by TLR4) and mitochondrial DNA (recog­
nized by TLR9).17,18 A second sensing system are NOD-like
receptors (NLR) that sense endogenous and exogenous
ligands to cause activation of inflammasomes (Fig. 21.3).19
Inflammasome assembly ultimately results in activation of
inflammatory caspases such as caspase-1. Activated caspase-
1, also known as IL-1-converting enzyme, causes cleavage of
pro-IL-1 and pro-IL-18 into active mature proteins. The IL-1
and IL-18 produced by this interaction are released from
cells and facilitate the proinflammatory response. Proposed
endogenous NLR ligands include adenosine triphosphate
(ATP), uric acid and endogenous DNA.19
In some cases, SIRS may precipitate a state of immunosup­
pression known as the counter anti-inflammatory response
syndrome (CARS). Frequently, SIRS and CARS coexist
(Fig. 21.1). Current research indicates that the injured host
responds to severe inflammation by activating anti-
inflammatory pathways that are aimed at protecting the host
from further inflammatory injury. Among these pathways are
increased production of anti-inflammatory cytokines such as
IL-10 and transforming growth factor-β (TGFβ) and leuko­
cyte apoptosis.20,21 However, this anti-inflammatory state
may lead to immunosuppression, which predisposes the
host to opportunistic infections. If uncontrolled, local infec­
tions may escalate to severe systemic infections and sepsis.
Sepsis can cause further inflammation and serve as an addi­
tional source of organ injury in severely burned patients. The
pathogenesis of injury-induced immunosuppression is dis­
cussed in detail elsewhere in this book.
The two-hit hypothesis
Some investigators have described a phenomenon in which
the injured host manifests an exaggerated inflammatory
response if confronted with a secondary inflammatory stim­
ulus during the post-injury period. This phenomenon
has been termed the ‘two-hit hypothesis.’ Although the

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endotoxin exposure, is provided in even a small dose, mac­
rophages are triggered to become fully activated and to
secrete large amounts of TNFα. Studies by Paterson et al.22
show that macrophages have increased responsiveness to
ligands for Toll-like receptor 2 (TLR2) and TLR4 following
burn injury. TLR2 and TLR4 are proteins that play an integral
role as components of receptor complexes for various micro­
bial products such as peptidoglycans, lipoproteins and
lipopolysaccharide. Enhancement of TLR2 and TLR4
responses during the post-injury period may be one mecha­
nism contributing to the two-hit phenomenon. T lym­
phocytes may also become hyperresponsive during the
post-injury period. Zang et al.23 showed an exaggerated
response to bacterial superantigens 1 day after burn injury
in mice. Superantigens, such as staphylococcal enterotoxins,
induce polyclonal activation of T cells and cause a shock
syndrome that is similar to endotoxin shock. This mecha­
nism may also contribute to the hyperinflammatory response
seen in many patients during the post-burn period.
The exaggerated response to a secondary stimulus seen in
severely injured patients appears to have functional conse­
quences. Several studies that focused on organ injury caused
by systemic inflammatory processes indicate that a phenom­
enon comparable to the cellular events described above can
occur in severely injured patients.24 Dehring et al. found
more persistent pulmonary hypertension and an exaggerated
hyperdynamic response to bacteremia in sheep when a
week-old thermal injury preceded systemic bacterial chal­
lenge.25 In a rat model of intestinal ischemia–reperfusion
injury and endotoxemia, lung albumin leak and mortality
rate increased only if both injuries occurred sequentially.26
Combined administration of low doses of endotoxin and
TNFα to rats caused hypotension and metabolic effects that
are commonly seen after giving a highly lethal dose of either
compound alone.27 These findings are in keeping with the
fact that multiple organ damage usually develops over a
prolonged period during which several insults might occur.
It also emphasizes why it is so important to minimize
inflammatory insults such as tissue ischemia or infection,
particularly in patients in whom systemic inflammation is
already present.
Cytokine and non-cytokine mediators of SIRS
Several proinflammatory cytokines, chemokines, and non-
cytokine inflammatory mediators play a role in the patho­
genesis of SIRS. Cytokines comprise a broad group of
polypeptides with varied functions within the immune
response (Table 21.2). The classic mediator of systemic
inflammation is TNFα. TNFα is released primarily by mac­
rophages within minutes of local or systemic injury, and
modulates a variety of immunologic and metabolic events.28
At sites of local infection or inflammation TNFα initiates an
immune response that activates antimicrobial defense mech­
anisms and, once the infection is eradicated, tissue repair. It
is a potent activator of neutrophils and mononuclear phago­
cytes, and also serves as a growth factor for fibroblasts and
as an angiogenesis factor. However, systemic release of TNFα
can precipitate a destructive cascade of events that can result
in tissue injury, organ dysfunction and, potentially, death.
Among the systemic effects of TNFα are the induction of
pathobiology of the two-hit hypothesis is not completely
understood, monocytes and macrophages appear to play a
central role in mediating the process. For example, the lym­
phokine α-interferon (IFN-α), produced during the initial
injury, might act as the first signal and prime macrophages
for a heightened inflammatory response if a second stimulus
is encountered. Several changes in macrophage function,
including an increase in the transcription rate of mRNA for
TNFα, can be induced by exposure to IFN-α. However, TNFα
protein is not produced in large amounts in response to
the first inflammatory insult. If a second stimulus, such as
Figure 21.3  The inflammasome is an intracellular signaling complex that is
activated by a variety of endogenous and microbial products and causes
activation of inflammatory caspases such as caspase-1. Activation of this
system results in release of IL-1 and IL-18 during periods of inflammation.
(From Schroder K, Tschopp J. The inflammasomes. Cell. 2010 140: 821–32)
3
1
2
LRR
NACHT
NACHT
PYD
PYD
CARD
CARD
CASP
CASP
CASP
CASP
CARD
CARD
PYD
LRR
PYD
ATP
K+
DAMP/
PAMP
DAMP/PAMP
Crystalline/
particulate
ligands
Lysosomal
rupture
Pannexin-1
Reactive oxygen
species
NLRP3
CASP1
Cathepsin B
inhibitor
(Ca-074-me)
NLRP3 inflammasome
assembly
Activated
Caspase-1
IL-1β
IL-1β
Pro-IL-1β
‘Priming’ by
proinflammatory stimuli
e.g. TLRs, TNF, IL-1β
ASC
Cytoplasm
Nucleus
P2X7

The systemic inflammatory response syndrome
253
been associated with poor outcome in trauma patients,
probably because it is a marker of ongoing inflammation.
The primary effect of IL-6 is to induce secretion of acute-
phase proteins from the liver as well as to serve as a growth
and differentiation factor for B lymphocytes.
Interferon-γ (IFN-γ) is a cytokine that facilitates the ampli­
fication of the acute inflammatory response, particularly the
stimulation of cytokine secretion, phagocytosis, and respira­
tory burst activity by macrophages. IFN-γ is secreted prima­
rily by T lymphocytes and natural killer (NK) cells in response
to antigen presentation as well as macrophage-derived
cytokines such as IL-12 and IL-18. The primary effect of
IFN-γ is to amplify the inflammatory response of macro­
phages. In response to IFN-γ, the phagocytic and respiratory
burst activities of macrophages are increased, secretion of
inflammatory mediators such as TNFα and IL-1 is enhanced,
and antigen presentation is potentiated by upregulation of
class II major histocompatibility complex. Blockade of IFN-γ
production or function has been shown to markedly reduce
the deleterious inflammatory effects induced by bacterial
endotoxin.32 Therefore, IFN-γ is believed to be an important
factor in the amplification of SIRS.
Chemokines are a family of proteins that function prima­
rily as chemotactic factors for leukocytes and, when pro­
duced inappropriately or in excess, can contribute to
damaging systemic or local inflammation (Table 21.3). IL-8
is the most widely studied chemokine in the setting of sepsis
and SIRS; it is a potent chemoattractant for neutrophils and
is a major factor in recruiting neutrophils to inflammatory
foci. Several studies have shown that IL-8 plays a role in
fever, stimulation of acute-phase protein secretion by the
liver, activation of the coagulation cascade, myocardial sup­
pression, induction of systemic vasodilators with resultant
hypotension, catabolism, and hypoglycemia.28,29 Numerous
studies have shown that administration of TNFα to experi­
mental animals will mimic the systemic inflammatory
response observed in sepsis and after severe injury. Another
important effect of TNFα is its ability to induce apoptosis of
a variety of cell types.30 TNF-induced apoptosis may be one
mechanism by which it induces tissue injury at high systemic
concentrations.
TNFα is also a potent stimulus for the release of other
proinflammatory mediators, particularly IL-1 and IL-6. IL-1
is released primarily by mononuclear phagocytes and its
physiologic effects are essentially identical to those of TNFα.31
However, important differences exist between the functions
of IL-1 and TNFα. Most notably, IL-1 does not induce tissue
injury or apoptotic cell death by itself, but can potentiate the
injurious effects of TNFα. The IL-1 family of proteins, includ­
ing IL-18, are the only group of cytokines for which known
natural antagonists have been identified. The IL-1 receptor
antagonists (IL-1ra) bind to the IL-1 receptor but do not
induce receptor activation.31 These proteins appear to func­
tion as competitive inhibitors of IL-1 action. As noted earlier,
the systemic release of IL-1 is dependent on the activation
of inflammasomes and caspase-1.19
IL-6 is another protein that is commonly increased in the
circulation of patients with SIRS.31 Macrophages, endothelial
cells, and fibroblasts secrete this protein. IL-6 itself does not
induce tissue injury but its presence in the circulation has
Table 21.2  Cytokine and chemokine mediators of systemic inflammation
Cytokine
Polypeptide size
Cell source
Cell target
Primary effects
Tumor necrosis
factor- α (TNFα)
17 kD
Monocytes, macrophages, T
lymphocytes
(a) Neutrophil
(b) Endothelial cells
(c) Hypothalamus
(d) Liver
(e) Muscle, fat
(f) Heart
(g) Macrophages
(h) T lymphocytes
(i) Various tissues
Activation (inflammation)
Activation (inflammation/coagulation)
Release of vasodilators (NO)
Fever
Acute phase response
Catabolism
Myocardial suppression
Release of cytokines, inflammation
Inflammation
Apoptosis?
Interleukin-1 (IL-1)
17 kD
Monocytes, macrophages
(a) T cells
(b) Endothelial cells
(c) Liver
(d) Hypothalamus
(e) Muscle, fat
Activation (inflammation)
Activation (inflammation/coagulation)
Release of vasodilators (NO)
Acute phase response
Fever
Catabolism
Interleukin-6 (IL-6)
26 kDa
Monocytes, macrophages, T
cells, endothelial cells
(a) Liver
(b) B cells
Acute phase response
Activation
Interleukin-8 (IL-8)
10 kDa
Monocytes, macrophages,
endothelial cells
Neutrophils
Chemotaxis, activation
Interferon-γ (IFN-γ)
21–24 kDa
T cells, NK cells
Macrophages
Activation (inflammation)
Interleukin-12 (IL-12)
70 kDa
Macrophages
T cells, B cells, NK cells
Activation, differentiation
Interleukin-18
Macrophages
T cells, NK cells
Activation, differentiation
IL-10
Monocytes/Th2 lymphocytes,
mast cells, regulatory T cells
Macrophages Th1
lymphocytes, NK cells
Inhibition, activation regulation

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(Fig. 21.4). NF-κB is composed of a family of proteins includ­
ing p50 (NF-κB1), p65 (RelA), C-Rel, and p52 (NF-κB2) that
combine to form homo- or heterodimers and ultimately
function to regulate the transcription of a variety of cytokine,
chemokine, adhesion molecule, and enzyme genes involved
in SIRS.35 Increased translocation of NF-κB has been associ­
ated with a poor outcome in some studies. Activation of
NF-κB in peripheral blood monocytes correlates with
increased mortality in septic patients, and alveolar macro­
phages from patients with adult respiratory distress syn­
drome (ARDS) exhibited higher nuclear NF-κB levels than
critically ill patients without ARDS.36,37 The AP-1 complex is
activated through activation of MAP kinases by stimuli that
are similar to those required for NF-κB mobilization. IRF-3
is mobilized through activation of the Trif-associated signal­
ing pathway and results primarily in transcription of type I
interferon (IFN-α) genes. The STAT1 pathway is induced by
activation of type I (IFN-α) and type II (IFN-γ) receptors.
Together, these transcription factors mediate the transcrip­
tion of numerous factors involved in inflammation and
tissue repair (Fig. 21.5).
Several non-cytokine factors have been implicated in the
pathogenesis of SIRS. Platelet-activating factor (PAF) is a
phospholipid autocoid released by endothelial cells that
regulates the release of cytokines and amplifies the proin­
flammatory response. It appears to be an important factor in
the adhesion of neutrophils to endothelial cells. The pro­
longed presence of PAF in the serum of patients with SIRS
has correlated with poor outcome.38 Eicosanoids are arachi­
donic acid metabolites that regulate many aspects of the
immune response. Leukotrienes (LTC4-LTE4) induce con­
traction of endothelial cells and encourage capillary leakage.39
Thromboxane A2, a macrophage and platelet-derived factor,
promotes platelet aggregation, vasoconstriction and, poten­
tially, tissue thrombosis.40
The complement cascade is composed of more than 30
proteins that interact in a complex fashion to mediate
inflammation and direct lysis of microbes and other cells
(Fig. 21.6). However, in SIRS, excessive complement activa­
tion appears to cause significant cellular injury in the host.
Products of the complement cascade, most notably C3a and
C5a, are potent activators of inflammation and leukocyte
chemotaxis.41 C3a and C5a also directly activate neutrophils
and promote release of reactive oxygen intermediates and
proteases. Excessive release of these factors can result in sig­
nificant tissue injury. The membrane attack complex (MAC)
is the terminal component of the complement cascade. MAC
results from the aggregation of the complement components
C5–C9 on biological membranes. The accumulation of MAC
on cell surfaces can result in significant tissue and cellular
injury and may be a major factor in the pathogenesis
of MODS. Suber and colleagues42 have reported that
complement-mediated responses to self-antigens exacerbate
tissue injury after burn injury.
Circulating cytokines as markers of SIRS and
predictors of outcome
Numerous studies have been undertaken with the goal of
using plasma cytokine levels as diagnostic and prognostic
markers in patients with SIRS or sepsis. This approach seems
mediating tissue injury in the setting of trauma and burn
injury, particularly in the lung.33,34
Production of most soluble mediators of inflammation is
regulated at the transcriptional level. Some of the key tran­
scription factors that control proinflammatory gene expres­
sion include nuclear factor-κB (NF-κB), AP-1 and IRF-3
Table 21.3  Classification of chemokines
Chemokine type
Target cell
CXC Chemokines
CXCL8 (IL-8, mouse MIP-2)
Neutrophils
CXCL1 (GROα, mouse KC)
Neutrophils
CXCL2 (GROβ, mouse KC)
Neutrophils
CXCL3 (GROγ, mouse KC)
Neutrophils
CXCL5 (ENA-78)
Neutrophils
CXCL6 (GCP-2)
Neutrophils
CXCL4 (PF4)
Fibroblasts, stem cells
CXCL9 (Mig)
T and NK cells
CXCL10 (IP-10)
T and NK cells
CXCL11 (I-TAC)
T and NK cells
CXCL12 (SDF-1α/β)
T lymphocytes
CC Chemokines
CCL3 (MIP-1α)
Monocyte/macrophages, T and B cells,
NK cells, basophils
CCL4 (MIP-1β)
same as above
CCL22 (MDC)
Monocyte, T lymphocytes
CCL25 (TECK)
Macrophages, T lymphocytes
CCL17 (TARC)
T lymphocytes
CCL5 (RANTES)
Monocyte/macrophages, T/NK cells
Basophils
CCL14 (HCC-1)
Monocytes
CCL16 (HCC-4)
Monocytes, lymphocytes
CCL18 (DC-CK-1)
T lymphocytes
CCL20 (MIP-3α)
T lymphocytes
CCL19 (MIP-3β)
T lymphocytes
CCL2 (MCP-1)
T lymphocytes, monocytes,
CCL8 (MCP-2)
same
CCL7 (MCP-3)
same
CCL13 (MCP-4)
same
CCL11 (Eotaxin)
Eosinophils
Other Chemokines
XCL1 (Lymphotactin)
T lymphocytes, NK cells
CX3CL1 (Fractalkine)
T lymphocytes, monocytes,
The current conventional names of chemokines are presented and original names
are provided in parentheses for reference.

