Phẫu Thuật Bỏng: Tiếp Cận Và Phương Pháp Điều Trị Từ Trung Quốc (Chinese Burn Surgery)

38
the activities of some enzymes in the metabolism, improving
cellular metabolism, and protecting cardiac muscle. Five
grams of fructose diphosphate should be dissolved into
50 ml of diluent and injected intravenously at the speed of
0.5–1 g/min, 1–2 times/day.
3.1.3.2 Apply the Appropriate Amount
of Diuretics
Once the blood volume has been corrected, solute diuretic
mannitol is usually used. The application of mannitol has
three main functions:
1. Protecting renal function: mannitol is not affected by
antidiuretic hormone, and it can also dilate afferent glo-
merular arteriole and increase renal blood fl ow.
2. Diuresis: mannitol does not pass through membrane and
cannot be reabsorbed by renal tubules. It is eliminated
rapidly and 75 % is eliminated by 2 h; thus, it has the
function of diuresis to reduce tissue edema.
3. Oxygen free radical scavenger: it can scavenge excessive
oxygen free radicals in the body and reduce lipid peroxi-
dation lesions. The usage of mannitol: 125 ml of 20 %
mannitol and 500 ml of physiological saline or 5 % glu-
cose are infused and applied two to four times per day
according to the severity of the burn. The infused amount
must be guaranteed before the application of mannitol,
and injection is usually used at 6–8 h after the burn. For
patients with cerebral edema, pulmonary edema or acute
renal dysfunction at admission, the 20 % mannitol should
be infused rapidly.
3.1.3.3 Application of Anisodamine (654-2)
The gastrointestinal tract is very sensitive to ischemia. It is
the earliest to occur and the latest to recover. The pHi exami-
nation (gastrointestinal pH) indicates that it can only recover
up to the lower limit of the normal value at 72 h after the
burn. With fl uid infusion within 48 h after the burn, anisoda-
mine (10–20 mg, i.v. once every 6–8 h) should also be
administered to make Phi reach the normal value at 24–48 h
after the burn and to rapidly correct the insidious shock. The
functions of anisodamine are:
1. To stabilize the cell membrane and enhance the cellular
tolerance to hypoxia so that the cell can still maintain
comparatively higher oxygen uptake at the status of lower
DO 2 (oxygen delivery).
2. To improve gastrointestinal microcirculation, enlarging
the blood fl ow of the portal vein, which is benefi cial to
protect the barrier function of the intestinal tract and pre-
vent the translocation of endotoxin and bacteria.
3. To relax the smooth muscle of bronchiole and improve
the ventilation function.
4. To reduce vascular resistance to decrease the cardiac load.
The application of anisodamine may result in adverse
effects, such as increased heart rate, abdominal distension,
etc., and the dose may be halved to once every 12 h. Ten
milligrams of hexadecadrol may be used to reduce the
adverse effects.
3.1.3.4 Application of Oxygen Free Radical
Scavenger
In the resuscitation, the dioxygen is reduced at single valence
into a large quantity of oxygen radicals O 2 , O 2 − , OH and
H 2 O 2 during the reperfusion, which combine with the
enzymes or receptors on biomembrane through covalent
bonds, react with lipids on cellular membrane through lipid
peroxidation to change the structure and function of bio-
membrane. To prevent or alleviate the damage to the organs
and cells caused by oxygen radicals, the oxygen free radical
scavenger or antioxidant may be applied. Besides mannitol,
the drugs commonly used include vitamin C (10 g/day), glu-
tamic acid (20–30 mg/day), and vitamin E (100 mg, i.m.,
once every 6 h).
3.1.3.5 Maintain Respiratory Function
For patients with moderate/severe inhalation injuries, the fol-
lowing items should be conducted immediately to maintain
pulmonary function at admission: “preventive” tracheal inci-
sion, chest X-ray, monitoring of blood gas and application of
assisted respiration with respirator if the dyspnea aggravates
with PaO 2 <60–70 mmHg and PaCO 2 >50 mmHg. If the spu-
tum is viscous, the airway lavage once every 4 h with 5 ml
each time and two to four repeats may be added in addition
to aerosol inhalation once every 2 h, and ambroxol (30 mg,
i.v., tid) should also be added to dissipate phlegm.
3.1.3.6 Basic Drugs
For patients with extensive burns, metabolic acidosis tends to
occur because of the anoxia metabolism and lactic acid accu-
mulation before satisfactory resuscitation is achieved. During
the treatment, the basic drugs are also needed to correct aci-
dosis in addition to rapid fl uid infusion and improvement of
tissue perfusion. For patients with hemoglobinuria and myo-
globinuria, basic drugs should also be administered to convert
the free hemoglobin into basic hemoglobin to avoid deposits
or blockages in the renal tubules. Sodium bicarbonate 5 % is
used clinically through intravenous injection with 125 ml of
5 % sodium bicarbonate added into 375 ml of physiological
saline. Two hundred and fi fty to fi ve hundred milliliters of
5 % sodium bicarbonate may be infused in a whole day.
3.1.3.7 Protect Gastrointestinal Function
1. Early feeding: a small quantity of liquid may be taken
at 50 ml at a time following the principle of multiple
meals with small quantities without nausea or vomiting.
Gastrogavage is better, and the total amount in the fi rst
24 h is 500–1,000 ml. The advantages of early gastroin-
testinal feeding are:
3 Burn Shock

39
(a) Helping to stimulate the secretion of gastrointestinal
hormones (e.g., gastrin, motilin) and enterokinesia.
(b) Protecting the gastrointestinal mucous membrane,
improving microcirculation, and maintaining the bar-
rier function of gastrointestinal mucous membrane.
(c) Buffering the acid in the stomach, reducing the
reverse diffusion of H + into the mucous membrane,
and decreasing the incidence of stress ulcers.
2. Prevent stress ulcer: to improve the gastrointestinal
microcirculation, the following items are also needed in
addition to rapid correction of insidious shock:
(a) Decreasing the concentration of H + in gastric juice
and applying antacids in the early stages, such as alu-
minum hydroxide gel (Colphos) and ulcermin (1–2 g,
4 times/day).
(b) H2-receptor blockers such as cimetidine (0.4–0.6 g,
i.v., 1/6 h), the effects of ranitidine and famotidine are
5 times and 20–50 times those of cimetidine respec-
tively. The application of omeprazole (20 mg, i.v.,
bid) is increasing.
3. Repair of the gastrointestinal membrane: glutaminate
0.5 g/(kg/day).
4. Hemostasis: Yunnan Baiyao (1 g, 4 times/day, 100 ml of
iced saline plus 10 mg of noradrenalin for gastrogavage.
3.1.3.8 Application of Antibiotics
For patients with severe burns, broad-spectrum antibiotics
should be applied in the early stages. One commonly used
type of antibiotics against Gram-negative rods and one
against Gram-positive cocci should be applied according
to the conditions of the hospital. The bacterial culture of
the wound surface should be taken immediately after
admission and the antibiotic is chosen based on the
sensitization test.
3.1.3.9 Reduce Exudation and Promote
Detumescence
Sodium aescinate has a parahormone-like effect, which has
the pharmacological actions of anti-infl ammation, improving
microcirculation, reducing exudation, and alleviating edema
through increasing the secretion of cortical hormone by pro-
moting the functions of the pituitary gland and the adrenal
gland. It also has the effect of eliminating oxygen radicals.
The dose is 25–30 mg for daily intravenous injection.
3.1.3.10 Reduce the Release of Infl ammatory
Mediators
Ulinastatin reduces the release of infl ammatory mediators,
increasing microcirculation to improve tissue perfusion,
inhibiting the activities of many hydrolases, decreasing the
production of oxygen radicals, protecting internal organs,
etc. The dose is 200,000–300,000 U dissolved in 100 ml of
solvent for intravenous injection twice a day.
3.2
Delayed Resuscitation of Burn Shock
Zhaofan Xia , Xiaoyan Hu , Pengfei Luo , and Shengde Ge
Delayed resuscitation of burn shock is defi ned as untimely
fl uid resuscitation that is performed when shock has already
occurred and continued for a period of time after burn injury.
As we know, the time when burn shock occurs is associated
with the severity of the burns. Therefore, the judgment of
delayed resuscitation in the clinic should not only be based
on the postponed time, but also take the severity of the burns
into account. Because of the backward transport and infor-
mation network, the poor medical conditions of basic-level
hospitals, insuffi cient education on burn aids and so on in
many areas of developing China, large numbers of burn
patients cannot be fl uid resuscitated timely and effectively,
and serious shock occurs before hospitalization. Therefore,
the subsequent fl uid resuscitation is often unable to take
effect, and the incidence of multiple organ failure (MOF) and
mortality increase with the subsequent course. A retrospec-
tive analysis of 184 cases reported by Yang Hong- Ming from
the Chinese PLA (People’s Liberation Army) 304 Hospital
showed that along with prolongation of delayed resuscita-
tion, anti-shock measures needed more time, and the inci-
dence of burn shock and resuscitation failure (death as a
result of shock) increased. Incidence of both early multiple
organ dysfunction syndrome (MODS) (within 1–8 days after
burn injury) and delayed MODS (more than 8 days after burn
injury) and the proportion of organ failure (≥2 organs) rose.
The incidence of systemic infection and the proportion of
mixed infection (more than two species of bacteria or com-
bined with fungal infection) also grew, and both fatality and
mortality increased as well.
3.2.1
Reperfusion Injury Caused by Delayed
Resuscitation of Burn Shock
Delayed resuscitation is an important and diffi cult conun-
drum in the clinical management of burns owing to its high
incidence of complications and low recovery rate. According
to researches, including a series of papers by Xia Zhao-Fan
of the Second Military Medical University, China, the effects
of delayed resuscitation encompass not only ischemic injury
but also reperfusion injury. In 1991, Xia Zhao-Fan put for-
ward a new therapeutic strategy: “It is necessary to combine
volume replacement with cytoprotection for burn shock
with delayed resuscitation.” This brought about a new focus
for burn shock and more researches on reperfusion injury.
“Reperfusion injury” refers to secondary injuries activated
by new perfusion after blockage of the blood supply or low
blood fl ow for a period of time. It was always ignored in
the past because it is not such a typical cutoff for the blood
3.2 Delayed Resuscitation of Burn Shock