The systemic inflammatory response syndrome
255
total body surface area (TBSA) burns demonstrated marked
increases in plasma TNFα levels and a significant correlation
between TNFα concentration and shock, MODS, and death.
These findings support the results of Marano et al.,47 who
showed a significant correlation between circulating TNFα
concentration and mortality in burned patients. Therefore,
taken together, these results show that TNFα could serve as
a useful marker of ongoing inflammation as well as an indi­
cator of morbidity and mortality in the setting of burn injury,
but controversy remains.
TNFα interacts with two known cell surface receptors des­
ignated tumor necrosis factor receptor (TNFR)-I and TNFR-
II. TNFR-I, also known as TNF-R55 or p55, is expressed on
a variety of cells and its activation mediates most of the
activities of TNFα, including induction of apoptosis. Activa­
tion of TNFR-II (TNF-R75 or p75) results in cellular prolif­
eration and activation. During inflammatory states, TNFR
logical, based on the observation that circulating cytokines
have been observed in several clinical studies of trauma,
sepsis, and thermal injury. Given its central role in the activa­
tion and regulation of the proinflammatory response, TNFα
has been studied extensively as a plasma marker of SIRS. The
results have been inconsistent. Martin et al.43 showed that
TNFα levels were markedly elevated in patients with septic
shock and correlated with fatal outcome. However, their
results also showed that trauma patients did not exhibit
the same marked elevations in circulating TNFα, nor did
circulating TNFα concentrations correlate with increased
mortality in trauma patients. In some published studies,
measurement of circulating TNFα levels in burn patients has
not provided a useful marker of outcome.44,45 Overall, plasma
TNFα levels have been variable and inconsistent and have
not correlated with mortality or the development of MODS.
However, a study by Zhang et al.46 in 25 patients with >30%
Figure 21.4  Major inflammation-associated transcription factors include NF-κB, AP-1 and IRF-3. Activation of these pathways is mediated through
MyD88- and Trif-dependent signaling after TLR ligation. (From Kawai and Akira, Cell Death and Differentiation 13: 816, 2006)
TIRAP/Mal
IRAK4
MyD88
Trif
TRAM
Cytoplasm
Nucleus
Endosome
TLR3
TLR4
TRAF6
TBK1
IKKi
IRF3
IRF3
RIP1
TRAF6
UB
TAB1/2/3
P
P
P
P
UB
TAK1
MAPKs
AP-1
Type 1 IFN
Inflammatory cytokines
IKKγ
IκBs
NF-κB
NF-κB
IKKαβ
Degradation

Total Burn Care
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256
between sTNFR and APACHE III scores, as well as the inci­
dence of shock and mortality in septic patients. Sikora and
colleagues50,51 have reported increased concentrations of
sTNFR-I and sTNFR-II in the plasma of burned children.
sTNR concentrations correlated with burn surface area and
decreased with adequate treatment. Children with hypovo­
lemic shock had higher plasma concentrations of sTNFR.
Overall, in the studies published to date, the presence of
high levels of circulating sTNFR correlate with ongoing
inflammation and may serve as an indicator of poor
prognosis.
Another family of proteins that has been extensively ana­
lyzed as markers of SIRS is IL-1 and IL-1 receptor antagonist
(IL-1ra). In burn patients, low IL-1ra levels correlated with
mortality in two independent studies.52,53 Plasma IL-1ra
levels have been shown to correlate with body surface area
burned, extent of third-degree burn, and the presence of
inhalational injury, both in adults and children.45,50–52
Of the cytokine markers studied to date, elevated levels of
IL-6 appear to be one of the more consistent markers of poor
outcome in burn, trauma, and septic patients. One of the
known functions of IL-6 is induction of acute-phase proteins
such as C-reactive protein (CRP) by the liver. In some studies,
CRP has been shown to parallel IL-6 as a marker of increased
mortality.53 Although IL-6 itself does not appear to have any
known direct injurious effects, it apparently serves as a con­
sistent marker of ongoing inflammation. Elevated plasma
IL-6 levels have correlated with increased mortality in experi­
mental and clinical studies of thermal injury, sepsis, trauma,
and hemorrhagic shock.44,54,55 A study by Taniguchi et al.55
showed that an increased ratio of IL-6 to the anti-inflammatory
cytokine IL-10 was a predictor of poor outcome in patients
with SIRS.
In trauma and burn patients it is often difficult to differ­
entiate whether SIRS is a result of the injury itself or due to
superimposed infection. Most of the clinical signs of sys­
temic infection, such as fever and leukocytosis, are by defini­
tion present in SIRS. Therefore, considerable attention has
are released from cells and may serve as antagonists of TNFα.
Several investigators have characterized surface-bound and
soluble TNFR (sTNFR) in sepsis and trauma.46,48,49 Hubl
et al.48 showed that surface TNFR-I were upregulated, whereas
TNFR-II were downregulated in patients with SIRS. Increased
TNFR-I correlated with increased body temperature but not
with survival. SIRS patients with decreased surface TNFR-II
had a trend toward increased mortality. A study by Zhang
et al.46 showed a higher incidence of shock, MODS, and
mortality in burn patients with increased plasma sTNFR-I
and sTNFR-II levels. Presterl et al.49 showed a correlation
Figure 21.5  Regulation of proinflammatory
gene expression. Inflammatory stimuli induce
activation of transcriptional pathways mediated
by NF-κB, AP-1 and STAT1 that result in
production of proinflammatory mediators. (From
Cotran R, Kumar V, Collins T, eds. Robbins Pathologic basis
of disease, 6th edn. Philadelphia: WB Saunders; 1999: 75.)
AP-1, NF-κB
transcription factors
Active STAT1
transcription factor
Stimulation of gene expression
Phagocyte
oxidase
iNOS
Tissue
factor
Cytokines
(TNF,
IL-12)
Increased MHC
molecules,
costimulators
Enhanced
antigen
presentation
Inflammation,
metabolic
alterations
Tissue
remodeling
and repair
Coagulation
Nitric
oxide
Reactive
oxygen
species
Killing of
microbes
Growth factors
Angiogenic factors
Metalloproteinases
Figure 21.6  The complement system can be activated by three primary
mechanisms and facilitates the amplification of innate and acquired
immune responses as well as directly mediating microbial lysis. The primary
functions of complement are opsonization, leukocyte chemotaxis and direct
killing of microbes. (From Abbas and Lichtman, Cellular and Molecular Immunology,
5th Edition, Saunders).
Antigen/antibody
complexes
(adaptive)
Microorganisms
Alternative
pathway
(innate)
Classic
pathway
Lectin
pathway
C3
C3b
C5a
C5-C9
terminal sequences
Membrane attack
complex (MAC)
C3a
C3a and C5a (anaphylactotoxins): increase vascular permeability,
chemotactic factors, opsonins

The systemic inflammatory response syndrome
257
in anti-TNFα-treated patients. Similarly, the use of sTNFR as
a strategy to neutralize the systemic effects of TNFα and
reduce sepsis-associated morbidity and mortality was unsuc­
cessful.64,65 Other anti-inflammatory approaches that have
been studied and found to be largely ineffective include
the use of IL-1ra,66,67 anti-bradykinin,68 PAFra,69,70 and
ibuprofen.71,72
Because of the relative ineffectiveness of anti-inflammatory
therapy aimed at neutralizing single mediators, more broad-
based strategies were developed with the goal of simultan­
eously neutralizing, removing, or inhibiting the production
of numerous inflammatory mediators. Hemofiltration was
one approach that received considerable attention. Several
studies have shown that hemofiltration will increase the
clearance of inflammatory mediators, particularly IL-6, from
blood in patients with sepsis.73,74 However, none of these
studies has demonstrated a significant reduction in IL-6
plasma levels. A study by Kellum et al.74 showed that con­
tinuous venovenous hemofiltration (CVVH) reduced plasma
TNFα concentrations by 13%, and the use of continuous
venovenous hemodialysis (CVVHD) resulted in a 32%
increase in circulating TNFα levels. Overall, the use of hemo­
filtration has been largely ineffective in removing significant
amounts of inflammatory mediators from the blood of
patients with sepsis, and there is currently no evidence that
this approach will reduce morbidity and mortality.
The use of glucocorticoids in the treatment of sepsis has
been proposed for more than 30 years. A meta-analysis75 of
studies using high-dose glucocorticoids in the treatment of
sepsis was published in 1995 and later summarized by Zeni
and colleagues.76 Overall, the use of high-dose glucocorti­
coids to treat sepsis and septic shock has not been beneficial.
In many studies, the use of glucocorticoids in septic patients
was associated with increased mortality. In burned patients
there is no evidence that administration of glucocorticoids
provides effective treatment for systemic inflammation.
More recent studies show that replacement dose steroids will
improve survival in septic patients who have adrenal insuf­
ficiency.77 Recent guidelines from the Surviving Sepsis Cam­
paign advocate the use of replacement dose glucocorticoids
in septic patients refractory to conventional management.78
The failure of anti-inflammatory approaches to improve
outcome in patients with severe sepsis or septic shock are
likely to be multifactorial. First, the inflammatory response
to injury and sepsis is induced by a complex array of media­
tors that are largely interrelated and have significant redun­
dancy. Therefore, blocking or neutralization of a single
mediator is not likely to have a marked effect on the overall
response. Second, the same mediators that are important in
inducing tissue injury also play an important role in antimi­
crobial immunity, and blockade of these mediators may
leave the host more susceptible to subsequent infection.
Third, many of the mediators, particularly TNFα and IL-1β,
are released within minutes of injury and mobilize the
inflammatory cascade shortly thereafter. Therefore, by the
time that signs of SIRS or sepsis are apparent, many of
the injurious effects of the inflammatory response have
already been set in motion, making therapy ineffective. A
recent emphasis has been placed on the identification of late
mediators of inflammatory injury. This search has been
prompted by the observation that SIRS and sepsis-associated
death occur days after the peak effect of inflammatory
been placed on identifying indirect markers of systemic
infection that could serve to differentiate SIRS caused by
infection from that caused by trauma. It is important clini­
cally to identify patients with systemic infection in order to
initiate antibiotic therapy in a timely fashion. Additionally,
positive blood cultures are the gold standard for diagnosis
of systemic infections. Although blood cultures provide
important information regarding the presence of infection
and the identity of the infecting organism, it can often take
several days to obtain reliable results, and the presence of
negative cultures does not assure the absence of infection.
Therefore, efforts have been made to identify other markers
of systemic infection. The two markers that have been most
consistently elevated in patients with infection are procalci­
tonin and C-reactive protein (CRP). Studies have shown that
increased plasma levels of procalcitonin or CRP are sensitive
markers of systemic infection.56–58 Both of these markers
have been shown to be more reliable than clinical signs in
the diagnosis of infection in high-risk surgical and trauma
patients. Recent studies show that procalcitonin and CRP
can be used to distinguish patients with systemic infection
from those with non-infectious systemic inflammatory
processes.59–61
Overall, several markers of inflammation and infection
have been identified in burn and trauma patients. Some of
these have been shown to be consistent indicators of injury
severity. However, cytokine and non-cytokine markers of
inflammation are not used routinely in the laboratory evalu­
ation of burned patients. With further research and demon­
stration of the reliability of these markers, they may become
an accepted part of clinical practice. In addition, technology
is evolving to measure these markers in a rapid and cost-
effective manner, which may allow blood cytokine markers
to become a component of patient management in the
future.
Anti-inflammatory therapy for SIRS
Despite our increased understanding of the role of inflam­
matory mediators in the pathogenesis of SIRS and sepsis,
most anti-inflammatory drug regimens have had little success
in the treatment of this problem. Neutralizing approaches
to several inflammatory mediators have been studied. All of
these studies have demonstrated, at best, marginal improve­
ment in septic morbidity and mortality. None of the direct
anti-inflammatory strategies has been successfully employed
to minimize burn-associated inflammation. One of the most
widely studied approaches for the treatment of SIRS is the
use of monoclonal antibodies to TNFα. Several multicenter,
prospective clinical trials were undertaken in septic patients
using several different antibodies to TNFα.62,63 Those studies
did not demonstrate improved outcome in patients receiving
anti-TNFα compared to placebo. One study evaluated the
efficacy of a chimeric antibody to TNF in patients with severe
sepsis.63 Circulating levels of TNFα as well as a variety of
other inflammatory mediators were assessed. Although cir­
culating levels of TNFα were transiently decreased, anti-
TNFα therapy did not result in reduction of circulating levels
of other inflammatory mediators such as IL-1β, IL-1ra,
sTNFR, or IL-6. In addition, evidence of systemic inflamma­
tion was not reduced and overall mortality was not improved