40
supply and reperfusion as post-infarction reperfusion dam-
age in the cerebral ischemic penumbra.
3.2.1.1 Contents of Reperfusion Injury
The research of the Second Military Medical University,
China, has shown that there were not only quantitative dif-
ferences but also qualitative differences between the effi cacy
of early resuscitation and that of delayed resuscitation. To
extensive burns patients, the metabolism and function of all
major organs could be well protected if fl uid resuscitation
starts before severe shock occurs. However, When resuscita-
tion was delayed, capillary permeability increased, cellular
energy metabolic dysfunction worsened, and various isoen-
zymes in the plasma were raised, such as lactate dehydroge-
nase-1 (LDH-1) and creatine phosphokinase MB-isoenzyme
(CPK-MB) from the myocardial cells, LDH-3 in pulmonary
epithelial cells, and LDH-5 in hepatocytes. Some indicators,
including cellular energy metabolism, serumal superoxide
dismutase (SOD), plasmic phosphocreatine kinase isoen-
zyme, malondialdehyde (MDA; immediate product of mem-
brane lipid peroxidation), pulmonary vascular permeability,
and so on, were even worse than in the nonresuscitation
group in animal experiments.
Early resuscitation can also improve energy metabolism
and raise the erythrocytic intracellular concentration of
adenosine triphosphate (ATP) and 2,3-DPG, neutralize
intracellular acidosis, protect the activity of ATPase, and
alleviate the damage of membrane band III proteins. The
sooner resuscitation, the better effect. In contrast, the
delayed resuscitation worsened the damage of the erythro-
cyte membrane lipid and membrane proteins during the
burn shock stage. Compared with early resuscitation or the
nonresuscitation group, erythrocyte tensile strength in the
delayed resuscitation group was the lowest; and the fl uidity
of the deep membrane lipid in the delayed resuscitation
group weakened mostly. Delayed resuscitation induced
cross- linking of erythrocyte membrane proteins, exposed
hydrosulfi de, and restricted the lateral movement of the
membrane proteins as well. Moreover, these studies
revealed that the mechanisms of the damage to the erythro-
cyte membrane were mainly due to the oxygen-derived free
radicals, which aggravated the peroxidation of membrane
lipid under reperfusion conditions. On the whole, the
abovementioned studies showed that delayed resuscitation
motivated reperfusion injury on the basis of ischemic
injury. In other words, on the basis of hypoxic–ischemic
injury caused by burn shock, delayed resuscitation worsens
these injuries.
According to Yang Zong-Cheng’s research from the Third
Military Medical University, China, the burn shock had
already occurred before admission, conventional fl uid
replacement was much less than needed. The calculated vol-
ume based upon generally accepted standard formulas was
required to be infused within 1–2 h after admission to correct
burn shock as soon as possible. However, if necessary,
aggressive fl uid resuscitation should be carried out under
close and continuous monitoring, such as central venous
pressure (CVP), pulmonary artery obstruction pressure
(PAOP), and cardiac output (CO).
Xia Zhao-Fan et al. found that according to the mech-
anisms for cellular reperfusion injury, application of
cytoprotection was suggested in the clinic in addition to
volume replacement therapy, such as oxygen free radical
scavengers, protease inhibitors, calcium channel blockers,
so as to block off different pathological or physiopatho-
logical pathways. Researchers proved that cytoprotection
lessened damage signifi cantly to the heart, liver, lungs,
intestinal mucosa, and other important organs. So, the
cytoprotection may improve energy metabolism, alleviate
tissue edema, and increase the level of high- energy phos-
phate compounds in major organs and intestinal mucosa
[ 1 , 2 ].
3.2.1.2 Mechanisms of Reperfusion Injury
The mechanisms of reperfusion injury caused by delayed
resuscitation of burn shock are quite complex and have not
yet been fully clarifi ed. However, the following factors are
involved:
1. Increase in oxygen-derived free radicals and other phys-
iopathological changes caused by burn shock. Burn shock
can activate many physiopathological pathways mediat-
ing organ injury. Except for the increase in oxygen-
derived free radicals in microvascular endothelial cells,
intracellular calcium overload, release of lysosomal pro-
tease and cytokines (e.g., endothelin), enhanced adhe-
siveness between leukocytes and endotheliocytes, and
others are involved in organ injuries. These physiopatho-
logical pathways result in two consequences, ischemic
injury of the major organs, and the cellular and molecular
basis of reperfusion injury.
2. Further increase in oxygen-derived free radicals caused
by delayed resuscitation. A major source of oxygen-
derived free radicals in burn trauma is xanthine oxi-
dase (XO; extensively existing in all tissues) pathway.
Dysfunction of cellular energy metabolism, reduction of
ATP production, and an increase in achrestic adenosine
monophosphate (AMP) are aggravated in the state of
hypoperfusion. Hypoxanthine, a degradation product of
accumulative AMP, increases and then diffuses across the
membrane into the intercellular space. A large number
of oxygen-derived free radicals are produced based on
AMP as the raw material, XO as the catalysis, oxygen
as the electron acceptor instead of nicotinamide-adenine
dinucleotide, the oxidized form; NAD + ). Another source
of oxygen-derived free radicals is the respiratory burst
pathway. Accumulative neutrophils in local tissue can be
3 Burn Shock

41
activated by adhesion to endothelial cells and produce
oxygen-derived free radicals under the catalysis of the
reduced form of nicotinamide-adenine dinucleotide phos-
phate (NADPH) oxidase. Oxygen-derived free radicals
can result in peroxidation injury to membrane and organ-
elle (e.g., mitochondria). The injury of mitochondria can
aggravate energy metabolism further, thus forming a
vicious cycle.
3. Reduction of anti-oxidation: under physiological circum-
stances, free radical scavengers (such as superoxide dis-
mutase, catalase, glutathione) play an important role in an
effective dynamic balance between the production and
removal of oxygen-derived free radicals. However, under
pathological circumstances of burns, the activity of these
scavengers is downregulated, and the removal of oxygen-
derived free radicals decreases. In turn, the balance is bro-
ken, and the production of oxygen-derived free radicals is
relatively overabundant, thus exacerbating the tissue
injury and increasing the products of lipid peroxidation
(e.g., malondialdehyde).
4. Intracellular calcium overload: four aspects may cause
calcium overload:
(a) Contributing to cellular energy metabolism dysfunc-
tion, The decrease in Na + -K + -ATPase activity can
increase intracellular Na + concentration, which in
turn enhances Na + -Ca 2+ exchange.
(b) Ca 2+ fl ows down the concentration gradient and accu-
mulates intracellularly under conditions of hyperper-
meability of the cell membrane, which is damaged by
oxygen-derived free radicals.
(c) Endoplasmic reticulum calcium pool is activated by
the increasing plasma Ca 2+ concentration; thus to
release Ca 2+ into cytoplasm.
(d) The disturbance of L-type calcium channels and the
ryanodine receptor system on endoplasmic reticu-
lum. As intracellular second messenger, calcium ions
play an important role in signal transduction; there-
fore, calcium overload will lead to cellular damage
and dysfunction.
5. Activation of phospholipase (PLA 2 ): the synergism
between oxygen-derived free radicals and intracellular
calcium overload activates PLA 2 , and activated PLA 2
acts on membrane phospholipids, mediating the produc-
tion of infl ammatory mediators such as prostaglandins,
leukotrienes, thromboxane, through the mechanisms
of arachidonic acid cascade reaction. The oxidation of
mitochondrial membrane can result in the de-coupling of
oxidative phosphorylation; through induction of platelet-
activating factor (PAF) on the cell surface, PLA 2 also
promotes neutrophil adhesion with endothelial cells, and
neutrophil infi ltration in target organs.
6. Activation and release of proteases: three pathways may
be related to the increase in proteases and their activity:
(a) Combination of cell lysosomal membrane burst-
ing caused by hypoxic–ischemic injury and release
and diffusion of lysosomal proteases caused by
reperfusion.
(b) Activation and release of lysosomal and nonlyso-
somal proteases attributing to reperfusion.
(c) Degranulation and enzyme release of agglomerative
neutrophils in local tissue.
7. Decrease in nitric oxide (NO) and accumulation of neu-
trophil: NO plays dual roles in cell protection and cell
injury, depending on the concentration of NO and signal
transduction pathways. Ni Jun, Yu Bao-jun, etc. found
that in the delayed fl uid resuscitation group, the activity
of MPO (marker enzyme of PMN) and water content
in tissue signifi cantly increased, and NO production
signifi cantly increased. They thought that reduction
of NO would promote some processes including PMN
adhesion to endothelial cells, infi ltration of PMN into
local issue and the release of reactive oxygen species,
proteases, and cytokines, etc. Increased expression
of adhesion molecules is also a major factor in PMN
aggregation.
8. Membrane structural damage and ionic metabolic distur-
bance: membrane structural damage and ionic metabolic
disturbance (e.g., intracellular sodium, phosphorus, mag-
nesium, chloride, etc.) lay the basis for cellular edema
and intracellular calcium overload under the conditions of
delayed reperfusion. A series of pathological processes of
oxygen metabolism and ionic metabolism, resulting from
improvement in tissue reperfusion, are activated and can
result in further cell damage.
9. Tissue/organ specifi city and multi-pathways of injury:
multiple physiopathological pathways can be found in the
mechanisms of reperfusion injury caused by delayed
resuscitation. Multimechanisms can be found even in the
same tissue or organ simultaneously, but one of them has
superiority over any other. Different tissues and organs
have different superiority. It has been proven by some
studies which different effects were observed when dif-
ferent drugs (oxygen free radical scavengers, protease
inhibitors, and calcium channel blockers) were used to
block different pathological pathways. Tissue/organ spec-
ifi city and multipathways of injury suggest that it might
be necessary to take comprehensive therapy to prevent
and control reperfusion injury induced by delayed resus-
citation of burn shock. For example, combined with
delayed fl uid replacement, oxygen free radical scaven-
gers reduced edema in lung tissue cells effectively, lyso-
somal protease inhibitors prevented energy metabolism
disorders in heart and kidney cells, both oxygen free radi-
cal scavengers, and lysosomal protease inhibitors pre-
vented and controlled energy metabolism disorders and
reduced edema in intestinal mucosa.
3.2 Delayed Resuscitation of Burn Shock