Total Burn Care
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258
acids, and nucleotides have been shown to improve outcome
in trauma patients.83,84 Overall, trauma patients receiving
immune-enhancing diets have been shown to have fewer
infectious complications. In general, enteral feeding has
been shown to maintain gut integrity and improve outcome
in burn patients.
Tracey and colleagues have described a cholinergic anti-
inflammatory pathway that may be important in the regula­
tion of inflammation and could be exploited for therapeutic
benefit.85,86 As described, local inflammation activates affer­
ent fibers of the vagus nerve that signal the brain to elicit an
anti-inflammatory response through efferent vagal fibers
(Fig. 21.7). Acetylcholine released by the vagus interacts with
α7 nicotinic acetylcholine receptors (α7 nAChR) on macro­
phages and suppresses the production of proinflammatory
mediators. Those investigators have shown that electrical
stimulation of the vagus nerve will attenuate the proinflam­
matory response induced by cecal ligation and puncture or
endotoxin challenge. Acetylcholine has also been shown to
inhibit the release of proinflammatory cytokines by cultured
macrophages following endotoxin challenge.85,86 More spe­
cific α7 nAChR agonists are under investigation for the treat­
ment of hyperinflammatory states, and the possibility of
exploiting the cholinergic anti-inflammatory pathway for
therapeutic benefit remains to be established.
Activation of the coagulation cascade
during inflammation
Inflammation and coagulation are intimately intertwined.
The coagulation cascade is activated during both tissue
injury and infection. It is divided into two pathways that
cytokines. One potential late mediator that has recently been
identified is high-mobility group protein-1 (HMGB-1).79
HMGB-1 is released by macrophages up to 8 hours after LPS
challenge and persists in the circulation for days. Administra­
tion of anti-HMGB-1 to septic mice has been shown to
improve survival. Conversely, systemic administration of
HMGB-1 to mice is lethal. Whether HMGB-1 plays an impor­
tant role in inflammatory injury in humans remains to be
determined. However, the concept of late mediators of
inflammatory tissue injury may improve our understanding
of the pathophysiology of SIRS.
As discussed earlier, factors that appear to be important in
limiting the extent of SIRS and, in many cases, reducing the
incidence of shock and MODS, are appropriate fluid resus­
citation, hemodynamic support, treatment of infection with
antibiotics, excision of necrotic tissue, and adequate nutri­
tional support.80 There is controversy regarding the ideal
fluid for volume resuscitation in trauma and burn patients.
However, recent studies show that hypertonic saline has ben­
eficial effects in modulating the SIRS-associated immuno­
logical cascade as well as restoring hemodynamic parameters
and microcirculatory flow. The effect of hypertonic saline on
immune function has largely centered on attenuation of
post-injury immunosuppression. Recent studies have shown
that resuscitation with hypertonic saline will improve mac­
rophage and T-cell function as well as increasing resistance
to infection in experimental models or trauma and hemor­
rhage.81,82 However, the use of hypertonic fluids has not
gained widespread support in burn resuscitation because of
the risk of hypernatremia and associated complications.
Proper nutritional support is also an important factor in the
treatment of severely injured patients. Enteral feeding formu­
las supplemented with glutamine, arginine, omega-3 fatty
Figure 21.7  The cholinergic anti-inflammatory pathway. Tissue inflammation sends afferent signals to the central nervous system, resulting in activation of
the cholinergic anti-inflammatory pathway. Release of acetylcholine by the vagus nerve induces anti-inflammatory effects by binding to nicotinic receptors
on the surface of leukocytes. (Adapted from Czura and Tracey J Int Med 257: 156, 2005; Metz and Tracey Nat Immunol 6: 756, 2005; Pavlov et al. Crit Care Med 35: 1139, 2007)
Central or
‘pharmacological’
vagus nerve stimulators
Liver
Brain
Electrical
vagus nerve
stimulator
TNF
Spleen
Macrophage
α7 agonists
α7 nAChR
α7 subunit
acetylcholine
receptor
Cholinergic
anti-inflammatory
pathway
Nucleus
Cholinergic
agonist
Jak-STAT
anti-inflammatory
pathway
Cytokine
receptor
↑SOCS3
↑Gene
transcription
NF-κB
↓NF-κB
transcription
Jak
Jak
ACh
Vagus nerve
stimulation
Anti-inflammatory
P
P
P
P
–
STAT3
STAT3
STAT3
STAT3

The systemic inflammatory response syndrome
259
periods of inflammation in response to TNFα, IL-1, IL-6 and
CRP.89 The presence of tissue factor causes activation of factor
VII, which then forms a complex with tissue factor and ulti­
mately causes the formation of thrombin by the activation
of a series of coagulation factors (Fig. 21.8). Activation of the
coagulation cascade is not only important in the formation
of fibrin clots but also has important effects on the proin­
flammatory response. Factor Xa, thrombin and the tissue
factor–VIIa complex have been shown to elicit proinflamma­
tory activity. Specifically, thrombin and the tissue factor–
VIIa complex can induce production of proinflammatory
cytokines such as TNFα by mononuclear and endothelial
cells.88 That effect appears to be mediated by the binding of
these factors to protease-activated receptors on the surface of
target cells. Therefore, acute inflammation causes activation
of the coagulation cascade, which can then further potentiate
the inflammatory response.
Activation of the clotting cascade during inflammation is
limited by several factors. This is important because it pre­
vents uncontrolled induction of procoagulant mechanisms.
The best-defined factors are antithrombin, the protein C
system and the tissue factor pathway inhibitor. Antithrombin
is produced in the liver and directly binds and inactivates
thrombin.90 The binding of antithrombin to thrombin is
greatly potentiated by heparin and by glycosaminoglycans
present on the endothelial cell surface. In rodents, interac­
tion of antithrombin with the endothelial cell surface pro­
motes the release of PGI2, which inhibits TNFα production
by monocytes through the inhibition of transcription factor
NF-κB activation.91 Thus, antithrombin may have anti-
inflammatory properties in addition to its function in regu­
lating coagulation.
Protein C is a circulating protein that is activated by the
thrombin–thrombomodulin complex on the surface of
endothelial cells (Fig. 21.9). Activation of protein C deceler­
ates the clotting cascade by inactivating factors Va and VIIIa.92
Activated protein C also inhibits thrombin-induced produc­
tion of TNFα by monocytes by inhibiting the activation of
transcription factors NF-κB and AP-1.93 Therefore, activated
protein C has both anticoagulant and anti-inflammatory
properties. During sepsis, activated protein C levels can
become depleted due to consumption and inflammation-
induced downregulation of thrombomodulin. This results in
converge and ultimately cause the activation of thrombin,
with subsequent cleavage of fibrinogen into fibrin
(Fig. 21.8). The intrinsic pathway is a series of plasma pro­
teins that are activated by Hageman factor (factor XII), a
protein synthesized in the liver that is activated by binding
to collagen, basement membrane or activated platelets.87
Activated Hageman factor triggers a cascade of proteins to
become activated, resulting in the formation of thrombin.
The intrinsic pathway is most commonly activated by direct
tissue trauma. In contrast, the extrinsic pathway is initiated
by the production of tissue factor. Recent studies indicate
that the extrinsic pathway is the primary coagulation pathway
activated during infection and systemic inflammation, par­
ticularly during sepsis and SIRS.88 Tissue factor is expressed
on tissue surfaces that are not normally exposed to the vas­
cular compartment, such as subcutaneous tissues and the
adventitial layer of blood vessels. In addition, endothelial
cells and activated monocytes produce tissue factor during
Figure 21.8  Regulation of the coagulation cascade during inflammation.
Inflammation primarily causes activation of the extrinsic coagulation
pathway.
Macrophage/
monocyte
Tissue factor
Intrinsic
pathway
VIIa
VIIIa
IXa
Degradation
of Va and VIIIa
Binds TF-VIIa
complex
Binds thrombin
Fibrin clot
Macrophage/
monocyte
activation
Xa
Va
+
Activated
protein C
Tissue factor
pathway
inhibitor
Antithrombin
III
Endothelial
cell
TNFα
IL-1
Thrombin
Figure 21.9  Protein C is a circulating protein
that is activated by the thrombin–
thrombomodulin complex on the surface of
endothelial cells . Activation of protein C
decelerates the clotting cascade by inactivating
factors Va and VIIIa. Activated protein C also
inhibits thrombin-induced production of TNFα
by monocytes by inhibiting the activation of
transcription factors NF-κB and AP-1.
Proteolysis of factors Va and VIIIa
Profibrinolysis
Activated protein C Protein C
Cytokine
production
Fibrin clot
formation
Inflammation
Thrombosis
Cytokine
production
Fibrin clot
formation
induce
induce
Tissue
factor
inhibit
Thrombin
Tissue
factor
Thrombin
Thrombomodulin
Endothelium
Normal
Sepsis
Consumption of
protein C

Total Burn Care
21
260
injury. The factors that determine the transvascular fluid flux
are summarized in the Starling–Landis equation:104,105
J
K
P
P
v
f
mv
i
mv
I
=
−
−
−
[(
)
(
)]
α π
π
where Jv is the transvascular fluid flux, Kf is the filtration
coefficient (measure of the endothelial permeability to small
solutes and water as well as of the permeability surface area),
Pmv is the microvascular hydrostatic pressure, Pi is the inter­
stitial hydrostatic pressure, α is the osmotic reflection coef­
ficient to protein, πmv is the microvascular oncotic pressure,
and πi is the interstitial oncotic pressure.
Several investigators have studied lymph flow and lymph
protein flux after administration of bacteria or short-time
infusion of 1–2 µg/kg of endotoxin in sheep. Two phases
of permeability change could be distinguished in these
models.106 During phase 1 there was a high microvascular
hydrostatic pressure as defined by the Gaar equation.107 This
was associated with an increase in lung lymph flow, but the
lymph protein concentration was low. It was concluded that
the high microvascular hydrostatic pressure was responsible
for the early increase in transvascular fluid flux. Thrombox­
ane A2 (TXA2) has been found to be responsible for the
vasoconstriction that causes local increases in hydrostatic
pressure. Therefore, it is not surprising that administration
of the thromboxane synthetase inhibitor OKY046 prevented
the rise in lymph flow during phase 1.108 That effect was also
noted after blockage of cyclooxygenase by ibuprofen.109 Early
edema formation at the site of burn injury might be due to
a different mechanism. Recent data suggest that a marked
fall in interstitial hydrostatic pressure might occur in the
injured tissue, which could explain the immediate onset of
edema formation after thermal injury.110,111 These changes
might be the result of an inhibition of the fibroblast β1-
integrin attachment to collagen.
During phase 2, lymph flow continues to be high. However,
the lymph protein concentration rises considerably and the
pulmonary artery pressure is only mildly elevated.106 The
oncotic pressure gradient between microvasculature and
interstitial space is reduced during that period.112 Together,
these data suggest that the permeability of the pulmonary
endothelium to protein increases in phase 2. In fact, the
reflection coefficient for total protein fell from 0.73 to 0.58,
with respective changes in the reflection coefficients for
albumin (0.66 to 0.5), IgG (0.76 to 0.64), and IgM (0.91 to
0.83) after 4 hours of Escherichia coli sepsis in sheep.113 Con­
firmation of this hypothesis is still pending in models of
endotoxemia, but it has been generally accepted that the
changes in pulmonary transvascular fluid flux in phase 2
represent changes in microvascular permeability. The mecha­
nisms of the increased microvascular permeability are still
under discussion.
Endothelial cells play an important role in the regulation
of vascular permeability. It has been hypothesized that
endothelial cells can contract upon stimulation.114 As a
result, the intercellular gaps might increase in number and/
or size, establishing the so-called capillary leak syndrome.
The development of the protein-rich high-permeability
edema can be ameliorated if substances are administered
that raise the endothelial cell content of cyclic adenosine or
guanosine monophosphate.115,116 However, endothelial cells
do not merely serve as targets during systemic inflammation:
unchecked formation of thrombin, causing accelerated coag­
ulation and increased proinflammatory activity. The impor­
tance of protein C in regulating thrombin formation during
sepsis is demonstrated by increased mortality in septic
patients with low activated protein C levels.94
A third important factor in the regulation of thrombin
formation is the tissue factor pathway inhibitor (TFPI). TFPI
is present on the surface of endothelial cells and bound to
lipoproteins in plasma. TFPI inactivates tissue factor by
forming a quaternary complex with tissue factor and factor
VIIa. Factor Xa is the fourth component of the complex.95
Inhibition of tissue factor function inhibits activation of the
extrinsic clotting pathway during inflammation. Infusion of
TFPI has also been shown to reduce proinflammatory
cytokine production during endotoxin infusion in baboons,
but not in humans.
The hemodynamic response
The full clinical picture of systemic inflammation after
thermal injury is characterized by two primary phases. After
the initial injury, inflammation leads to increased vascular
permeability and the exudation of protein-rich fluid from
the vascular compartment to the interstitium. This early fluid
leak results in intravascular hypovolemia and interstitial
edema formation. If the patient is adequately resuscitated, a
hyperdynamic phase will ensue which is characterized by a
low systemic vascular resistance and high cardiac output.
Patients who are not well resuscitated or whose cardiac func­
tion is compromised may not be able to increase their
cardiac output to the extent needed to maintain arterial
blood pressure during states of extensive vasodilatation, and
so might exhibit tissue hypoperfusion and shock. A reduced
vascular responsiveness to vasoconstrictors may inhibit
successful pharmacologic intervention and patients could
develop irreversible shock. An intravenous bolus injection of
4 ng/kg endotoxin into healthy volunteers mimics some
aspects of the hemodynamic response seen in septic patients
and adequately resuscitated burn victims.96,97 The low sys­
temic vascular resistance and the elevated cardiac output can
also be induced in animal models by continuous infusion
of low-dose endotoxin98 or bacteria.99,100
Changes in endothelial permeability
Burn injury, trauma and sepsis increase microvascular per­
meability in both the systemic101,102 and the pulmonary cir­
culation.103 Increased vascular permeability and cutaneous
edema are hallmarks of burn shock. The increase in systemic
vascular permeability results in the exudation of protein-rich
fluid from the vascular compartment into the interstitium.
This results in intravascular volume loss and the concomi­
tant development of interstitial edema. If resuscitation is not
prompt and adequate, this loss in intravascular volume will
lead to intravascular hypovolemia, hypotension, and inad­
equate tissue perfusion. Severe interstitial edema formation
can lead to the development of compartment syndrome,
with compromise of neurovascular integrity. The lungs may
also be affected. Edema formation due to an increase in
microvascular permeability is a hallmark of the acute lung