42
3.2.2
Injury to Myocardial Mitochondria,
Intestinal Barrier, and Erythrocyte
Membrane Caused by Delayed
Resuscitation from Burn Shock
3.2.2.1 Peroxidation, Activated PLA 2 , and Ca 2+
Overload in Myocardial Mitochondria
It has been proved that many active substances and others in
the delayed resuscitation group increased more obviously
than in the early resuscitation group, such as myocardial O 2 − ,
MDA content (malondialdehyde, intermediate product of
lipid oxidation), energy metabolism disorders and activity of
LDH 1 , CPK-MB, etc. PLA 2 activity was enhanced, Ca 2+ /Na +
accumulation occurred, and free calcium also increased in
myocardial mitochondria.
The phenomenon that reduction of myocardial contractil-
ity and cytoplasmic Ca 2+ overload occurred at the same time,
proved the dysfunction of the myocardial excitement–
contraction coupling.
The mechanisms of Ca 2+ overload are relevant to the four
aspects mentioned above, including enhanced Na + -Ca 2+
exchange, hyperpermeability resulting from structural mem-
brane damage, L-type calcium channel abnormalities, and
ryanodine receptor system disorders [ 3 ].
The damage of myocardial cell membrane, due to oxygen-
derived free radicals and activated PLA 2 , manifests in
decreased fl uidity of the deep membrane lipid, changes in
membrane protein conformation, and restricted membrane
protein movements. Moreover, sympathetic excitement and
excessive catecholamine release can induce myocardial cell
membrane damage (through lipid peroxidation, activation of
lipase and phospholipase). Animal experiments showed that
sympathetic efferent and afferent impulses increased con-
stantly and, combined with the frequent ventricular, prema-
ture, simultaneous, sympathetic bursting activity, were
observed simultaneously in rats with major burns.
These changes exacerbated the imbalance of myocardial
oxygen supply and oxygen consumption, myocardial electri-
cal instability, and acidosis. Wang Guang-Qing et al. found
that delayed resuscitation of burn shock could accelerate the
apoptosis of myocardial cells, and this may be the important
factor of cellular injury caused by delayed resuscitation.
3.2.2.2 Intestinal Ischemia–Reperfusion Injury
Intestinal mucosa is a major target of ischemia–reperfusion
injury, because its abundant xanthine dehydrogenase (XD)
can be converted to XO by protease under conditions of
ischemia–reperfusion. ATP can be degraded to adenosine
diphosphate (ADP) and AMP, but the latter cannot be syn-
thesized by the former under conditions of hypoxia.
Hypoxanthine and inosine (degradation products of accumu-
lative AMP and ADP) increase, and thus diffuse into the
intercellular space and lead to an increase in oxygen-derived
free radicals under the catalysis of XO. In addition, as a cata-
lyst, XO can accelerate transformation from O 2 (as electron
acceptors) to oxygen free radicals. The imbalance between
generation and degradation become worse progressively,
and excessive free radicals seriously damage the intestinal
barrier, thus deepening intestinal infection and endotoxemia.
Zhang Cheng et al. found that the intestinal epithelial cell
apoptosis rate increased signifi cantly in the delayed resusci-
tation group. The antioxidant N-acetyl-l-cysteine (NAC)
could reduce effectively the apoptosis of intestinal epithelial
cells.
Reduction of intestinal perfusion not only occurs early,
but also continues for quite a long time; thus, blood supply
recovery occurs much later than in other organs after a burn
injury. Clinical studies have shown that even enough fl uid
resuscitation has already raised urine output and the periph-
eral circulation of the limbs and hemodynamic parameters
(which can refl ect the circulation volume well) to normal,
pHi (internal/intracellular power of hydrogen, refl ected
gastrointestinal mucosa blood supply) was still lower than
normal, and this state was called “concealed shock”.
3.2.2.3 Injury to Erythrocyte Membrane
Excessive oxygen free radicals bring about oxidative damage
to erythrocyte membrane in the following three aspects.
1. Cross-linking of erythrocyte membrane proteins weakens
its molecular movement.
2. Reduction of erythrocyte membrane deformability results
in adverse effects on the microcirculation.
3. Decrease in stability and increase in fragility may cause
hemolysis (Fig. 3.1 ).
3.2.3
A New Therapeutic Strategy for Burn
Shock with Delayed Resuscitation:
“Combination of Volume Replacement
and Cytoprotection”
3.2.3.1 Timely Post-Burn Volume Replacement
In the treatment of burn patients with delayed resuscitation,
domestic standard fl uid replacement formulas are still gener-
ally accepted and are commonly used to calculate the vol-
ume. However, it is better to speed up the initial infusion.
Some researchers suggested that the calculated volume
should be infused within 1–2 h after admission to restore cir-
culation volume as soon as possible. In other words, hypovo-
lemia and shock should be controlled, and sometimes
aggressive volume replacement can be undertaken after
weighing up its pros and cons [ 4 , 5 ].
3.2.3.2 Cautions on Fluid Therapy
Greater proportions of colloidal solution and higher sodium
concentrations have a better effect on the rapid, effi cient
3 Burn Shock

43
expansion and prevention of cell edema [ 6 ]. Additional dila-
tive capillary capacity and extravascular effused volume
should be included in the amount of replacement volume
because inadequate circulation and microcirculation have
occurred before fl uid therapy started. Rapid fl uid replace-
ment should be carried out carefully under the continuous
monitoring of cardiorespiratory functions, especially in
patients with cardiopulmonary dysfunctions (e.g., the elderly,
infants, etc.). Too much emphasis on normal cardiac output
is unnecessary because cardiac contractility recovery needs
more time owing to various continuous adverse factors.
3.2.3.3 Cytoprotection
At the same time as fl uid resuscitation, the application of
drugs (cytoprotectors) to block pathological reperfusion
pathways can alleviate reperfusion injury and avoid effec-
tively further cellular injury. These drugs include:
1. Xanthine oxidase inhibitors and oxygen free radical scav-
engers. The former include allopurinol and folic acid. The
latter include ligustrazine, tiopronin, SOD, vitamin C,
vitamin E, and mannitol. Antioxidants such as vitamin C
or vitamin E can inhibit NF-κΒ from transferring into the
nucleus and reduce transcription of pro-infl ammatory
factors.
2. Protease inhibitors, e.g., ulinastatin, inhibit the activity of
lysosomal and nonlysosomal enzymes, restrain the
increase in cytoplasmic free calcium concentration and
prevent the conversion of XD into XO. Therefore, prote-
ase inhibitors have a wide range of protective effects.
3. L-type calcium channel blockers and antagonists of endo-
plasmic reticulum ryanodine receptor. The former include
verapamil, nimodipine, and the latter procaine and dan-
trolene [ 7 ]. These drugs can lessen intracellular calcium
overload, suppress PLA2 activity, and reduce the secre-
tion of macrophage-derived pro-infl ammatory factors.
Researchers from the Second Military Medical University
found that patients with extensive burns, who were treated
with a combination of fl uid resuscitation and calcium
channel blockers, had less exacerbation or apostases at
the shock stage, and the edema resorption phase occurred
much earlier . [ 8 , 9 ]. The calcium channel blocker vera-
pamil (5 mg/time) should be used carefully because of its
cardiovascular effects.
4. L-arginine, as a NO donor, improves myocardial contrac-
tile function and reduces bacterial translocation from the
intestine.
5. Small doses of intermediate/short-acting glucocorticoids,
e.g., dexamethasone, can be used as stabilizers of the cel-
lular membrane and lysosome membrane, but usage
should be ensured within 72 h.
6. Sulfur-containing β-amino acid. In addition, taurine, a
sulfur-containing β-amino acid, regulates cellular cal-
cium homeostasis, inhibits membrane lipid peroxidation,
maintains cellular osmotic pressure, stabilizes the cellular
membrane, and has other cellular protective effects.
According to multicenter data statistics, compared with
the simple volume replacement group, the incidence of vis-
ceral complications decreased from 47.5 % to 23.3 %, and
Delayed resuscitation of
burn shock
Free radicals increase
Membrane
proteins cross-
linked
Membrane proteins
lateral diffusion
restricted
Molecular motion of deep
membrane lipid and
membrane protiens
restricted
Erythrocyte stability
reduced
Hypotonic
hemolysis
increase
Conformational
changes of
membrane
proteins
Lipidperoxidation
intansified
Fig. 3.1 Mechanisms of
hemolysis due to delayed
resuscitation of burn shock