The systemic inflammatory response syndrome
261
cyclooxygenase metabolite.109 This discrepancy is still unex­
plained; however, prostacyclin is elevated after endotoxin
administration, and this material has many actions that
counter the actions of thromboxane. Administration of a
cyclooxygenase inhibitor will prevent the release of this salu­
tary eicosanoid.
TNFα is one of the early mediators in systemic inflamma­
tion. It has been reported to be elevated during sepsis and
endotoxemia after hemorrhagic shock or thermal injury. It
is considered to be one of the most important mediators in
the cascade because it has the potential to stimulate or
enhance most of the steps in the inflammatory response.
Moreover, administration of human recombinant TNFα
reproduced most of the effects of endotoxemia, including
alterations in pulmonary microvascular permeability in the
chronic sheep model.133,134 TNFα also induces the secretion
of PAF, which is a further early mediator of systemic inflam­
mation. PAF causes an increase in lung lymph flow and
permeability to protein when it is infused into conscious
sheep.135 Administration of a PAF antagonist abolished the
cardiopulmonary response that occurs during phase 1 and
attenuated it during phase 2.136 However, PAF had no direct
effect on endothelial cells. This suggests that it probably
increases microvascular permeability through other mecha­
nisms, such as its priming effect on PMNs.137,138
If burn patients are adequately resuscitated, they most
commonly enter into a phase characterized by hyperdy­
namic cardiovascular function. The hyperdynamic cardiovas­
cular response is associated with profound changes in
pulmonary transvascular fluid flux in the ovine model of
continuous endotoxemia.102,139 The lymph protein concen­
tration gradually decreased after phase 2, and after 24 hours
of endotoxemia the reflection coefficient to protein was at
baseline level, whereas the lymph flow was still high. Micro­
vascular hydrostatic pressure, evaluated by Holloway’s tech­
nique, was not significantly different from baseline.140 The
elevated transvascular fluid flux was attributed to a high fil­
tration coefficient. An increase in both perfused surface area
and pore numbers might have contributed to the change in
filtration. Repeated injections of endotoxin also reduced
subsequent lung lymph production in response to endo­
toxin.133 These changes in lung lymph flow were associated
with elevations in endothelin and atrial natriuretic
peptide.140,141 However, further studies must determine
whether these factors affect pulmonary microvascular
changes during the late phases of sepsis and multiple organ
failure.
Increased epithelial permeability
Permeability changes during systemic inflammation are not
restricted to the endothelium. Loss of epithelial barrier func­
tion has been noted both in the lung and in the intestine.
Administration of 2–4 ng/kg endotoxin to healthy human
volunteers increased their alveolar epithelial permeability to
the inhaled 492 Da molecule [99mTc] diethylenetriamine
pentaacetate (DTPA) 3 hours after endotoxin had been
given.97 Human volunteers demonstrated a higher intestinal
epithelial permeability to mannitol/lactulose.142 Bacterial
translocation occurred during endotoxemia,143 thermal
injury,144 and multiple trauma with hemorrhagic shock.145
they actively contribute to the ongoing inflammatory process.
The endothelial cell can be stimulated by endotoxin, TNFα,
or IL-1 to express E-selectin, an adhesion molecule.117
E-selectin on the surface of endothelial cells interacts with
the corresponding L-selectin complex on PMNs to facilitate
rolling of these cells along the endothelium.118 Moreover,
endothelial cells secrete the proinflammatory cytokines
TNFα and IL-1, which activates PMNs.119 Conflicting data
exist regarding the role of PMNs in SIRS. PMNs are usually
found at the site of tissue injury, to which they migrate fol­
lowing a concentration gradient of chemotactic stimuli.
Upon stimulation, PMNs roll along endothelial cells, and in
a further step mediated by PMN CD18/CD11b interactions
with endothelial ICAM-1, emigrate from the vessel into the
interstitial space. Antibodies against the common CD18β
chain showed beneficial effects in an animal model of sepsis-
induced lung injury, suggesting that integrin-mediated PMN
emigration is a functionally important process in the devel­
opment of acute lung injury.120 On the other hand, patients
who are deficient in CD18 have abundant PMNs in their
alveolar spaces, and the monoclonal antibody 60.3 was inef­
fective in completely blocking the migration of PMNs into
the lung in a number of conditions.121 We have reported that
in chronic endotoxemia there were few PMNs in the lung
but numerous macrophages.122 Activated PMNs and macro­
phages release oxygen free radicals and proteases at sites of
inflammation. Those processes appear to be functionally
important in the development of vascular permeability
because administration of oxygen free radical scavengers and
antiproteases proved to be useful in diminishing edema
accumulation after endotoxin challenge.123,124 However, pro­
teases and oxygen radicals are also released by macrophages,
which are already present in the tissue, and by monocytes
that migrate to sites of inflammation. Depletion of granulo­
cytes by anti-PMN antiserum or by treatment with nitrogen
mustard did not prevent the changes in microvascular per­
meability following the administration of endotoxin.125,126
Moreover, patients deficient in PMNs would still develop
the adult respiratory distress syndrome (ARDS) associated
with sepsis.126,127 On the other hand, treatment of sheep or
goats with hydroxyurea, which is another compound used
to deplete granulocytes, was effective and diminished fluid
accumulation in the lung after endotoxin challenge.128
However, urea scavenges free radicals, which might explain
its efficacy.129 As the inflammatory response becomes chronic,
many mediators have been released and more than one
mechanism might be assumed to be responsible for the
capillary leak.
The role of arachidonic acid metabolites in facilitating
increased vascular permeability has been extensively investi­
gated. Administration of the thromboxane synthetase inhibi­
tor OKY046 not only reduced transvascular fluid flux in
phase 1, but was also effective in phase 2 after endotoxin
challenge.108 This finding suggests that thromboxanes partici­
pate in permeability alterations during systemic inflamma­
tion. Oxygen free radicals can also increase microvascular
permeability, both by activation of endothelial cell contrac­
tion and by damaging the endothelial cell membrane.130
OKY046 has been shown to reverse oxygen free radical-
induced lung injury.131,132 On the other hand, inhibition
of the cyclooxygenase did not affect transvascular fluid
flux during phase 2, even though thromboxane A2 is a

Total Burn Care
21
262
(Fig. 21.10). The calcium-dependent constitutive nitric oxide
synthases (NOS) such as endothelial NOS (eNOS) and neu­
ronal NOS (nNOS) are responsible for the basal release of
NO, which seems to play an important role in the regulation
of vascular tone under physiologic conditions. In vitro data
suggest that these enzymes might become inactivated early
after administration of endotoxin, thereby accounting for
some of the vasoconstrictive phenomena seen in phases 1
and 2.157 Inducible NOS (iNOS) is the major NOS isoform
induced during acute inflammation. Depending on the
species, cells producing the inducible NOS upon stimulation
by endotoxin, TNFα, IL-1, or IFN-α include macrophages,
vascular smooth muscle cells, and vascular endothelium.158
NO is a lipophilic gas, which can easily enter vascular
smooth muscle cells where it stimulates the soluble guan­
ylate cyclase to synthesize cyclic guanosine monophosphate
(cGMP).159,160 High levels of cGMP stimulate cells to lower
their intracellular Ca2+ concentration. This leads to vascular
dilatation and hyporesponsiveness to vasoconstrictors.
Administration of an NOS inhibitor to septic humans and
to endotoxemic sheep increases their vascular resistance
and restores their responsiveness to vasoconstrictors.161–163
Overall, it appears that NO is an important mediator of
SIRS-induced vascular alterations. However, administration
of NOS inhibitors in humans has not improved overall
outcome during sepsis or SIRS. Therefore, the mechanisms
by which NO alters vascular function during SIRS in humans
require further investigation.
Peroxynitrite is an additional NO-associated factor that
appears to contribute to SIRS-induced pathology. Peroxy­
nitrite is a free radical that is generated through interactions
of NO and oxygen free radicals during periods of severe
inflammation and is known to cause cellular injury and
organ dysfunction in experimental burn models.164,165 Treat­
ment of burned sheep with a peroxynitrite degradation cata­
lyst has been shown to reduce lung injury in an ovine model
of burn and smoke inhalation injuries.166 Therefore, perox­
ynitrite appears to be an important mediator of organ injury
during periods of systemic inflammation. However, further
research is needed to determine the efficacy of treatment
approaches aimed at promoting peroxynitrite degradation
and neutralization in the clinical setting.
This might well be interpreted as a loss of intestinal barrier
function. Nevertheless, one must bear in mind that epithelial
permeability to molecules such as lactulose/mannitol and
bacterial translocation do not necessarily relate to each
other. The epithelium could also be injured by ischemia–
reperfusion.146 In addition to changes in vascular permeabil­
ity, burn injury also causes marked alterations in vascular
tone and myocardial function that are characterized by a
variety of temporal alterations.
The hyperdynamic state
Continuous infusion of endotoxin into sheep and pigs
results in a hyperdynamic circulation.138,147,148 Besides a low
systemic vascular resistance and a high cardiac output with
a slightly decreased mean arterial pressure, the hyperdy­
namic response is further characterized by hyporesponsive­
ness of isolated vessels to vasoconstrictors and an increased
pulmonary shunt fraction in the presence of a reduced pul­
monary hypoxic vasoconstriction.147,149–151 The high cardiac
output is due to low systemic vascular resistance and
increased heart rate.152,153 Paradoxically, myocardial function
is depressed during sepsis and in severely burned patients.154,155
The underlying cause of impaired myocardial function is not
fully understood. However, reports indicate that proinflam­
matory mediators such as TNFα, IL-1, IL-6 and nitric oxide
contribute to this alteration.155,156 The treatment of myocar­
dial function during sepsis and after burn trauma is an
important consideration in overall hemodynamic manage­
ment. The combination of myocardial dysfunction and
increased pulmonary vascular resistance is a likely cause of
right heart failure in pediatric burn patients. Treatment
options include dobutamine and phosphodiesterase inhibi­
tors such milrinone. The Surviving Sepsis Campaign recom­
mends dobutamine as a first-line agent for treatment of
hypotension and hypoperfusion in pediatric patients with
sepsis, especially when myocardial dysfunction is present.78
Nitric oxide (NO) has been implicated as a mediator of
systemic vasodilation and myocardial depression during
sepsis and after major burn injury. NO can be synthesized
from its precursor L-arginine by three different enzymes
Figure 21.10  Nitric oxide is an important
mediator of inflammation-induced vasodilation,
myocardial depression and organ injury. The
synthesis of nitric oxide is mediated by three
major nitric oxide synthase (NOS) isoforms.
Endothelial
stimulation
Endothelium
Cytoxicity
Activation
stimulus
Calcium influx
and eNOS
activation
eNOS
eNOS
NO
NO
NO2 + OH- ← O2
- + NO
Microbe
Macrophage

The systemic inflammatory response syndrome
263
Further reading
dos Santos CC, Gattas DJ, Tsoporis JN, et al. Sepsis-induced
myocardial depression is associated with transcriptional changes in
energy metabolism and contractile related genes: a physiological
and gene expression-based approach. Crit Care Med. 2010;38:
894-902.
Goldstein B, Giroir B, Randolph A. International pediatric sepsis
consensus conference: definitions for sepsis and organ dysfunction
in pediatrics. Pediatr Crit Care Med. 2005;6(1):2-8.
Muckart DJ, Bhagwanjee S. American College of Chest Physicians/
Society of Crit Care Med Consensus Conference definitions of
the systemic inflammatory response syndrome and allied
disorders in relation to critically injured patients. Crit Care Med.
1997;25(11):1789-1795.
Szabó C, Módis K. Pathophysiological roles of peroxynitrite in
circulatory shock. Shock. 2010 Sep;34(Suppl 1):4-14.
Westphal M, Enkhbaatar P, Schmalstieg FC, et al. Neuronal nitric
oxide synthase inhibition attenuates cardiopulmonary dysfunctions
after combined burn and smoke inhalation injury in sheep. Crit
Care Med. 2008;36:1196-1204.
Summary
Burn injuries, associated ischemia–reperfusion injury, the
presence of necrotic tissue, and sepsis are all events that
contribute to SIRS after severe burn injury. Widespread
increases in microvascular permeability lead to intravascular
hypovolemia and interstitial edema, thereby impairing
oxygen diffusion to the tissue. Blood flow may become
maldistributed owing to a loss of vasoregulatory function
and as a result of widespread microthrombosis. Oxygen uti­
lization also appears to be impaired. The resultant hypoxic
cell damage further promotes organ dysfunction. Oxygen
free radicals, peroxynitrite and cytokines also appear to con­
tribute to tissue damage and organ dysfunction. Despite
improved understanding of the cellular and molecular
mechanisms underlying SIRS, targeting the inflammatory
response is not currently an effective treatment option for
patients with burn-induced SIRS. Treatment is supportive
and includes adequate fluid resuscitation, appropriate use
of vasoactive drugs, support of failing organ systems, exci­
sion of necrotic tissue and treatment of infection with
antibiotics.
Access the complete reference list online at