3.2 Delayed Resuscitation of Burn Shock

44
the recovery rate rose from 77.5 % to 90.0 % in the “combi-
nation of volume replacement and cytoprotection” group
when treating burn shock with delayed resuscitation.
3.2.3.4 Organ Protection and Function Support
Corresponding treatments can be administered to various
organs according to their pathophysiological characteristics,
such as:
1. Cardiac support: lanatoside C, dobutamine, etc., can be
used to enhance the myocardial contractility if the cardiac
output is still low when hypovolemia is corrected ade-
quately; a fi tting complement to myocardial energy sub-
strate, such as 1,6-diphosphate, is advisable.
2. Gastrointestinal mucosal protection: It is necessary
to take some measures to promote the gastrointesti-
nal blood supply, apply mucosal protectants to prevent
mucosal erosion, and take enteral feeding as soon as
possible. Enteral feeding has another two main effects
besides energy supply. One is to stimulate gastroin-
testinal nerves to improve the intestinal blood supply;
the other is to reduce intestinal permeability and bacte-
rial and endotoxin translocation. If glutamine is added
into the formulation, it has more protective effects on
intestinal mucosa.
3. Appropriate application of alkaline drugs and diuretics in
order to protect renal function is proportional according
to the depth of the burn wound.
3.2.3.5 Anti-infection and Anti-infl ammatory
Patients with delayed resuscitation from burn shock are
prone to infections because homeostasis and immunity are
disrupted by shock, especially when wounds have not been
completely covered. Moreover, intestinal infection caused
by bacterial translocation easily occurs under the circum-
stances of shock and reperfusion injury, which impair the gut
barrier. Therefore, delayed resuscitation of burn shock can
be regarded as an indication for the use of preventive anti-
biotics to prevent and control the systemic infection during
the edema reabsorption phase. Some externally applied anti-
microbial agents, such as silver sulfadiazine and mafenide,
should be used on uncovered burn wounds. Patients with
delayed resuscitation from burn shock are prone to excessive
systemic infl ammatory response and MODS owing to dou-
ble injuries brought by shock and reperfusion. As a result,
comprehensive measures are suggested to blunt excessive
infl ammatory response, including early surgical removal of
necrotic tissue to reduce the source of infl ammatory media-
tors, continuous blood fi ltration to remove infl ammatory
mediators in serious cases, and some of the Chinese herbal
compounds (e.g., xuebijing) to inhibit the excessive infl am-
matory response.
3.2.4
Indicators for Monitoring the Recovery
from Burn Shock
The replacement volume calculated by standard formulas is
merely an approximation for clinical fl uid replacement. The
actual implementation should be individualized and should
be based on the characteristics of burn injury, age, health sta-
tus, the time when fl uid therapy began, etc.. before being
adjusted appropriately.
Hemodynamic parameters are important indicators
refl ecting the adequacy or inadequacy of perfusion and can
be divided into non-invasive and invasive indicators, accord-
ing to the needs of the surgical procedures.
3.2.4.1 Non-invasive Indicators
Traditionally, non-invasive indicators have mainly referred
to urine output, consciousness, heart rate (HR), blood pres-
sure (BP), and other vital signs. With the development of
technology, they now include transcutaneous oxygen pres-
sure (PtcO 2 ), peripheral blood oxygen saturation (SpO 2 ), and
transesophageal Doppler echocardiography.
1. Vital signs, such as urine output, consciousness, heart
rate, and blood pressure, are important non-invasive indi-
cators refl ecting tissue perfusion, and they are still most
commonly used in the clinic. Fluid resuscitation is gener-
ally suffi cient when achieving the following criteria:
(a) Urine output is maintained at the level of 0.5–1 ml/
(kg h) in adults, and 1 ml/(kg h) in children.
(b) HR/pulse <120 beats/min.
(c) systolic blood pressure (SBP) >90 mmHg and pulse
pressure >20 mmHg.
(d) red blood cells (RBCs) <5 × 10 12 /L; hematocrit (HCT)
<50 %.
(e) Patients are conscious and quiet, extremities are
warm, and peripheral venous fi lling and capillary fi ll-
ing respond well. Urine output of 50–70 ml/h in
adults is generally accepted during the period of fl uid
resuscitation. Excessive fl uid input will increase the
capillary permeability and wound edema. Some cir-
cumstances should be treated carefully, for example,
hemoglobinuria or myoglobinuria need more urine
output and intravenous administration of alkaline
drugs to rise urinary pH value to >7; on diabetic
patients, the urine output cannot be regarded as a ter-
minal indicator of recovery, because osmotic diuresis
attributed to urine glucose may mask oliguria caused
by insuffi cient fl uid recovery.
2. PtcO 2 and SpO 2 are sensitive to peripheral hypoperfusion
caused by a decrease in cardiac output. It is noteworthy
that both blood oxygen content and blood fl ow can affect
the two indicators; thus, arterial blood gas (ABG) should
3 Burn Shock

45
be detected fi rst to identify the reasons for the decrease in
PtcO 2 or SpO 2 .
3. Transesophageal Doppler echocardiography. As a new,
non-invasive hemodynamic monitoring technology,
transesophageal Doppler echocardiography can record
CO, myocardial contractility, afterload, and other hemo-
dynamic parameters instead of invasive fl oating catheter
technology. It can avoid disseminated infection, which
may be caused by a deep venous cannula through the
wound surface.
3.2.4.2 Invasive Indicators
1. CO, CVP, and pulmonary artery wedge pressure (PAWP).
The application of a fl oating catheter to monitor the above
hemodynamic parameters can improve the effectiveness
and safety of fl uid replacement because of the guidelines
on clinical recovery.
2. Mixed venous oxygen saturation (SvO 2 ) refl ects post-
perfusion blood oxygen content. Typically, hypoperfu-
sion decreases SvO 2 (because of the increase in oxygen
uptake), and hyperperfusion increases SvO 2 . Theoretically,
an increase in SvO 2 implies that cells do not need more
oxygen, but under oxygen achrestic conditions or oxygen
uptake disorders (e.g., infectious toxic shock), an increase
in SvO 2 cannot account for adequate oxygen supply. SvO 2
still plays an important role in the diagnosis and treat-
ments of hemorrhagic shock.
3. Oxygen deliver/oxygen consumption (DO 2 /VO 2 ). Under
conditions of shock, the oxygen supply in the local tissue
is inadequate, thus resulting in oxygen debt. During the
period of resuscitation, oxygen debt caused by hypoper-
fusion should be compensated; therefore, an extraordi-
nary level of oxygen delivery is more suitable theoretically.
To reduce the oxygen supply defi ciency, enhancement of
cellular oxygen uptake is effective in addition to an
extraordinary level of oxygen delivery.
4, Blood lactate (BL). During the period of anaerobic
metabolism, lactic acid production increases. Therefore,
the concentration of blood lactate can indicate the status
of anaerobic metabolism.
5. Base defi cit (BD) refers to the number of millimoles of
alkali required to neutralize 1 l of whole blood to pH = 7.4
under standard conditions (oxygen saturation = 100 %,
PaCO 2 = 40 mmHg). If BD<−6, it means inadequate tis-
sue perfusion, and continued deterioration of BD strongly
suggests more fl uid replacements. Shock can increase
intracellular hydrogen ion (H + ) concentration, and H + can
diffuse across the cell membrane easily; therefore, both
intracellular and extracellular pH decrease, thus resulting
in high consumption of the buffer base. Exogenous alka-
line can raise extracellular pH to normal, but it cannot
correct intracellular acidosis directly because it is diffi cult
for alkaline to go across the cell membrane.
6. Gastric mucosal pH. The gastrointestinal mucosa is quite
sensitive to ischemia. When intravascular volume is
reduced, gastrointestinal mucosal ischemia is the earliest
to occur and the last to be restored. While hemodynamic
parameters have returned to normal levels, the gastroin-
testinal mucosa may still be ischemic (known as “occult
compensatory shock”). Detection of gastrointestinal
mucosal pH with use of a carbon dioxide tensometer is
important to estimate the intracellular pH (pHi) value,
which refl ects the intracellular acid-base balance. The
decrease in pHi implies inadequate DO 2 (oxygen
delivery)/anaerobic metabolism and it is also related to
the decline in intestinal blood fl ow, intestinal hyperper-
meability, micro-organisms, and endotoxin translocation,
etc. Moreover, it has a very good correlation with hepatic
vein pulse oxygen saturation (SPO 2 ), pressure of oxygen
(PO 2 ), and lactate concentration. Therefore, it is regarded
as the gold standard to evaluate the quality of fl uid
resuscitation.
7. Tissue oxygen monitoring. Subcutaneous oxygen tension
(PsqO 2 ) can be measured by a tissue oxygenation probe,
which is can be inserted into the subcutaneous tissue.
Continuous dynamic determination of PsqO 2 is quite
valuable for clinical administration. PsqO 2 reduction can
be found in 35–70 % of burned patients, and an increasing
fraction of inspired oxygen (FiO 2 ) gradually raises PsqO 2 .
3.2.5
Comprehensive Therapy for Burn Shock
3.2.5.1 Regulation of Cardiovascular Function
Under the conditions of adequate volume recovery and/or
inadequate oxygen supply, positive inotropic agents should
be candidates for raising cardiac output, increasing oxygen
supply, and reducing anaerobic metabolism of major organs
and tissues [ 11 ].
As an important hemodynamic indicator, peripheral vas-
cular resistance (PVR) refl ects not only the effect of fl uid
resuscitation but also the effi cacy of drugs and second-
ary reactions. Progressive alleviation of increasing PVR
is observed during the process of fl uid recovery, and indi-
cates that vasodilatation is necessary for fl uid recovery.
Vasodilators have been proven to have signifi cant therapeutic
value for left cardiac inadequacy and oxygen delivery insuf-
fi ciency, and do not induce hypotension, because adequate
volume recovery can prevent blood pressure from signifi -
cantly decreasing. Renal vasodilatation caused by a small
dose of dopamine [ 12 ] can dispel renal ischemia caused by
norepinephrine, and have protective effects on the kidney.
3.2 Delayed Resuscitation of Burn Shock

46
3.2.5.2 Support and Protection of
Respiratory Function
Burns, as systemic damage, can cause acute respiratory
distress syndrome (ARDS) [ 13 ], whose main clinical mani-
festations are dyspnea, severe hypoxemia, decreased lung
compliance (X-ray shows infi ltration of invasive mottling at
the base of both lungs). The treatments for ARDS include
supportive therapy and etiological treatment, such as blood
volume replacement, removal of local infected wounds, and
usage of antifungal/anti-bacterial drugs. There are no spe-
cifi c treatments to stop or reverse the capillary leakage and
secondary pulmonary fi brosis. Airway support is the most
basic measure, and tracheotomy or tracheal intubation is
required for patients with severe hypoxemia, deep and rapid
breathing, or those having diffi culty in clearing airway secre-
tions. When the rise in oxygen concentration is not effective
in hypoxemia, positive end-expiratory pressure (PEEP)
should be taken to reduce the shunt fraction (Qs/Qt). As the
PVR and pulmonary artery pressure increase, vasodilator
therapy (e.g., nitroprusside) is advised to reduce right car-
diac afterload, thus improving cardiac output and blocking
hypoxic pulmonary vasoconstriction. Moreover, Mucosolvan
promotes alveolar type II cells to secrete pulmonary surfac-
tant and prevent pulmonary atelectasis. It also promotes air-
way mucous secretion of serofl uid, which is conducive to
clearing the airway and reducing ischaemia.
3.2.5.3 Protection of Gastrointestinal
Mucosal Barrier
Increasing evidence shows that bacterial translocation from
the intestine induced by intestinal mucosal injury plays a key
role in systemic infl ammatory response syndrome (SIRS)
and metal–organic framework (MOF) [ 14 ].
To prevent gastrointestinal mucosal injury and hyper-
permeability, the most important measure is early enteral
feeding. Enteral feeding has two more main effects besides
energy supply. One is to stimulate gastrointestinal nerves to
improve the intestinal blood supply, the other is to reduce
intestinal permeability, bacterial and endotoxin transloca-
tion. If glutamine is added to the formulation, it has further
protective effects on the intestinal mucosa [ 15 ].
Type II histamine (H2) receptor antagonists and gastric
mucosal protective agents reduce the incidence of stress
ulcer. Selective decontamination of the digestive tract
(SDD), which refers to the usage of G – bacteria-sensitive
antibiotics with intestinal malabsorption through nasogastric
feeding, decreases the infection rate from 81 % to 15 %. In
addition, some drugs (e.g., IGF-1) [ 16 ] can promote regen-
eration of intestinal mucosa, prevent mucosal atrophy effec-
tively, and reduce the incidence of bacterial translocation.
Therefore, the promotion of gastrointestinal blood supply,
mucosal protectants, and early enteral feeding are important
to burn management.
3.2.5.4 Support and Protection of Hepatic
Function
The liver is a vital organ providing endogenous protection.
It has a wealth of glutathione reductase (GR/GSR), and pro-
tects the lungs and other organs from oxidative damage
effectively [ 17 ]; and Kupffer cells in hepatic sinusoid can
clear bacteria and toxins from intestine [ 18 ]; well-preserved
hepatic function can mobilize the endogenous protective
mechanism and prevent MODS effectively. It also improves
hypoproteinemia and supplies glucoses, which are needed in
hepatic detoxifi cation and metabolism [ 19 , 20 ].
Nonspecifi c hepatoprotective drugs include the following:
vitamins (vitamin B group, C, E, K, etc.), the drugs promot-
ing hepatic detoxifi cation such as glutathione, glucuronolac-
tone, diisopropylamine ascorbate, thioctic acid; the drugs
promoting energy metabolism, e.g., ATP, the drugs promot-
ing protein synthesis (e.g., hepatamine, Aminosol, etc.), the
drugs promoting microcirculation (e.g., radix salviae milt-
iorrhizae, dextran, etc.). These can be used as ancillary drugs
for protective medication for hepatic function, but polydrug
abuse should be avoided.
3.2.5.5 Support and Protection of Renal Function
Reduction of renal blood fl ow and acute renal failure can be
triggered by various factors. Hypovolemia, delayed recovery
or inadequate recovery can cause circulatory insuffi ciency
which, in turn, causes subsequent reduction of renal blood
fl ow and acute renal failure; other factors can also cause
acute renal failure, such as excessive secretion of ADH, renal
medullary osmotic pressure gradient elution, injury of renal
vascular epithelia, obstruction of a renal tubule caused by
cellular fragments, hemoglobin or myoglobin. Excessive
activity of the renin–angiotensin system and renal endothe-
lial cell edema are other factors in the reduction of renal
blood fl ow. Early adequate fl uid resuscitation is the key to
preventing acute renal failure owing to the mechanisms of
suffi cient renal blood fl ow. In general, urine output >60 ml/h
reveals adequate fl uid resuscitation [ 21 ].
To patients with hemoglobinuria or myoglobinuria, higher
urine output and high urine pH are required to prevent protein
coagulation, which would cause secondary obstruction of a
renal tubule. If necessary, mannitol can be used for diuresis.
However, loop diuretics and osmotic diuretics cannot increase
the creatinine clearance rate. Under the conditions of hypo-
volemia or vascular hyperpermeability, high doses of man-
nitol increase the incidence of renal failure. In recent years,
clinical usage of glycerin fructose as an osmotic diuretic
instead of mannitol has been shown to reduce the incidence
of renal failure. Moreover, prostaglandin E 2 , as an endoge-
nous vasodilator (also known as angiotensin antagonist), can
improve renal blood fl ow. Also, increasing atrial natriuretic
peptide after burns [ 22 ] increases renal blood fl ow and uri-
nary excretion, which have protective effects on the kidneys.
3 Burn Shock

47
3.2.5.6 Protection of Ecological Tissue Around
the Burn Wound
Some researchers have shown that the center of the burn
wound is an avascular area. The surrounding vascular is thin-
ner than normal because of arteriole contraction, and seg-
mental contraction/expansion and partial necrosis occurred
after 4 h. It was more serious 16–24 h later. Linear fl ow was
found in arterioles and line-segment fl ow or fl occulent fl ow
was found in capillaries and venules, then it changed into a
pendular fl ow, and fi nally, it became silt-like. Jackson divided
burn wounds into three bands from the center to the periph-
ery: zone of coagulation, zone of stasis, and zone of conges-
tion. The direction in which the zone of stasis would convert
into (zone of coagulation or zone of congestion) depended on
when the microcirculation of the wound was improved [ 23 ].
Therefore, the burn injury should be treated promptly and
correctly. Some researchers have advocated the use of hepa-
rin and moist therapy, and both of them have proven effective
in the clinic. Additionally, one experiment proved that
batroxobin could improve microcirculation and accelerate
wound healing of blister burns [ 24 ].
3.2.5.7 Sequential Cytoprotection
In recent years, owing to the development of modern science
and technology and advances in molecular biological tech-
nology, further research into the early-injury mechanism
after burns has been processed at the cellular and molecular
levels and the results have brought many improvements in
the clinical administration and expansion of therapeutic
strategies. Xia Zhao-fan et al. found that, along with burn
shock and systemic infl ammatory response, a major burn ini-
tiates endogenous cell damage in the distant organs and tis-
sues; thus, they proposed a clinical strategy of sequential
cytoprotection [ 25 ]. Release of oxygen-derived free radicals
and disorder of removal would be induced by either SIRS or
ischemia–reperfusion injury [ 26 ].
Recently, some domestic burn centers have combined
fl uid resuscitation with antioxidant treatment from the very
early phase, not under conditions of delayed resuscita-
tion, which proved effective. Vitamin C and vitamin E are
mostly medicated. Some animal experiments showed that
some antioxidants (e.g., SOD), zinc metallothionein, tiopro-
nin) have signifi cantly protective effects on major organs.
Improvement of cellular energy metabolism and reduc-
tion of membrane permeability are of great importance in
the prevention and treatment of burn shock. Adenosine
triphosphate- magnesium chloride (ATP-MgCl 2 ) or energy
mixture can promote cellular energy metabolism and enhance
the activity of the Na + -K + -ATP enzyme. Increased levels of
free fatty acids in the blood inhibit mitochondrial function
and disturb cellular energy metabolism. Intravenous albu-
min supplement reduces the increased free fatty acid levels
and relieves inhibition of cell mitochondria induced by free
fatty acids. In addition, the cellular uptake of metabolic sub-
strates is suppressed in a state of shock, and 1,6-diphosphate
can improve the cellular uptake and utilization of metabolic
substrates.
3.2.5.8 Sedation and Analgesia
As a strong stimulus, a burn can cause a series of pathologi-
cal responses of the neuroendocrine system, and repeated
and continual pain may disrupt the functioning of the central
nervous system. According to observational reports from
Harborview Medical Center of Washington University, anxi-
ety, depression, and other symptoms occurred in patients
with extensive burns, and the duration of these symptoms
was quite closely related to the early post-injury pain inten-
sity (the more severe the pain, the longer the duration).
Therefore, the appropriate use of analgesic or sedative drugs
is not only benefi cial to prevention and treatment of shock
but is also effective for the follow-up mental state.
1. Analgesic drugs. Opium alkaloid, represented by mor-
phine, is in common use. Although synthetic morphine
substitutes have a strong analgesic effect, they may result
in respiratory depression, and long-term use may lead to
addiction. Therefore, the should be carefully adminis-
tered, especially in patients with craniocerebral injury or
cerebral edema. In addition, these drugs have a mild
histamine- like effect; combination with promethazine
may enhance analgesia and reduce the histamine-like side
effects.
2. Sedative drugs have a wide range of inhibitions of the
central nervous system and may make excited and anx-
ious patients calm. Large doses can induce hypnosis.
Continuous use can cause drug dependency and drug
resistance. Of all the sedative drugs, diazepam is used
most widely. In recent years, nitrazepam, midazolam,
propofol, lorazepam, etc., have gradually increased in
clinical use. According to the suggestion of US emer-
gency medicine experts, midazolam and propofol are the
short-term (use within 24 h) drugs of fi rst choice. The
pharmacological action of midazolam is similar to that of
diazepam, but it has shorter term effi cacy than diazepam.
The general starting dose is 0.03 mg/(kg/h), and then the
maintenance dose is given. Propofol is similar to mid-
azolam, and its use should be from the central vein.
Lorazepam is the long-term drug of fi rst choice. Compared
with midazolam, it has a longer effective term, and its
initial dose is 0.044 mg/kg. It can be repeated every 2–4 h
if necessary. Ketamine has sedative, hypnotic, and anes-
thetic effects, and it effect is rapid and transient. It can
stimulate the cardiovascular system to a certain extent
and large doses may inhibit breathing. In addition, vomit-
ing may occur during the process of spontaneously
breathing and conscious recovery. Therefore, fasting is
needed before use, and its administration route is usually
3.2 Delayed Resuscitation of Burn Shock