The systemic inflammatory response syndrome
263.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
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The immunological response and
strategies for intervention
Erle D. Murphey, Edward R. Sherwood, Tracy Toliver-Kinsky
Introduction
Despite improvements in the management of burn injury1,2
and the development of broad-spectrum antibiotics, infec­
tions still remain a major cause of morbidity and mortality
in burn patients.3,4 Many infections are associated with
organisms considered to be opportunistic in nature, which
supports the concept that antimicrobial function may be
impaired in these patients. One paradigm of burn-induced
immune dysfunction asserts that the initial burn injury
induces a severe inflammatory response characterized by the
systemic release of proinflammatory cytokines, chemokines
and acute-phase reactants that cause leukocyte and endo­
thelial cell activation (Fig. 22.1). This initial inflammatory
response has been termed the systemic inflammatory
response syndrome (SIRS) and causes a variety of hemody­
namic, immunologic and metabolic responses that can lead
to significant tissue injury and organ dysfunction. However,
if adequately resuscitated, most burn victims survive the
initial injury and enter a phase characterized by varying
degrees of immune dysfunction. This state of immunologic
dysfunction, along with the loss of the skin barrier and the
use of invasive instrumentation such as central venous cath­
eters, peritoneal dialysis catheters and endotracheal tubes,
places the burned host at increased risk of infection. Some
practitioners have proposed that post-burn immunologic
dysfunction is caused by an anti-inflammatory response,
termed the counter anti-inflammatory response syndrome
(CARS), which is initiated by the host in an effort to mini­
mize inflammation-induced tissue injury during the acute
post-burn period. CARS is characterized by a relative prepon­
derance of anti-inflammatory cytokine production, leuko­
cyte apoptosis, regulatory lymphocyte generation and a shift
in adaptive immunity from a Th1 to a Th2 phenotype. Accu­
mulation of inflammatory insults during the post-burn
period may potentiate injury-induced immunosuppression.
Therefore, there is keen interest in developing immunomo­
dulatory strategies aimed at normalization, or enhancement,
of antimicrobial function. Interventions that can improve
the host response to infection are also becoming increasingly
attractive because of the emergence of antibiotic-resistant
microorganisms as pathogens in burn patients.5,6 However,
few effective immunomodulatory approaches have been
developed for clinical application in burn patients. This may
be because immune dysfunction parallels failure of other
organ systems and may be a reflection of multiorgan system
dysfunction. Leukocytes in that environment appear to be
ineffective in responding to infection, and may also be
refractory to immunomodulatory interventions. Therefore,
the early initiation of immunomodulation may be most
advantageous, although further research is needed to deter­
mine whether immunomodulation will be effective in burn
patients and which approaches have the most potential for
improving overall outcome.
The depth and size of the burn wound are well-known risk
factors for infection and sepsis.4,7 The overall incidence of
bacteremia in burn patients is approximately 19%, but bac­
teremia rarely occurs in patients with <40% TBSA burns.8
Concomitant inhalation injury is also associated with an
increased risk of infection, particularly pneumonia. The pre­
disposition to pneumonia seen in patients with inhalation
injury is likely due to impairment of mucociliary clearance,
alveolar macrophage dysfunction, and airway obstruction
with casts and debris in conjunction with a high incidence
of tracheal intubation and mechanical ventilation.9
Some investigators have reported a gender effect on post-
burn mortality, with females having a lower chance of
survival.10 However, a study of children did not show a rela­
tionship between gender and the incidence of sepsis.11 Nev­
ertheless, age appears to be a predisposing factor for the
development of septicemia after burn injury. Not surpris­
ingly, young children and elderly patients have the highest
incidence of sepsis.12
Relative to other catheters, central venous catheters are
particularly prone to bacterial contamination. Approxi­
mately 25% of central venous catheters become colonized
with bacteria. Lesseva et al. reported an incidence of catheter-
related bacteremia of 6.6%, accounting for approximately
20% of sepsis in burn patients.13 Peripheral catheters are
much less likely to be associated with infection because of
their shorter duration of use. The risk of catheter-related
infection is greatly increased if devices are inserted through
infected or contaminated skin, such as burn wounds. Femoral
vein catheters are more likely to become infected than
subclavian or internal jugular vein catheters, and catheter
replacement via guide wire exchange has a higher infection
rate than catheterization at a separate site. One of the most
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00022-9
CHAPTER 22 
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266
Innate immune function after burn injury
After a large burn injury with extensive tissue necrosis, the
innate immune system is activated both locally and systemi­
cally. Subsequent dysfunction of innate immune function
may lead to increased susceptibility to infections. Study of
immune function in burn patients is limited by feasible
tissue access and generally consists of measuring circulating
soluble factors and immune cells. Not surprisingly, this pro­
vides only a limited view of the entire immune response, as
suggested by animal studies in which alternate tissues such
as spleen and liver are available.24–27 This review will high­
light observational data from clinical studies and try to use
results from experimental research to provide some context
for these observations.
Healthy individuals resist many infectious challenges
without pre-existing specific (acquired) immunity because
of the effectiveness of the innate immune response. Innate
immunity is a protective set of rapid and primitive non-
specific responses to infection, including epithelial barrier
defenses, cytokine elaboration, complement activation, and
phagocytosis of microorganisms. These mechanisms may
eradicate or contain the infection during the time needed to
generate an adaptive immune response to the offending
microbe. The hallmarks of innate immune system activation
are acute inflammatory changes characterized by increased
vascular diameter and blood flow, increased vascular perme­
ability and neutrophil recruitment. These alterations allow
for a rapid response to tissue damage or infection, which is
crucial for initial damage control. Although the innate
immune system is critical for an effective host response to
infection, inappropriate or excessive activation can lead to
tissue damage and severe systemic physiologic alterations.
Furthermore, dysfunction of innate immunity may predis­
pose burn patients, and other critically ill individuals, to
infectious complications.
Physical barriers
A mechanical barrier against invasion of microbial patho­
gens is provided by the epithelium of skin and mucosal
tissue. This protective barrier is lost after destruction by full-
thickness burn injury. Furthermore, the presence of necrotic
tissue provides a favorable environment for microbial
growth. Cellular damage may also cause the release of mol­
ecules that predispose the host to bacterial infections. Syn­
decans are heparin sulfate proteoglycans that regulate innate
immune responses, and their release after cellular damage
activates tissue repair processes, including vascular permea­
bility, angiogenesis, wound repair, and modulation of chem­
okine activity.28 In general, syndecans have been shown to
attenuate inflammatory responses and protect tissues from
inflammatory injury. However, recent studies in burned mice
suggest that syndecan shedding may potentiate systemic
dissemination of P. aeruginosa from burn wound infections,
an effect that may be attenuated by the application of
protamine.29,30
Besides the loss of epidermal integrity in burned skin,
barrier function may also be compromised at other remote
anatomic locations. Epithelial barrier function in the gas­
trointestinal tract can be compromised after burn injury,
common causes of Gram-negative sepsis in hospitalized
patients is urinary tract infection, especially in the presence
of Foley catheters. Nearly all patients with large TBSA burns
require bladder catheterization. The incidence of urinary
tract infection in burn patients ranges from 10% to approxi­
mately 18%.3 The incidence of respiratory infections in burn
patients ranges from 20% to 40%.14 Nosocomial pneumonia
is frequently associated with prolonged intubation and
mechanical ventilation.15 Gram-negative bacteria such as
Pseudomonas aeruginosa are commonly isolated, but Gram-
positive bacteria and yeasts such as Candida spp. should also
be considered.
Medications administered to burn patients may in some
instances also be a contributing factor to post-burn immu­
nosuppression and increased susceptibility to infection.
Despite the need for aggressive administration of systemic
antibiotics, there is an increasing emergence of antibiotic-
resistant bacteria in burn patients which has significantly
affected infection control efforts.16 In addition, some clinical
reports indicate that systemic antibiotic administration may
be a predisposing factor for the development of fungal infec­
tions.17,18 Recent experimental work suggests that admini­
stration of opiate analgesics may contribute to post-burn
immunosuppression by adversely affecting T-cell prolifera­
tion and altering the predominant T-helper phenotype.19
Transfusion of blood products has also been reported to
predispose burn victims and other critically ill patients to
nosocomial infections.20 Although the exact mechanism of
immunosuppression is unknown, blood transfusions have
been associated with a decrease in the T-helper–lymphocyte
ratio, as well as adverse effects on natural killer cell activity
and antigen presentation.21,22 Finally, victims of large TBSA
burns usually require numerous operative procedures for
debridement and grafting of burn wounds. Intravenous and
inhalation anesthetics have demonstrated variable and
inconsistent effects on neutrophil function, including altera­
tions in chemotaxis, endothelial adherence and trans­
migration, phagocytosis, and respiratory burst, and could
contribute to post-injury immunosuppression.23
Figure 22.1  Paradigm of inflammation and immune dysfunction after burn
injury. As depicted, the initial burn insult induces a systemic inflammation
response (SIRS) that is counteracted by anti-inflammatory mechanisms such
as the production of anti-inflammatory cytokines (IL-10, TGFβ) and leukocyte
apoptosis, resulting in the so-called counter anti-inflammatory response
syndrome (CARS). It is postulated that CARS leads to impaired antimicrobial
function and predisposition to infection.
Early MODS
IL-6
SIRS
SIRS
CARS
CARS
TNF-α
IL-10
TNF-β
Late MODS
Infection
Normal
Anti-inflammatory
Inflammatory
Injury

The immunological response and strategies for intervention
267
microbial stimulation would invoke an appropriate level of
activation in affected areas.39
Phagocytes and Toll-like receptors
Beyond the physical barriers, the key cellular components of
the innate immune response are the professional phago­
cytes, including macrophages, dendritic cells and neutro­
phils, which are not only important in removing microbes
and debris from sites of inflammation but also are key regu­
lators of the innate immune response (Fig. 22.2). Macro­
phages are capable of engulfing and killing microbes, but
probably function most importantly as supervisors of the
immune response to infection. They elaborate chemotactic
factors for the recruitment of other cells, particularly neu­
trophils, to the site of infection. Along with dendritic cells,
macrophages also function to initiate the adaptive immune
response by presenting bacterial antigens to CD4+ T cells.
Neutrophils are effective at killing microbes through an
arsenal of specialized antimicrobial functions (discussed
below). Because the innate immune system must react to
potential pathogens before they proliferate and disseminate,
detection is dependent on the recognition of microbial mol­
ecules that are consistently found among a vast assortment
of microorganisms.
Toll-like receptors, found on mononuclear phagocytes,
provide a primitive, non-specific mechanism of pathogen
recognition based on the detection and binding of conserved
microbial products rather than recognition of specific micro­
bial antigens.40 Human leukocytes express at least 10 TLRs,
which recognize microbial ligands such as lipopolysaccha­
rides, lipoproteins, lipotechoic acid, flagellin, unmethylated
possibly owing to decreased mesenteric blood flow in the
early post-burn period.31 This may lead to systemic transloca­
tion of bacterial toxins or enteric bacteria. Increased intesti­
nal permeability after burn injury has been associated with
systemic infection in a number of studies, and forms the
basis for the therapeutic strategy of selective decontamina­
tion of the digestive tract as well as interventions aimed at
improving gut barrier function, such as early enteral feeding.32
In the respiratory tract, defense mechanisms include mucus
secretion and ciliary movement, which serve to trap microbes
and sweep them into the upper airways and oropharynx,
where expulsion by coughing may occur. These defenses can
be diminished after inhalation injury or compromised by
endotracheal intubation, resulting in microbial proliferation
and expansion into the distal branches of the respiratory
tract, causing bronchitis or pneumonia.33,34 Smoke inhala­
tion also facilitates the development of bronchial casts
composed of neutrophils, sloughed respiratory mucosa and
fibrinous products, which impair microbial clearance mech­
anisms and aid bacterial growth.35 Pneumonia is one of the
most common infections encountered in burn patients and
is associated with a higher risk of mortality.36
Epithelial cells contribute further protection by manu­
facturing antimicrobial peptides, including defensins, lys­
ozymes, and cathelicidins. Defensins exert antimicrobial
activity against a broad range of bacteria and fungi and
appear to function through disruption of the bacterial cell
wall.37 Although epithelial cells display some constitutive
production of defensins, production is increased after micro­
bial activation of Toll-like receptors (TLRs) on the epithelial
cells.38 However, burn injury has been associated with
decreased defensin mRNA expression, and it is not clear that
Figure 22.2  The innate immune response to
infection is typically initiated by macrophages,
which recognize microbial products and produce
a variety of immunomodulatory factors such as
cytokines and chemokines that initiate alterations
that are prototypical of acute inflammation, such
as vasodilation and increased blood flow,
increased vascular permeability and neutrophil
recruitment. Neutrophils are instrumental in the
initial response to infection and are critical for
effective phagocytosis and clearance of
microbes. (From Abbas and Lichtman, Cellular and
Molecular Immunology, 5th Edition, Saunders).
Neutrophil
infiltration
Macrophage
activation
T cell
NK cell
Chemokines
Thrombosis
0
LPS
Macrophages
1
Hours after LPS injection
Cytokine leveld in serum
3
6
IFN-γ
IL-12
IL-1
TNF