48
via intravenous and intramuscular injection. A report
from the department of surgery of the Virginia Medical
School, USA, showed that oral administration (10 mg/kg)
was also very effective, and it was much safer than intra-
muscular and intravenous injection.
3.2.5.9 Application of Antibiotics
Burns damage the defensive barrier (e.g., the skin), and the
bacteria remaining in the appendages of skin can proliferate
aggressively on the basis of local necrotic tissue and nutri-
tious exudation, and most of them are G + bacteria such as
staphylococcus, streptococcus, etc. In addition, the decline
in immunological function after burns creates conditions for
bacterial invasion. If coupled with inadequate or untimely
fl uid recovery or occult shock, intestinal mucosal injury may
be induced by ischemia and hypoxia. And enterogenic infec-
tion will occur owing to the translocation of bacteria and tox-
ins. Moreover, drug-resistance bacteria in burn wards are
important sources of pathogens; they spread throughout the
wounds and respiratory tract or urinary tract, through the uri-
nary catheter, even the blood circulation through the fl uid
infusion catheter, thus resulting in an early invasive infec-
tion. Accordingly, both severe burns and the serious pollu-
tion of burn wounds are indications for the early application
of antibiotics.
3.3
Pathogenesis of Burn Shock
Zhaofan Xia , Xiaoyan Hu , Pengfei Luo , and Shengde Ge
In the past, shock was the most important lethal factor in
burns, but nowadays, death from burn shock is not common
owing to further research into the pathogenesis of burn shock
and the widespread application of corresponding treatments
in the clinic. However, shock is still the most common com-
plication of burn patients and plays an important role in the
follow-up prognosis.
3.3.1
Research into the Pathogenesis
of Burn Shock
3.3.1.1 Changes in Vascular Permeability During
the Burn Shock Stage
Phasic Response of Capillary Permeability After Burns
Increased capillary permeability after a burn can be divided
into two phases. The fi rst phase occurs within 30 min after
the burn, mainly in the venules, which can be antagonized by
inhibition of histamine receptor. Therefore, the pathogenesis
of this phase is considered to be closely related to that of
histamine. The second phase is also called the delayed
response of vascular permeability.
Generally, it occurs half an hour after the burn, and
reaches its peak 4 h later. However, not only venules but
also capillaries are involved. The severity and duration are
more than those of the fi rst phase, and cannot be inhibited
by the antagonists of the histamine receptor. Therefore, it is
considered to be related to chemical mediators other than
histamine.
Humoral Factors
1. Histamine–PLC-NO pathway. The specifi c binding of
histamine and histamine receptor mediates the increase
in venule permeability, contraction of small arteries and
bronchial smooth muscle, and the expansion of small
veins. Some experiments showed that during the early
post-burn period, histamine increased cardiac microvas-
cular permeability to albumin, but it only maintained it
for 20–30 min. The exact mechanism is as follows: bind-
ing of histamine and its receptor on the endothelial cell
surface activates phospholipase C, thus causing changes
in the calcium concentration or calmodulin system
directly or indirectly. As a second messenger, changes in
calcium activate NO synthase, hence leading to the pro-
duction and release of NO [ 27 ]. NO activates guanylate
cyclase, thereby resulting in increased synthesis of cyclic
guanosine monophosphate (cGMP), which promotes the
contraction of contractile proteins in endothelial cells and
activates endothelial leakage. In addition, bradykinin,
5-hydroxytryptamine, P substance, ADP, and others are
related to increasing permeability as well.
2. Effects of oxygen-derived free radicals on microvascular
structure. Four aspects are involved in the effects of
oxygen- derived free radicals on microvascular structure:
(a) As the generation system of oxygen-derived free
radicals, hypoxanthine-xanthine oxidase (HX-XO)
reacts with hyaluronic acid in microvascular basal
membrane. Within 10 min, 44 % of the hyaluronic
acid is degraded.
(b) Radicals, such as O 2 − and OH − , interact with poly-
unsaturated fatty acid and produce (lipid peroxyl
radicals (ROO − ), lipid hydroperoxide (ROOH),
and others, which can damage endothelial cells.
An animal experiment showed that along with lipid
hydroperoxidation in the serum/pulmonary tissues
of scalded rats, pulmonary vascular permeability
increased [ 28 ].
(c) Oxygen free radicals raise Ca 2+ infl ux, thus leading to
endothelial cell contraction, a widened gap, and
increased permeability [ 29 ].
(d) Arachidonic acid and leukotrienes pathways are
involved indirectly with oxygen free radicals as well.
3. Effects of PAF. Researchers showed that PAF increased
signifi cantly in the scald group (1.93 ng/ml ± 0.83 ng/ml;
control group, 0.53 ng/ml ± 0.24 ng/ml, p < 0.01) and the
3 Burn Shock

49
increase lasted 8 h ( p < 0.05). It was also found that skin
exudates of LYSO-PAF (a PA precursor) increased sig-
nifi cantly (scaled group 52 ng/ml, control group 34 ng/
ml, p < 0.01). It is known that LYSO-PAF is produced
under the conditions of phospholipase A 2 (PLA 2 ) in cell
membrane and degraded to PAF under the catalysis of
acetyltransferase.
Platelet-activating factor induces various processes, such
as hypotension, bronchoconstriction, blood concentra-
tion, an increase in pulmonary arterial pressure (PAP) and
vascular permeability, a decrease in platelets, neutrope-
nia, and even death. Moreover, it also results in the pro-
duction of prostaglandins, leukotrienes, and free radicals
through its action on endothelial cells, platelets, and white
blood cells.
4. Effects of leukotrienes (LTs). Delayed response after
burns may be mediated by LTs, which produce the cas-
cade effects of arachidonic acid. Leukotrienes LTC 4 ,
LTD 4 , or LTA 4 increase microvascular permeability
(about 1,000 times that of histamine). In addition, 2 h po
burn, the prostaglandins PGA 2 , PGE 1 , and PGF2d in
plasma increased immediately. The increase in PGA 2 and
PGE 1 lasted until 48 h later. PGE 1 and PGG 2 damage
endothelial cells and increase vascular permeability.
Local Mechanisms of Increased Capillary
Permeability
Capillary wall is composed of monolayer endotheliocytes
and its thickness is about 1 μm. True capillaries are quite
close to tissue cells, about 20–25 μm at most, which is con-
ducive to the exchange of matter (Fig. 3.2 ).
Water and electrolytes keep exchanging between plasma
and intercellular fl uid in the fi ve ways described above.
About three quarters of the blood volume is exchanged every
minute; thus, the electrolyte concentration (crystal osmotic
pressure) keeps in balance between plasma and intercellular
fl uid.
The concentration of plasma protein (PP) is 60–80 g/L
and that of intercellular fl uid protein is only 0.5–3.5 g/L.
Therefore, the concentration of electronegative proteins
( colloid osmotic pressure) is the biggest difference in osmotic
pressure. The balance between plasma and interstitial fl uid
depends primarily on colloid osmotic pressure and capillary
hydrostatic pressure.
Microfi lament contraction occurs in endothelial cells dur-
ing burn shock, and the intercellular gap is widened, thus
resulting in fl uid extravasation. There are also many local
mediators involved in fl uid extravasation, such as histamine,
5-hydroxytryptamine, bradykinin, prostaglandin, oxygen-
derived free radicals, NO, etc. With capillary permeability
signifi cantly increasing, leakage, even “leak syndrome” (if
leakage is quite severe) occurs. It is reported in the literature
that micromolecule (molecular weight is less than 350,000)
were able to traverse capillaries freely in the burned area [ 30 ].
3.3.1.2 Changes in Hemodynamics and Cardiac
Function During the Burn Shock Stage
Decrease in the Volume of Circulation
and Plasma After Burns
Researchers have shown that plasma volume (PV) may be
reduced by 50 % at 2 h post-burn, and total blood volume
would fall to the lowest at 4–6 h post-burn. Tissue water con-
tent would increase by 20 %. At the same time, cardiac out-
put and cardiac index decrease immediately after injury, and
they are separately reduced by 40 % and 45.7 % 2 h later.
Mean arterial blood pressure may increase slightly at fi rst,
and then decreases. Systemic vascular resistance may
increase by 51.8 % at the early post-burn stage, and then
decrease by 60 % after 2 h later. Femoral artery blood fl ow
(FAF/FABF) would drop from (120 ± 30) ml/min (pre-injury)
to 60–67.5 ml/min (post-injury) before the change in mean
arterial blood pressure.
Changes in Myocardial Contractility: Contractility
of Heart Changes After Burns [ 31 ]
Left ventricular systolic pressure (LVSP) increases immedi-
ately, and drops to 74.4–82.1 % of the pre-injury value 2 h
post-burn and to 59.4 % of the pre-injury value 4 h later.
Maximum left intraventricular pressure change rate [(d p /d t )
max] rises temporarily, decreases to 69.8 % 2 h later and then
to 29.4 % 8 h later. The ratio of maximum left intraventricular
pressure change rate to left intraventricular pressure [(d p /d t )
Basal Lamina
Surface Glycocalyx
Endothelial Cell
Fenestrate
1
2
4
3
5
Fig. 3.2 Structure of the
capillary wall and transcapillary
transportation

3.3 Pathogenesis of Burn Shock

50
max/IP] changes immediately in the early period (decrease
by 20 %) and then remains at a low level at all times. Left
intraventricular pressure–pressure change rate (p-d p /d t ring,
also called cardiac force loop, CFL) would increase fi rst,
then fall to 67.5–75 % 1.5 h later. It is worthwhile to noting
that the (d p /d t ) max/IP decreases before LVSP and it may
rule out interference of preload and afterload.
Decrease in Myocardial Regional Blood Flow
The immediate decline in myocardial contractility and the
decrease in myocardial regional blood fl ow (RBF) are paral-
lel, suggesting that the decrease in myocardial RBF is the
pathological basis of decreased myocardial contractility.
3.3.1.3 Mechanisms of Neuroendocrine
Regulation During the Burn Shock Stage
In 1959, Hume and Egdahl [ 32 ] carried out an animal experi-
ment using dogs under Nembutal anesthesia. The animals
were catheterized in the adrenal vein and scalded. They
found that the secretion rate of cortical steroids increased
rapidly within minutes after the injury. However, if the spinal
nerves or peripheral nerves around burn wounds were cut
beforehand, the above response would be blocked. This
experiment suggested the existence of a neuroendocrine
refl ex arc. Signals from the damaged area were conducted
through the afferent nerve to the central nervous system, and
nerve impulses and hormone secretions were induced after
the integration of the brain.
Sympathetic Nervous System and Catecholamine
Within a few minutes/hours post-burn, the adrenal medulla
would be activated through the neural pathways, and the
release of catecholamine (CA) increased. In patients with
burns in an environment of 21 °C, it was observed that those
who ultimately survived in the low-temperature environ-
ments had increased CA secretion and an increase in the
metabolic rate. Pathological examinations of those who died
of burns showed that the storage capacity of catecholamine
in adrenal medulla, nerve endings, and sympathetic gangli-
ons decreased signifi cantly. In addition, other studies have
shown that those patients who ultimately died of burns had
lost cardiovascular response to large doses of medicinal CA
before they died.
Hypothalamic–Pituitary–Adrenal Axis
As a stress factor, burns keep the hypothalamic–pituitary–
adrenal (HPA) axis in a highly active state, and insuffi ciency
of the circulating volume can activate the HPA system as
well. In the anterior lobe of the hypophysis/pituitary and
hypophysenmittellappen, there is a macromolecule called
proopiomelanocortin (POMC), which can be dissolved into
adrenocorticotropic hormone (ACTH), β-endorphin, and
other molecular fragments without known functions under
catalysis of corticotropin-releasing hormone (CRH) and
arginine vasopressin hormone (AVP), which are released
from the hypothalamus. ACTH is the main regulator of the
growth and secretion of the adrenal cortex. Three types of
hormones are secreted from the adrenal cortex, including
glucocorticoids, mineralocorticoid, and adrenal androgens.
The energy metabolisms of some of the important organs
and tissues (e.g., brain) depend largely on the glucose supply
as an energy substrate, but glucose storage capacity is usu-
ally limited. In state of the shock and stress, the ability to
ensure adequate glucose supply has great signifi cance for
survival. Glucocorticoids inhibit the glucose utilization of
some organs and tissues (such as skin, muscle, connective
tissue) except for the brain and heart, and stimulate gluco-
neogenesis to maintain normal or hypernormal levels of
blood glucose, which supply energy substrates for brain
metabolism and repair of wounds. Moreover, glucocorti-
coids stimulate protein catabolism, mobilize muscle, and
other tissues to release amino acids, which not only provide
raw materials for gluconeogenesis, but can also be used for
the synthesis of acute phase proteins and wound repair. In
addition to glucocorticoids, burns induce increased catechol-
amine and glucagons, thus increasing blood glucose and
insulin resistance in coordination with glucocorticoids.
Inadequate glucocorticoids or glyconeogenesis dysfunction
directly affect the compensatory ability with regard to burn
shock and the clinical survival of patients.
Renin–Angiotensin–Aldosterone System
Aldosterone is the most important mineralocorticoid, and it
is extremely sensitive to blood pressure and changes in water
and electrolytes. Synthesis and secretion of mineralocorti-
coid are affected by many factors, such as POMC and its
cleaved products (ACTH, β-endorphin, β-adipokinetic hor-
mone), and plasmic potassium and sodium concentrations,
catecholamine, 5-HT, and the sympathetic nervous system,.
but, the renin–angiotensin–aldosterone (RAA) system is
the most important. The RAA system plays a crucial role
in maintaining blood pressure and a relatively stable equi-
librium of the internal environment, especially the condi-
tions of water and electrolytes. The system consists of renin,
angiotensin- I (A-I), angiotensin-converting enzyme (ACE),
angiotensin- II (A-II), angiotensin-III (A-III), and aldoste-
rone. The RAA system is activated by the transfer or loss
of body fl uid, low blood volume, and electrolyte imbalance,
etc. As a proteolytic enzyme, renin, which would be widely
released into the blood from the kidneys owing to sodium
reduction or renal hypoperfusion, accelerates the degrada-
tion of angiotensinogen into angiotensin-I, angiotensin-II,
and angiotensin- III. Angiotensin-II has a strong vasocon-
strictive effect, by acting directly on the vascular smooth
muscle. Moreover, it not only stimulates myocardial cells
directly but it also promotes the sympathetic nerve to release
3 Burn Shock

51
norepinephrine so that cardiac contractility increases. Renin
also acts on the central nervous system, in turn increas-
ing cardiac output and total peripheral vascular resistance.
Angiotensin-II and angiotensin-III may stimulate the adre-
nal synthesis and secretion of aldosterone, which act on the
renal distal convoluted tubule to promote the resorption of
salt and water. In addition, renin can act on the central ner-
vous system, thus increasing cardiac output and total periph-
eral vascular resistance in turn. Mineralocorticoid plays a
specifi c role in the regulation of sodium and potassium to
maintain environmental stability and the water–electrolytes
balance. Mineralocorticoid acts on the distal convoluted
tubule, renal collecting ducts, sweat glands, and digestive
gland cells. Through specifi c enzyme-controlled endergonic
mechanisms, it regulates electrolytic transmembrane trans-
port, including the absorption of sodium and the secretion
of potassium. The absorption of sodium promotes water
retention and expansion of the extracellular fl uid so that the
effective circulating blood volume increases. During the
burn shock stage, many factors can stimulate the produc-
tion and release of renin, angiotensin-II, and ACTH, such
as a decrease in blood pressure, a reduction in the effec-
tive circulating blood volume, a highly excited sympathetic
nerve, an increase in plasmic catecholamine, and changes
in sodium and potassium. However, in a small number of
severely burned patients, dissociation between renin activ-
ity and aldosterone secretion may be observed; namely, a
constant increase in renin activity that is not accompanied
by increased aldosterone secretion. This phenomenon may
result from energy shortages of aldosterone cells or the
abnormal production of cAMP caused by changes in cal-
cium and potassium. In most cases, this phenomenon can be
corrected by adequate fl uid resuscitation and improvement
of the electrolyte imbalance.
The stress response caused by burns is usually accompa-
nied by increased ACTH, thus increasing aldosterone secre-
tion. However, aldosterone secretion is usually not as durable
as ACTH. It may be induced by β-endorphin. β-adipokinetic
hormones are also involved in the regulation of aldosterone
secretion. Either increased serum potassium or decreased
serum sodium directly stimulates aldosterone secretion
through mechanisms of cAMP as the second messenger.
Dopamine and 5-HT also affects aldosterone secretion. The
former has a depressant effect and the latter a stimulatory
effect, but both increase after a burn.
3.3.1.4 Effects of Endotheliocytes During
the Burn Shock Stage
Over the past few years, endothelial cells have been consid-
ered to be irrelevant to traumatic reaction and responses
induced by shock. However, in recent years, a large amount
of evidence has shown that endothelial cells play a key coor-
dinating role in those responses. Trauma and hypovolemic
shock cause cellular damage through two mechanisms at
least, including ischemia/reperfusion injury and acute sys-
temic infl ammatory response. Both would lead to functional
changes in endotheliocytes via the following four
mechanisms:
1. Regulation of blood coagulation
2. Regulation of vascular tone
3. Integration of vascular permeability [ 33 ]
4. Regulation of leukocytic adhesion and spread
In a state of stress, endothelial cells stimulate thrombosis,
increase vascular permeability, produce chemical chemo-
taxis, promote leukocytic adhesion and migration, and
release chemical mediators.
Regulation of Blood Coagulation
The endothelial cell is the interface of the metabolic activity
between the blood and extravascular tissue. Normally, its
surface has an anti-coagulation and anti-thrombosis effect,
and secretes various regulatory molecules (regulators of
platelet function and coagulation function), such as nitric
oxide (NO), prostaglandin I 2 (PGI 2 ), von Willebrand factor
(vW factor), thrombomodulin. When endothelial cells
undergo less synthesis of NO, prostacyclin or thrombomodu-
lin, or more synthesis of vW factor, these changes in plasma
can result in hypercoagulable tendencies. Pre-infl ammatory
factor regulates endothelial function. For example, it can
reduce the expression of thrombomodulin and increase the
release of vW factor, which in turn may cause disseminated
intravascular coagulation (DIC). Later, with the ratio of his-
totype plasminogen activator and plasminogen activator
inhibitor-1(PAI-1) changing, systemic hemorrhagic tenden-
cies occur, especially under conditions of septic shock.
Regulation of Vascular Tone
Endothelial cells regulate vascular tone, the stability of the
intravascular environment and perfusion in tissues mediated
by two cytokines, including endothelium-derived relaxing
factor (EDRF), also known as endothelium-derived nitric
oxide (EDNO), and vascular endothelial constricting factors
(VECF), also known as endothelin (ET) [ 34 ], released from
endothelial cells. Under circumstances of severe trauma,
shock, infection, ischemia, and reperfusion, endothelial cells
constantly produce and release the above two cytokines dur-
ing the early period, and later, the production and release of
cytokines
are
reduced
by
endothelial
dysfunction.
Preinfl ammatory factors, e.g., tumor necrosis factor (TNF),
interleukin-6 (IL-6) are also involved in stimulating the gen-
eration and release of ET and EDRF. Either excessive pro-
duction and release, or reduction due to endothelial
dysfunction, anomalies of EDRF and ET play an important
role in shock and multiple organ dysfunctions. Under normal
circumstances, EDRF is produced from L-arginine under the
catalysis of calcium–calmodulin-dependent nitric oxide
3.3 Pathogenesis of Burn Shock