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Neutrophil microbicidal function
Large-scale neutrophil infiltration is characteristically seen in
burn wounds. Although this is probably an advantageous
response to protect against potential pathogens, it may also
be associated with some undesirable biologic effects. Oxi­
dants and hydrolytic enzymes released from activated neu­
trophils can contribute to proteolysis within the wound and
aid in the spread and dissemination of bacteria. Abnormal
neutrophil function has been associated with bacteremia in
patients with burns and other major injuries.52 Neutrophil
microbicidal mechanisms are generally classified as
either oxygen dependent or oxygen independent. Oxygen-
independent microbicidal activity of neutrophils involves
several peptides and proteins stored within the primary
(azurophilic) granules, including lysozyme, bactericidal/
permeability-increasing protein, β-defensins, and cathelici­
din. In the oxygen-dependent mechanism, NADPH oxidase
in the phagosome of neutrophils (and macrophages) con­
verts molecular oxygen into superoxide anion (O2
–), and a
series of reactions creates further oxidant products with
microbicidal activity, including H2O2, OCl− (hypochlorite)
and NH3Cl and RNH2Cl (chloramines). A reduction in
neutrophil-mediated oxygen-dependent bacterial killing has
been reported in several studies of burn patients.53,54 Poor
tissue perfusion and low oxygen tension in wound sites are
additional factors likely to contribute to impaired oxidative
killing. Chemotactic gradients are provided by chemoattract­
ants such as the complement protein C5a, endothelium-
derived IL-8, and leukotrienes. Chemoattractants and other
stimuli also induce increased expression of surface phago­
cytic receptors. Bonding between phagocyte receptors and
bacterial CpG DNA, and viral RNA, as well as endogenous
ligands such as heat shock proteins, HMGB-1 and mitochon­
drial DNA (Fig. 22.3). TLR ligation results in activation of
specific signaling pathways that cause nuclear translocation
of transcription factors such as NF-κB, AP-1 and IRF-3, which
induce transcription of genes encoding proinflammatory
gene products such as cytokines, chemokines and nitric
oxide synthase.41,42
The importance of TLRs for recognition and clearance of
microbes has been demonstrated in studies using mice that
are genetically deficient of specific TLRs. TLR-deficient mice
are highly susceptible to microbial infections owing to the
inability to effectively respond to infection and clear in­vading
organisms.43–45 Furthermore, analysis of a cohort of humans
with congenital loss of MyD88, an important signaling inter­
mediate required by most TLRs, showed a high incidence of
infections with Pseudomonas spp, streptococci and staphylo­
cocci, which are common opportunistic pathogens among
burn patients.46 It is not known whether alterations in TLR
expression or function directly contribute to impaired innate
antimicrobial functions in burn patients. However, Barber
and colleagues have reported an association between TLR
polymorphisms and the development of sepsis in burn
patients.47 In addition, several studies indicate that TLR acti­
vation contributes to the systemic inflammatory response
and associated alterations caused by thermal injury, such as
altered vascular and gut permeability, myocardial dysfunc­
tion and microvascular inflammation.48–50 Macrophages
seem primed for innate immune activity after burn injury
through increased TLR4 expression and increased reactivity
to LPS challenge, which may predispose burn victims to
further inflammatory injury.25,51
Figure 22.3  Toll-like receptors are surface proteins that are instrumental in the recognition of microbial products and endogenous inflammatory mediators
by leukocytes of the innate immune system. There are at least 11 identified Toll-like receptors in humans. (From Kawai and Akira, Cell Death and Differentiation 13: 816,
2006).
Triacyl
lipopeptide
TLR1 TLR2
Inflammatory
cytokines
Inflammatory
cytokines
Type I IFN
Inflammatory
cytokines
Inflammatory
cytokines
Type I IFN
Inflammatory
cytokines
TLR2 TLR6
TLR3
TLR4
TLR7/8
TLR9
TLR5
TLR11
Adapters
TIRAP
MyD88
MyD88
MyD88
Trif
TIRAP
TIRAP
MyD88
MyD88
MyD88
MyD88
Trif
TRAM
Imidazoquinolines
ssRNA
Diacyl
lipopeptide
CpG DNA
Hemozoin
Profilin-like protein
Uropathogenic
bacteria
LPS
dsRNA
Flagellin

The immunological response and strategies for intervention
269
constitute the complement system: the classic pathway, the
mannan-binding lectin pathway, and the alternative pathway
(Fig. 22.4). Binding of IgG or IgM to antigens on microbial
surfaces activates the classic pathway. The remaining two
pathways can be activated in the absence of specific antibod­
ies. The mannan-binding lectin pathway is similar to the
classic pathway but is initiated after mannan-binding lectin
protein binds to mannose-containing carbohydrates on
microbial surfaces. The alternative pathway is dependent on
low constitutive expression of complement activity which is
amplified and potentiated when circulating complement
components bind to microbial membranes. All three of the
activation pathways act on microbial surfaces to assemble a
convertase that cleaves C3 to form C3b, which either binds
to the surface as an opsonin or helps activate C5 and the
remainder of the complement cascade. Opsonization facili­
tates the removal of microbes by macrophages and neu­
trophils. C3a and C5a are potent chemoattractants for
monocytes and neutrophils. Cleavage of C5 also leads to
assembly of the membrane attack complex, which causes
disruption of the microbial membrane. After burn injury,
neutrophil surface expression of receptors for complement
is increased, but the complement cascade itself is diminished
opsonins on microbial surfaces activates cytoskeletal con­
tractile elements, resulting in invagination of the cell
membrane and extension of pseudopods around the
microbe. Clinical studies of neutrophils from burn patients
demonstrate a reduction in neutrophil adhesion molecule
expression and phagocytic activity.53,55 Theoretically, these
alterations could lead to decreased innate antimicrobial
activity and increased susceptibility to infection. However, a
specific cause and effect relationship between altered neu­
trophil function and the development of infections in burn
patients has not been firmly established.
Innate lymphocytes – natural killer (NK),
natural killer T (NKT), and γδ T cells
Natural killer (NK) cells are lymphoid cells that do not
express T-cell receptors (TCR) or immunoglobulins on the
cell membrane but rapidly respond to infections through
activating specific chemokine receptors and other activating
innate receptors. NKT cells express both NK cell markers and
restricted T-cell receptors (TCRs) that respond primarily to
lipid antigens presented by the antigen-presenting molecule
CD1d. γδ T cells comprise about 10% of all T cells and play
important immunoregulatory roles in skin, gut, respiratory
tract and other mucosal sites. All three innate lymphocytes
are able to induce dendritic cell (DC) maturation through a
combination of cell contact-dependent mechanisms and
cytokine signaling. In turn, matured DCs can stimulate NK,
NKT, and γδ T cells to sustain the innate immune response
during the development of adaptive immunity. γδ T cells,
which are in found in high numbers in intestine, may play
a role in the recruitment of neutrophils to that site after burn
injury.56 Some studies indicate that γδ T cells facilitate
neutrophil-independent and neutrophil-mediated organ
injury after burn injury.57,58 NK cells are best known for their
role in containing viral infections prior to the adaptive
immune response, as well as assisting in the control of
malignant tumors. Activated NK cells are an important
source of IFNγ, which promotes the development of specific
protective immune responses but may also contribute to the
systemic inflammatory response after severe burn injury.59
NK cells kill infected cells through the release of perforin and
granzymes and through the binding of the death receptors
Fas and TRAIL-R on target cells. NK cells also interact with
other cells of the immune system, including dendritic cells,
by providing signals for maturation or apoptosis. Studies of
patients after burn injury have revealed a decline in NK-cell
activity over time.60 The decline in NK cell activity is most
apparent more than 1 week after the occurrence of the burn
injury and corresponds with the period during which sepsis
is more likely to be identified.60
Complement
As well as Toll receptors, the innate immune system has
additional mechanisms for recognizing and neutralizing
microbial pathogens, including the complement system,
scavenger receptors, and specialized receptors on NK cells.
Activation of the complement system results in the produc­
tion of a cascade of proteins that function to opsonize
microbes and recruit phagocytes. Three distinct pathways
Figure 22.4  The complement system can be activated by three primary
mechanisms and facilitates the amplification of innate and acquired
immune responses as well as directly mediating microbial lysis. The primary
functions of complement are opsonization, leukocyte chemotaxis and direct
killing of microbes. (From Abbas and Lichtman, Cellular and Molecular Immunology,
5th Edition, Saunders).
Alternative
pathway
Microbe
Initiation of
complement
activation
C3
C3
C5
C5b
C5b
C3
C3b
C3b
C3b
C3b
C3b
C3a
C5a
Early steps
C3b is
deposited
on microbe
Membrane attack
complex (MAC)
Late steps
Effector
functions
C3a:
Inflammation
C5a:
Inflammation
Lysis of
microbe
C3b:
Opsonization
and
phagocytosis
Classical
pathway
Lectin
pathway
Antibody
Mannose
binding
lectin

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changes that occur after burn injury. Some of the most recent
reports on cytokine function in burn patients are reviewed
below, and a brief list of cytokines that have been studied in
burned populations is presented in Table 22.1.
The description of the cytokine response after burn injury
has varied widely in several clinical studies. It is likely, based
on accumulated evidence and results from well-controlled
animal experiments, that burn injury by itself evokes only
a modest increase in circulating cytokines. This limited
cytokine response may be related, in part, to burn-induced
expression of anti-inflammatory signaling pathways and
factors such as suppression of cytokine signaling-3 (SOCS 3)
within hours of burn injury.65 Nevertheless, concentrations
of cytokines remain elevated in plasma for weeks after major
burn injuries, and there appears to be a significant difference
in cytokine production between children and adults.66
Cytokines may also be elevated in the circulation of post-
burn patients because of stresses during treatment, including
intubation and ventilation, surgery, transfusions, and expo­
sure to microorganisms. In fact, there is evidence to suggest
that the cytokine response to a secondary insult, such as
infection, may be greater after burn injury than under basal
conditions.67 Burn injury appears to ‘prime’ immune and
inflammatory cells for an exaggerated response to endotoxin
and other microbial products.68,69 Post-burn ‘hyperreactivity’
in terms of cytokine production has been well described in
macrophages.70 Priming for an exaggerated response to LPS
stimulation has also been described in alveolar macrophages
harvested from bronchoalveolar lavage of smoke inhalation
and may serve as a prognostic indicator.61,62 In a clinical
study of severely burned patients (>60% TBSA, third-degree)
serum concentrations of complement proteins were meas­
ured sequentially. All patients had decreased concentrations
of C3 initially; however, serum concentrations of C3
rebounded fully in surviving patients while remaining
depressed in non-survivors.63 Diminished complement, in
combination with decreased concentrations of fibronectin
and serum immunoglobulins, contributed to the depression
of opsonic activity in both serum and blister fluid from burn
patients, and may predispose burn patients to wound
infections.64
Cytokines and chemokines
Cytokines are a heterogeneous group of small polypeptide-
soluble mediators that are important for the regulation of
antimicrobial immunity. In conjunction with hormones
and neurotransmitters, cytokines regulate tissue repair and
immune responses. Most cells of the immune system either
release cytokines and/or respond to cytokines through spe­
cific receptors. The cytokine response evoked by microorgan­
isms controls both innate and adaptive immune responses,
including inflammation, defense against viruses, leukocyte
recruitment and proliferation of specific T- and B-cell clones,
while regulating the function and interaction of a variety of
immune cells. A complete discussion of cytokine biology is
beyond the scope of this chapter. It is likely that a broad
array of cytokines regulate the pro- and anti-inflammatory
Table 22.1  Cytokine and chemokine mediators of systemic inflammation
Cytokine
Polypeptide size
Cell source
Cell target
Primary effects
Tumor necrosis
factor α (TNFα)
17 kD
Monocytes, macrophages, T
lymphocytes
(a) Neutrophil
Activation (inflammation)
(b) Endothelial cell
Activation (inflammation/coagulation)
(c) Hypothalamus
Release of vasodilators (NO)
(d) Liver
Fever
(e) Muscle, fat
Acute phase response
(f) Heart
Catabolism
(g) Macrophages
Myocardial suppression
(h) T lymphocytes
Release of cytokines, inflammation
(i) Various tissues
Inflammation
Apoptosis?
Interleukin-1 (IL-1)
17 kD
Monocytes, macrophages
(a) T cells
Activation (inflammation)
(b) Endothelial cell
Activation (inflammation/coagulation)
(c) Liver
Release of vasodilators (NO)
(d) Hypothalamus
Acute phase response
(e) Muscle, fat
Fever
Catabolism
Interleukin-6 (IL-6)
26 kD
Monocytes, macrophages,
T cells, endothelial cells
(a) Liver
Acute phase response
(b) B cells
Activation
Interleukin-8 (IL-8)
10 kD
Monocytes, macrophages,
endothelial cells
Neutrophils
Chemotaxis, activation
Interferon-γ (IFN-γ)
21–24 kD
T cells, NK cells
Macrophages
Activation (inflammation)
Interleukin-12 (IL-12)
70 kD
Macrophages
T cells, B cells, NK cells
Activation, differentiation
Interleukin-18
Macrophages
T cells, NK cells
Activation, differentiation
IL-10
Monocytes/Th2 lymphocytes,
mast cells, regulatory T cells
Macrophages, Th1
lymphocytes, NK cells
Inhibition, activation regulation

The immunological response and strategies for intervention
271
patients or from rabbits after experimental smoke inhalation
injury.71 Interestingly, although surgery may potentially
invoke an inflammatory response, burn wound excision has
been associated with a reduction in circulating concentra­
tions of endotoxin and cytokines, likely resulting from the
removal of inflammatory stimuli such as necrotic tissue and
bacteria.66,72
IL-6 is one of the most consistently elevated cytokines in
the circulation of post-burn patients and experimental
animals.67,73 A recent study indicates that elevated plasma
IL-6 concentrations may correlate with mortality in patients
with burn and smoke inhalation injuries.74 It is unclear what
specific function IL-6 has in the burn-induced immune
response, but a study showed improved cell-mediated immu­
nity after blockade of IL-6 in burned mice.75 In another
study, the proinflammatory response and mortality were
attenuated in post-burn mice subjected to endotoxin when
IL-6 was blocked.76 IL-6 has also been shown to contribute
to myocardial dysfunction during the post-burn period.
Horton and colleagues have described the contribution of
IL-6 to burn-induced myocardial dysfunction in several
experimental studies, an effect that is likely orchestrated by
numerous proinflammatory mediators and initiated by acti­
vation of Toll-like receptors.77–79
Perhaps more important than the burn-induced cytokine
response is the secondary cytokine response to potential
pathogens in the post-burn period. In this regard, burn
injury may be followed by a period of attenuated expression
of some cytokines that are important in the immune response
to microbial organisms, and increased expression of
cytokines that may hinder the immune response. For
example, expression of IFNγ and a number of IFNγ-inducing
cytokines, including IL-2, IL-12, and IL-15, is reduced in
response to a secondary immune stimulus after burn
injury.80,81 IFNγ facilitates numerous beneficial effects on the
immune response to infection, including induction of class
II major histocompatibility complex (MHCII) proteins on
antigen-presenting cells. Antigen-presenting cells such as
macrophages and dendritic cells use the MHCII as a mecha­
nism for presenting microbial antigens to CD4+ T cells at
sites of infection. Decreased monocyte expression of the
MHCII is a consistent finding in burn patients.82,83 IFNγ
activity also contributes to phagocytosis and microbial
killing through several mechanisms. In mice, IFNγ induces
IgG2a, which opsonizes bacteria and promotes the expression
of FcγR1 receptors on phagocytes. IFNγ also potentiates the
availability of NO, hydrogen peroxide, and superoxide in
phagocytic cells, and promotes expression of chemotactic
factors and adhesion molecules for mononuclear cell recruit­
ment to areas of infection. In experimental burn models,
lack of IFNγ activity has been associated with diminished
ability to clear bacteria.81
Impaired production of IL-12 in response to endotoxin
has also been described in mice after burn injury.81 IL-12, an
important product of dendritic cells and monocytes, serves
to stimulate production of IFNγ by NK cells as well as playing
a role in determining the class of T-helper lymphocyte
response. IL-10 is a cytokine that has anti-inflammatory
activity and may serve to attenuate the proinflammatory
response and prevent excessive inflammation after burn
injury. Increased and prolonged production of IL-10 may
contribute to immunosuppression in the post-burn period.
Immune cells from burn patients demonstrated an exagger­
ated IL-10 response to secondary stimulation with endotoxin
or other microbial products, and this finding correlated
with septic episodes. Experimental studies confirmed an
increased IL-10 response to microbial stimuli in animals that
had previously been subjected to thermal injury.81,84 Concen­
trations of IL-10 have been reported to reach a peak in
the plasma of patients approximately 1 week after burn
injury, which correlates with the time when septic episodes
begin to occur with increased frequency.85 In another
clinical study, serum concentrations of IL-10 appeared to be
highest in non-surviving patients with sepsis.86 However, the
functional role of increased IL-10 and decreased IFNγ pro­
duction in facilitating post-injury immunosuppression is
not completely clear. Murphey and colleagues87 reported
that IL-10 neutralization and IFNγ administration did not
improve survival or bacterial clearance in a model of post-
injury immunosuppression.
Chemokines or chemotactic cytokines are a group of spe­
cialized polypeptides that play a complex role in the innate
immune response by directing migration of immune and
inflammatory cells. They are named and grouped based on
the position of cysteine residues near the amino terminus,
which determines the typical three-dimensional structure
of these polypeptides (Table 22.2). The leukocytes and
endothelial cells of most inflamed tissues can release a
variety of chemokines that recruit specific sets of leukocytes
to a site of infection, based on the nature of the inciting
pathogen. Chemokines also recruit leukocytes to sites of
tissue injury such as the burn wound. IL-8, a neutrophil-
specific chemoattractant, is one of the most widely studied
chemokines. IL-8 has been reported to be significantly
elevated in the circulation of post-burn patients, and the
highest concentrations are detected in non-survivors.88,89
Severe burn injury is often associated with a period of neu­
tropenia, perhaps as a function of neutrophil activation and
exit from the circulation. Besides the burn wound, the lung
is a preferred site for neutrophil sequestration in burn
patients, even in the absence of inhalation injury. Experi­
mentally, neutrophils can appear in lung tissue within hours
of burn injury, and this phenomenon can be attenuated by
neutralization of complement C5a or of the chemokines
keratinocyte-derived cytokine (KC) or macrophage inflam­
matory protein-2 (MIP2).90–92 MIP-2 is an IL-8 homolog in
the mouse. Furthermore, Schmalsteig and colleagues have
shown that IL-8-mediated neutrophil recruitment is a central
factor contributing to pulmonary injury caused by burns
and smoke inhalation.93,94 However, several studies have
demonstrated diminished neutrophil chemotaxis in post-
burn patients which may, in part, be due to a combination
of suppressive circulating soluble factors and a reduced
ability to upregulate the MAC-1 (CD11b/CD18) adherence
receptors on the cell surface.95,96 A recent clinical study of
burn patients demonstrated an association between the
development of bacteremia and a decrease in neutrophil
expression of CD11b, an adhesion molecule that functions
in endothelial binding and migration from the circulation.97
Overall, it is likely that burn injury has significant effects
on neutrophil function, which is dependent on the size of
the burn, the time elapsed after burn injury, the specific
tissue being analyzed, and the specific stimulus that is elicit­
ing the neutrophil response.

Total Burn Care
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272
are designed to eliminate established infections and prevent
reinfection by the same microbial organism. After an initial
exposure to an antigen, the adaptive immune system
provides the patient with immunologic memory, whereby
re-exposure to the same microorganism is associated with an
immune response that is more rapid and greater in magni­
tude. This response is characterized by the production of
antibodies that target specific antigens associated with the
microbe, and the generation of antigen-specific T-cell
responses. Alterations in antigen presentation and lym­
phocyte responses have been described after major burn
injury.
Adverse effects of burn injury
on antigen presentation
Cellular adaptive immunity is initiated by antigen presenta­
tion to T cells by dendritic cells and other antigen-presenting
cells. However, both myeloid and plasmacytoid dendritic
cells have been found to be decreased in burn patients
suffering sepsis compared to non-septic burn patients and
healthy controls.98 Antigen-presenting cells present peptides
for T-cell recognition in association with an MHCII mole­
cule. HLA-DR is the MHCII molecule that is critical for
antigen presentation in humans. However, in burn patients
a significant decrease in expression of HLA-DR was detected
on circulating monocytes. Additionally, HLA-DR expression
was further suppressed in burn patients who became septic
compared to those who did not develop sepsis.99,100 In
murine models antigen presentation is significantly
impaired early after burn injury.101 As in burn patients, this
was associated with decreased expression of class II MHC
and may be a result of diminished IFNγ production,102–104 a
known inducer of class II MHC gene expression.105 One
experimental study has suggested that the use of α-galactosyl-
ceramide, which targets natural killer T cells (NKT), can
prevent some of these derangements, including burn injury-
induced suppression of Ag-specific T-cell responsiveness and
diminished expression of MHCII and CD40 on antigen-
presenting cells.106
Adverse effects of burn injury
on T-cell activation
The majority of observations of immune function in burn
patients have come from analysis of T cells and their
responses to ex vivo stimulation. The effects of burn injury
on specific T-cell subsets is not clear, and may vary depend­
ing on the time from injury, patient care, and exposure to
microorganisms. One study found that the proportion of
CD4+ T helper cells was significantly lower 7 days post burn
in patients who developed septicemia, whereas the CD8+
cytotoxic T-cell numbers were increased, and suggested that
inverted CD4/CD8 ratios may be of prognostic value for
septic complications.107 However, this does not appear to be
a reliable prognostic indicator, as other studies have reported
a decrease in CD8+ T-cell numbers in burn patients.100,108
A consistent finding among these studies was that
CD4+ T-helper cell numbers were decreased in burn
patients, and were even further depleted in burn patients
with sepsis.109 This depletion of CD4+ T cells may be due to
Table 22.2  Classification of chemokines
Chemokine type
Target cell
CXC chemokines
CXCL8 (IL-8, mouse MIP-2)
Neutrophils
CXCL1 (GROα, mouse KC)
Neutrophils
CXCL2 (GROβ, mouse KC)
Neutrophils
CXCL3 (GROγ, mouse KC)
Neutrophils
  CXCL5 (ENA-78)
Neutrophils
CXCL6 (GCP-2)
Neutrophils
CXCL4 (PF4)
Fibroblasts, stem cells
CXCL9 (Mig)
T and NK cells
CXCL10 (IP-10)
T and NK cells
CXCL11 (I-TAC)
T and NK cells
CXCL12 (SDF-1α/β)
T lymphocytes
CC chemokines
CCL3 (MIP-1α)
Monocyte/macrophages, T and B cells,
NK cells, basophils
CCL4 (MIP-1β)
same as above
CCL22 (MDC)
Monocyte, T lymphocytes
CCL25 (TECK)
Macrophages, T lymphocytes
CCL17 (TARC)
T lymphocytes
CCL5 (RANTES)
Monocyte/macrophages, T/NK cells
Basophils
CCL14 (HCC-1)
Monocytes
CCL16 (HCC-4)
Monocytes, lymphocytes
CCL18 (DC-CK-1)
T lymphocytes
CCL20 (MIP-3α)
T lymphocytes
CCL19 (MIP-3β)
T lymphocytes
CCL2 (MCP-1)
T lymphocytes, monocytes
CCL8 (MCP-2)
same
CCL7 (MCP-3)
same
CCL13 (MCP-4)
same
CCL11 (Eotaxin)
Eosinophils
Other chemokines
XCL1 (Lymphotactin)
T lymphocytes, NK cells
CX3CL1 (Fractalkine)
T lymphocytes, monocytes
The current conventional names of chemokines are presented and original names
are provided in parentheses for reference.
Adaptive (acquired) immune function after
burn injury
Whereas innate immunity provides non-specific responses
that limit the growth and spread of infection, adaptive
immunity provides potent antigen-specific responses that

The immunological response and strategies for intervention
273
determined, there does appear to be a correlation between
T-cell dysfunction and susceptibility to infection and subse­
quent mortality after severe burns. In a clinical study of
trauma and burn patients, those who had depressed cell
proliferation of isolated T cells were at high risk for the
development of multiple organ failure and mortality.130
Teodorczyk-Injeyan et al. reported that burn patients who
were unable to recover IL-2 production and T-cell IL-2 recep­
tor expression over time developed fatal sepsis.131
Adverse effects of burn injury
on B-cell-mediated immunity
Hansbrough et al. noted a defect in the ability of burn
patient sera to opsonize bacteria, which subsequently
affected in vitro phagocytosis.132 Schluter et al. reported a
decrease in expression of the B-cell activation marker
CD25 both before and after cytokine stimulation of burn
patient samples.111 In a clinical study, mitogen-induced
immunoglobulin production was increased initially but
suppressed at 3–4 weeks after burn injury. In survivors,
immunoglobulin production returned to baseline levels or
higher, whereas production remained suppressed in burn
patients who developed fatal septicemia.133
Analysis of immunoglobulin production in murine burn
models has indicated that injury has a significant suppressive
effect on antigen-specific antibody production. The reported
effects on specific immunoglobulin subtypes vary, perhaps
owing to the use of different eliciting antigens or other exper­
imental conditions. Production of tetanus toxoid-specific
IgG, specifically IgG2a, was impaired after burn injury in mice
but could be restored by exogenous IL-12, suggesting that
impaired IgG2a production after burn injury is related to
impairments in Th1-associated cytokine production.134,135
Similarly, production of Pseudomonas-specific IgG was sup­
pressed after burn injury in mice previously exposed to Pseu­
domonas aeruginosa.136 Treatment with fms-like tyrosine
kinase-3 ligand promoted greater IgG production, in associa­
tion with increased IL-12, IFNγ, and enhanced opsonization
capacity.136 Restoration of specific antibody responses may
diminish septic complications and improve outcome in
burn patients, as high titers of specific IgG in patients with
Pseudomonas aeruginosa bacteremia were associated with a
significant reduction in the frequency of shock and death.137
Other studies have reported that numerous B-cell functions
are impaired after burn injury, including antigen-specific
IgM, total IgM, and total IgG production at 8 days after burn
injury in mice. LPS-specific IgM could be restored to normal
by cyclooxygenase inhibition, suggesting a role for PGE2 in
impaired B-cell responses to antigen.138,139 Others have
reported a role of TGFβ in impairment of B-cell clonal
expansion, and inhibition of IgM synthesis and antigen-
specific antibody production after burn injury.126,140,141
Hematopoiesis after burn injury
In addition to the numerous injury-associated alterations in
innate and acquired immune cell functions, there are also
effects of burn injury on immune cell production from bone
marrow-derived progenitor cells (Fig. 22.5). Analysis of
activation-induced apoptosis, as on analysis a significant
proportion of burn patients’ circulating lymphocytes were
undergoing apoptosis, and apoptosis could be further
increased by mitogenic stimulation in vitro.110 Additionally,
expression of the T-cell activation marker CD25 was reported
to be increased both spontaneously, suggesting in vivo acti­
vation, and after mitogenic stimulation in vitro.111 Perhaps
related to these alterations are burn-associated effects on
T-cell phospholipid and fatty acid composition and defective
transmembrane signaling.108,112 Mouse models of burn injury
have confirmed burn-induced apoptosis in T cells from
various lymphoid and non-lymphoid organs, and have sug­
gested that glucocorticoids are responsible for increased
caspase-3 activity and subsequent apoptosis.113,114 Murine
burn models have also demonstrated suppressed expression
of c-fos and relA, and altered activities of the AP-1 and NF-κB
transcription factors that regulate genes involved in the
maintenance of cell survival and inflammation.115–117
It has been proposed that an early, ‘non-specific’ activation
of immune cells after severe burn injury results in a subse­
quent impairment of their specific effector functions.118
There appears to be at least a correlation between these early
activation markers and T-cell dysfunction after burn injury.
T-cell proliferation after mitogenic stimulation and alloreac­
tivity in mixed leukocyte reactions have been consistently
reported as being impaired in samples from burn
patients.100,111,119,120 Significant alterations in elicited cytokine
production have also been reported to occur after major
burns, with a decrease in the production of Th1-associated
cytokines relative to Th2 cytokines. IFNγ production by
mitogen-stimulated peripheral blood leukocytes from burn
patients was significantly attenuated, whereas IL-4 produc­
tion was significantly augmented.84 Another study reported
that IL-2 and IFNγ production by stimulated T cells was
significantly lower in non-survivors than in survivors of
severe burn injury.121 Zedler et al.122 found that the number
of IL-4-producing CD8+ T cells was significantly higher and
the number of IFNγ-producing memory T cells significantly
lower in non-survivors than in patients who survived after
burn injury. Additionally, IL-10 production is reported to be
higher after burn injury, and elevated plasma levels in burn
patients correlated with poor prognosis.123,124 Experimental
studies in a mouse model of burn injury have demonstrated
a significant increase in the activity of regulatory T cells
(CD4+/CD25+) in lymph nodes draining the burn wound.
Specifically, regulatory T cells isolated from burned mice
were potent suppressors of T-cell proliferation and IL-2 and
IFNγ production, owing in part to elevated surface expres­
sion of transforming growth factor-β1 (TGF-β1). Depletion
of these cells prior to burn injury ameliorated the burn-
induced suppression of antigen-specific Th1-type immune
responses.125,126 Regulatory T cells promote an anti-
inflammatory response to injury, as enhanced inflammatory
responses are measured in immune cells of T reg-deficient
mice after burn injury.125,127 These experimental findings
seem to correlate to the clinical situation as increased
CD4+CD25+ T reg activity was associated with suppression
of the Th1 phenotype in post-trauma patients.128 Burn injury
also induces rapid T-cell receptor signaling in regulatory T
cells, but not in other CD4+ or CD8+ cells, isolated from the
draining lymph nodes.129 Although the exact significance
of each of these functional impairments remains to be

Total Burn Care
22
274
in burn patients.150 Perhaps the most promising nutritional
supplement after burn injury is the amino acid glutamine.
Depletion of glutamine after burn injury is associated with
an increased risk of infection,151 and several studies have
demonstrated benefits of glutamine supplementation in
burn patients. Peng and colleagues reported that enteral
supplementation with glutamine improved intestinal
barrier function and reduced the period of hospitalization.152
Additionally, glutamine supplementation in burn patients
enhanced several indices of cellular immune function,
including lymphocyte proliferation, IL-2 production and
neutrophil phagocytosis.153 However, there was no observed
effect of glutamine on immunoglobulin or complement
protein levels. Garrel et al. found that enteral supplementa­
tion with glutamine after burn injury significantly reduced
the incidence of infections, specifically positive blood cul­
tures and detection of P. aeruginosa, and reduced mortality
in burn patients.154 In this study, however, no effect of
glutamine on neutrophil phagocytosis was observed.
Parenteral glutamine supplementation was also found to
significantly reduce the incidence of Gram-negative infec­
tions in burn patients, as well as to decrease inflammatory
markers.155
Selective decontamination of digestive tract
Selective decontamination of the digestive tract (SDD) has
been proposed as a prophylactic treatment to prevent serious
infections in burn patients. There is considerable debate
regarding the implementation of SDD as a standard pre­
ventative maneuver in burn patients. One study in which
polymixin E, tobramycin and amphotericin B were admin­
istered to burned children showed no effect on the incidence
of infections or the production of inflammatory cytokines.156
However, Mackie and colleagues reported that SDD reduced
the incidence of infections with Pseudomonas species and
peripheral blood leukocytes in burn patients has revealed
fluctuations in immune cell composition, with periods of
neutropenia, monocytopenia, and at other times monocyto­
sis.142 Analysis of hematopoiesis in murine models has
suggested that burn injury increases myelopoiesis in both
spleen and bone marrow, with alterations occurring at the
level of the myeloid cell phenotype.143 Burns appear to shift
the hematopoietic potential of myeloid progenitor cells
towards monocytopoiesis at the expense of neutrophil
production, an effect that may be mediated in part by
norepinephrine.7,144
Immunomodulation and burns
Immunonutrition
One of the most successful interventions for improving
immune status and reducing infections in burn patients
is nutritional supplementation. Dylewski and colleagues
recently reported that although infectious complications
were more common in malnourished than in well-nourished
burn patients, the difference in the incidence of infections
between groups was not statistically significant.145 However,
others have reported that early enteral feeding may reduce
intestinal permeability and enterogenic infection.146 A study
comparing early enteral feeding with total parenteral nutri­
tion reported that early enteral feeding significantly reduced
the incidence of pneumonia, P. aeruginosa bacteremia, septic
shock, and mortality in burn patients. Early enteral feeding
also accelerated the recovery of CD4/CD8 T-cell ratios and
increased plasma IgG and IgM and intestinal secretory IgA
in burn patients.147 Berger and colleagues reported that trace
element (Cu, Zn, Se) supplementation, given early, reduced
the incidence of bronchopneumonia infections and reduced
hospital stay.148,149 However, supplementation with fish oil
and the amino acid arginine did not improve infection rates
Figure 22.5  Proposed influence of burn injury
on hematopoietic stem cell (HSC) differentiation.
Burn injury is believed to shift the differentiation
potential of myeloid progenitor cells towards
monocytopoiesis. Specifically, injury induces the
release of myeloid progenitors from the bone
marrow, associated with granulocyte and
macrophage infiltration of burn wounds.
Subsequent preferential production of monocyte
progenitor cells (highlighted region) is increased
in the bone marrow compartment at the
expense of granulocytopoiesis.
Common
lymphoid
progenitor
Common
myeloid
progenitor
Multipotent
progenitors
Short
term-
HSC
Long
term-
HSC
Pro-T
Granulocyte/
macrophage
progenitor
Megakaryocyte/
erythrocyte
progenitor
Pro-B
T cells
Dendritic cells
Monoblast
Myeloblast
Dendritic cells
Monocytes
Granulocytes
Erythrocytes
Platelets
NK cells
B cells

The immunological response and strategies for intervention
275
cytokine network, therapies targeted to modulate the levels
of a single cytokine may not be sufficient to restore immu­
nological homeostasis after severe burn injury.
Hematopoietic factors
Another approach to improving immune function in burn
patients is to stimulate the process of hematopoiesis to
generate new immune cells from bone marrow-derived
stem and progenitor cells. The supposition underlying this
approach is that accelerated production of new effector cells
to outnumber cells that have been impaired by injury may
be more effective than therapies designed to compensate for
specific burn-induced impairments in immune function.
Given the risk of uncontrolled inflammation in burn patients,
it is imperative to consider factors that can enhance hemat­
opoiesis without triggering or exacerbating inflammation.
Granulocyte–colony-stimulating factor (G-CSF), a neutro­
phil growth factor, and granulocyte–macrophage colony-
stimulating factor (GM-CSF), a growth factor for neutrophils
and macrophages, have been considered as post-burn immu­
nomodulators. Both G-CSF and GM-CSF improved immune
function in animal models of burn-associated sepsis.176,177
Treatment of burn patients with GM-CSF was shown to
increase white cell counts and improve neutrophil activity,
but further evaluation of infection rate and patient outcome
was not reported.178 Another hematopoietic factor that has
been examined experimentally is fms-like tyrosine kinase-3
ligand, or Flt3L, a hematopoietic cytokine and dendritic cell
growth factor (Fig. 22.6). Treatment of burned mice with
Flt3L has been shown to stimulate the production of den­
dritic cells, restore pathogen-elicited Th1-associated cytokine
production, enhance bacterial clearance, and increase sur­
vival after a P. aeruginosa burn wound infection.179–181 Resist­
ance to infection was dependent on both dendritic cells and
neutrophils,182 suggesting that modulation of these cell types
may have potential for the prevention of infections after a
major burn injury.
Other approaches
There are numerous ongoing attempts to develop prophy­
lactic treatments to prevent infections after major burn
injury. This discussion has focused on some of the more
promising treatments that are being investigated. Many of
the potential treatments have been, and will continue to be,
borrowed from clinical studies in trauma patients, as there
are similarities in the immunological alterations that occur
after major burns and other types of trauma. One treatment
that shows promise is glucan, a β-1,3-linked glucose polymer
derived from the cell wall of Saccharomyces cerevisiae. Glucans
have been shown experimentally to reduce sepsis-induced
inflammation while enhancing microbial clearance.183,184
Clinical studies with trauma and high-risk surgical patients
have shown that glucans can reduce infectious complica­
tions and mortality in this patient population.185–187 Although
these compounds have not yet been tested in burn patients,
they have been effective in reducing susceptibility to burn
wound infection and mortality in a mouse model of burn
injury.104
Another approach that is under investigation is the use
of resuscitation fluids as immunomodulators. Junger and
Enterobacteriaceae in burn patients.157 de la Cal et al. reported
that SDD, by the immediate administration of parenteral
cefotaxime and intestinal non-absorbable antibiotics, sig­
nificantly reduced mortality and the incidence of pneumo­
nia in burned adults.158 Additionally, it was reported that
enteral vancomycin reduces MRSA infections in burn
patients.159 However, the American Burn Association does
not encourage SDD because of concerns about emerging
antibiotic resistance.15
Vaccination
A technique that may be highly effective for the prevention
of P. aeruginosa infections after burn injury is vaccination
with P. aeruginosa outer membrane proteins. In 1970, this
approach was investigated in a rat burn model160 and it was
later demonstrated that vaccination of burned mice reduced
systemic bacterial load and increased survival upon lethal
infection with P. aeruginosa.161 In 1983, it was reported that
both active and passive vaccinations for Pseudomonas were
effective in inducing antibodies to Pseudomonas and reducing
mortality in both burned adults and children.162 Since then,
numerous studies have reported that vaccination of burn
patients with P. aeruginosa outer membrane proteins is safe,
significantly increases P. aeruginosa-specific titers, and is asso­
ciated with a decrease in detection of P. aeruginosa by nested
PCR in the blood of vaccinated patients.163–166 Although this
approach may be effective for enhancing humoral responses
to common microorganisms in the burn unit, the efficacy of
vaccinations will be restricted to single organisms, unless
vaccinations against widely common pathogenic motifs are
developed.
Cytokine modulation
Owing to the profound effects of severe burns on pathogen-
elicited cytokine production, and the observed correlations
between these alterations and negative outcome in burn
patients and in experimental models of burn injury, many
attempts to modulate immune function after burns have
been directed towards restoration of normal cytokine
balance. One approach has been the administration of exog­
enous Th1 or Th1-promoting cytokines to enhance antimi­
crobial immune responses. IFNγ has been administered to
burn and trauma patients in clinical studies but unfortu­
nately has shown no benefit with respect to the incidence of
infections or mortality.167,168 Experimentally, administration
of IL-12 and IL-18 has shown some benefit in animal models,
but these cytokines have not been tested in the clinical
setting.169–171 Adverse reactions to IL-12 in other clinical trials
may preclude its introduction as an immunomodulator in
burn patients.172,173
Neutralization of cytokines believed to contribute to post-
burn immunopathology has also been evaluated. Treatment
of mice with antibodies specific for IL-10 was shown to
increase resistance to infection, but only if given immedi­
ately after burn injury.174 In a murine model of burn and
sepsis, the utility of antibodies against TNFα was found to
be limited in that TNFα neutralization was only effective
during a narrow timeframe after burns, and may have wors­
ened the outcome when high doses of antibodies were
used.175 Given the interactive and dynamic nature of the

Total Burn Care
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276
in burn wounds.196,197 Human cathelicidin hCAP-18/LL-37
is another class of defense peptide that is expressed in
the skin. Using a rat model of burn wound infection,
Jacobsen and colleagues showed that transient cutaneous
adenoviral delivery of hCAP-18/LL-37 to infected burn
wounds induced hCAP-18/LL-37 and significantly inhibited
bacterial growth.196 Future studies should evaluate the
efficacy of host defense peptides for the treatment and/or
prevention of infections after burn injury.
Further reading
Bohannon J, Fang G, Cui W, et al. Fms-like tyrosine kinase-3 ligand
alters antigen-specific responses to infections after severe burn
injury. Shock. 2009 Oct;32(4):435-441.
Cox RA, Burke AS, Soejima K, et al. Airway obstruction in sheep with
burn and smoke inhalation injuries. Am J Respir Cell Mol Biol.
2003 Sep;29(3 Pt 1):295-302.
D’Avignon LC, Hogan BK, Murray CK, et al. Contribution of bacterial
and viral infections to attributable mortality in patients with severe
burns: an autopsy series. Burns. 2010 Sep;36(6):773-779.
Mosier MJ, Pham TN. American Burn Association Practice guidelines
for prevention, diagnosis, and treatment of ventilator-associated
pneumonia (VAP) in burn patients. J Burn Care Res. 2009
Nov;30(6):910-928.
Peng YZ, Yuan ZQ, Xiao GX. Effects of early enteral feeding on the
prevention of enterogenic infection in severely burned patients.
Burns. 2001 Mar;27(2):145-149.
von BH, Picard C, Jin Z, et al. Pyogenic bacterial infections in humans
with MyD88 deficiency. Science. 2008 Aug 1;321(5889):691-696.
others have found that hypertonic saline has the ability to
attenuate inflammation, reduce neutrophil-mediated lung
damage, and rescue T cells from experimental trauma-
associated suppression. It was reported that IL-2 production
by phytohemagglutinin-stimulated human peripheral blood
mononuclear cells was completely suppressed by sera from
trauma patients, but that co-stimulation with hypertonic
saline could restore IL-2 production.188 Additionally, it was
found that resuscitation of mice with hypertonic saline
(compared to lactated Ringer’s solution) after hemorrhagic
shock reduced bacteremia and increased survival upon sub­
sequent cecal ligation and puncture.189 These authors have
proposed that leukocytes respond to hyperosmotic stress
through an osmosensory system that signals a phosphoryla­
tion cascade and p38 MAP kinase activation.190,191 Clinical
studies have examined resuscitation of burn patients with
hypertonic saline and have reported that it is safe, provides
adequate resuscitation, and may reduce pulmonary dysfunc­
tion,192–194 but its effects on inflammation and immune
function in burn patients remain largely unknown. In
trauma patients with hemorrhagic shock, hypertonic
saline plus dextran reduced inflammation by reducing neu­
trophil activation and the production of proinflammatory
monocytes.195
Host defense peptides are another potential mechanism
for immunomodulation after burn injury. Defense peptides
are naturally occurring antimicrobial effector molecules of
the innate immune system. Human β-defensins are pro­
duced in the skin by keratinocytes, and expression of one of
these peptides, human β-defensin 2, is significantly decreased
Figure 22.6  Flt3 ligand facilitates the
differentiation of bone marrow myeloid and
lymphoid progenitors into dendritic cells
(see text).
Conventional DCs
Plasmacytoid DCs
Common
lymphoid
progenitors
Common
myeloid
progenitors
Monocytes
Flt3+
Flt3+
Flt3–/Io
M-CSF
GM-CSF
IL-4
CD11c+
MHC II+
CD8+/–
CD11b+/–
Flt3Io
+
+
CD11c –/Io
MHC II+
B220+
GR–1+
Flt3Io
CD11c+
MHC II+
CD8+/–
CD11b+/–
Flt3Io
CD11c+
MHC II+
CD8–
CD11b+
Flt3–
CD11c –/Io
MHC II+
B220+
GR-1+
Flt3Io
DC
DC
DC
DC
DC
 
Access the complete reference list online at

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276.e1
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