52
synthase in endothelial cells and many exogenous nitro-
vasodilators imitate the effectiveness of EDRF. Increased
EDRF synthesis in endothelial cells induces more diffusion
into smooth muscle cells, activating guanylyl cyclase and
resulting in an increase in cGMP in turn, and thereby smooth
muscle
relaxation
occurs
and
lasts
just
seconds.
Preinfl ammatory cytokines can lead to the constantly exces-
sive production and release of EDRF.
The production and release of ET is regulated positively by
both preinfl ammatory cytokines and EDRF. ET has a strong
effect on the contraction of capillaries and leads to a decrease
in coronary perfusion, which in turn induces a decline in car-
diac function and an increase in capillary permeability.
Currently, ET receptor antagonists and NO synthase inhibi-
tors are considered for use as therapeutic drugs to improve the
pathological processes caused by excessive release of ET and
EDRF. Magnesium chloride (MgCl 2 )-ATP is considered for
the treatment of endothelial insuffi ciency in the late stages.
Prostacyclin also has a relaxation effect on smooth muscle. It
is mainly produced by endothelial cells, platelets, and mono-
nuclear cells. Under conditions of thromboxane histamine or
leukotriene C 4 , intracellular calcium is elevated and in turn
phospholipase A 2 activated. Activated phospholipase A 2 cata-
lyzes membrane phospholipids into arachidonic acid, to be
converted into prostacyclin. IL-1β or TNF increases the activ-
ity of the enzymes that are involved in the synthesis of prosta-
cyclin. In addition, the endothelial cells produce platelet-derive
growth factor (PDGF), PAF, and IL-1α.
Regulation of Leukocytic Adhesion and Spread
Shock or ischemia/reperfusion injury in tissues or cells is
induced mostly by local leukocyte adhesion, aggregation,
infi ltration, release of proteases, oxidative stress, and cellular
calcium overload. Leukocyte infi ltration and aggregation
based on adhesion in various organs of scalded rats are com-
monly seen. Three molecules play an important role in adhe-
sion: endotheliocyte–leukocyte adhesion molecule (ELAM),
intracellular adhesion molecule (ICAM), and vascular cell
adhesion molecule (VCAM).
1. ELAM-1 is a mass of 110 kDa glycoprotein, which rest-
ing endothelial cells do not express. Ischemia, trauma,
etc., can induce its expression, and it is also expressed
within 2 h of contact with TNF and IL-1.
2. The expression of ICAM-1 in resting endothelial cells is
at quite a low level. In contact with TNF/IL-1 or
γ-interferon, it increases signifi cantly. Its receptor on
lymphocytes is CD11α/CD11β 2 , and on monocytes and
neutrophils CD11β/CD18β 2 .
3. Expression of VCAM-1 is induced by IL-1/TNF as well
and reaches its local peak concentration 24 h after contact
with IL-1/TNF. Its receptor is CD29/CD49d, only exists
on the monocytes and activated memory lymphocytes,
not on neutrophils.
Adhesion of leukocytes and endothelial cells is mediated
by adhesion molecules, which in turn activate to release a
variety of active substances [ 35 ]. During the process of adhe-
sion, leukocytes release a large number of reactive oxygen
species, leukotrienes, PAF, etc., targeting endothelial cells.
Endothelial cells would suffer from membrane lipid peroxi-
dation, thus resulting in increased permeability, tissue edema,
and organ dysfunction [ 36 ]. Animal experiments have shown
that adhesion molecules and their receptors increased in burn
shock, and the tolerance of shock, ischemia or hypoxia under
conditions of leukocyte defi ciency was better than that of
leukocyte existence. The tolerance in the chemotherapy
group with aleukocytosis was better than in the control group
[ 37 ]. The use of CD11β monoclonal antibodies decreases
mortality to 30 % from 100 % in a lethal shock rabbit model.
The use of adhesion molecule antibodies may also alleviate
local leukocyte accumulation and infi ltration. Serum from a
burned-animal model was used to incubate normal white
blood cells or vascular endothelial cells, thus inducing an
increase in the expression of adhesion molecules and their
receptors. Some researchers suggested the usage of some
special drugs or immunotherapy to block the adhesion
between leukocytes and endotheliocytes so as to reduce cell
damage and necrosis caused by burn, ischemia/reperfusion,
etc.
3.3.1.5 Damage to Circulating Red Blood Cells
Caused by Burns
Burn shock will be further aggravated by injury to RBCs
through mechanisms of exacerbation of circulatory dysfunc-
tion and hypoxia in organs. During the early post-burn
period, thermodynamic activity is generally considered to be
the direct injury factor. In vitro tests have shown that the
thermal threshold of RBCs is 50 °C and 40–50 °C can reduce
the antioxidant capacity of the red cell membrane, ATP con-
tent, and intracellular potassium. This results in delayed
hemolysis and hemoglobinuria in the clinic. Thermal effects
caused by burns can reduce ATP content in RBCs and when
it is 15 % lower than normal, dephosphorylation of mem-
brane contractile proteins can be induced rapidly, thereby
resulting in a reduction of membrane deformability; and
inadequate ATP weakens the calcium pump, thus inducing
intracellular calcium overload and more indurative RBCs
(i.e., reduction of membrane deformability) so that it is eas-
ily captured by the mononuclear phagocyte system. Shortage
of ATP also increases the permeability of the membrane,
causing osmotic hemolysis.
Membrane lipid peroxidation is another important factor
in erythrocytic injury. As an indicator of the erythrocytic
potential antioxidant capacity, the ratio of glutathione per-
oxidase/lactoperoxidase (GSH-PX/LPO) decreases progres-
sively along with the persistence of burn shock. It suggests
that the oxidative damage of RBCs is exacerbated along with
3 Burn Shock

53
the extension of the time of burn shock. According to the
different locations, the membrane is divided into the superfi -
cial and the deep and, the different location induces the dif-
ferent fl uidity changes attributed to lipid peroxidation.
Cross-linked proteins have less impact on the superfi cial
membrane and more on the deep membrane. Therefore, with
regard to the superfi cial membrane, lipid peroxidation mainly
causes the breakage of the unsaturated fatty acid chain and
lipid degradation, thus resulting in an increase in membrane
fl uidity.
On the contrary, as the deep membrane is close to mem-
brane skeleton protein, cross-linked proteins caused by per-
oxidation reduce membrane fl uidity signifi cantly after a
burn. In addition, lipid peroxidation can also bring about
antigenic changes in membrane band 3 proteins and promote
the binding of autoantibodies.
Changes in red blood cells are also related to the sustained
actions of some substances in body fl uids during burn shock.
It has been proven that catecholamine, prostaglandins etc.,
can increase the rigidity of the red cell membrane [ 38 ].
3.3.1.6 Immunological and Infl ammatory
Responses During the Burn Shock Stage
As they cause severe stress and trauma, burns can induce
SIRS mediated by the neuroendocrine system cytokines and
other infl ammatory mediators [ 39 ].
These responses lead body fl uids, proteins, and cells to
the injury site from the blood to remove or mitigate injury
factors, and to repair the injured site. However, they can also
cause a series of complications and further cell and tissue
damage, even resulting in a serious organ system dysfunc-
tion [ 40 ], such as ARDS, DIC, renal failure shock, MODS,
and usually some excessive responses. Abundant mediators
also play an important role in the process of SIRS, including
infl ammatory cytokines, NO, ET thrombomodulin, arachi-
donic acid, phospholipase A 2 , multinucleate neutrophil,
adhesion factors, and receptors. Infl ammatory mediators
related to burn shock include the following categories: vaso-
active
substances,
preinfl ammatory
cytokines,
anti-
infl ammatory cytokines, chemical factors, acute phase
reactant, bioactive lipid, products of the plasmin system, and
the fi brinolytic system.
The imbalance between preinfl ammatory cytokines and
anti-infl ammatory cytokines is an important pathogeny of
SIRS and many other immunological diseases. In recent
years, with the use of cytokine gene knockout technology, it
has been proven that with defi cits in interleukin 10 (IL-10)
normal intestinal symbiotic bacteria may cause a lethal sys-
temic infl ammatory response. Besides IL-10, researchers
have found that IL-4 and IL-3 are also anti-infl ammatory
cytokines.
The neuroendocrine system is the highest regulator of
immune infl ammatory response, which is proved by the
following examples: prolactin and growth hormone stimulate
the proliferation of white blood cells and maintain immune
function; the HPA axis constitutes a powerful immune
system- regulating loop; neuropeptides are also involved in
this loop; both α-melanocyte-stimulating hormone (α-MSH)
and β-endorphin are immune-regulators; peptidergic nerve is
the main regulator of the infl ammatory response; P substance
and calcitonin-gene-related peptide (CGRP) are important
pre-infl ammatory mediators; growth hormone release inhibi-
tory factor (GHRIF) has anti-infl ammatory effects. Therefore,
the neuroendocrine regulation of infl ammatory response has
great signifi cance for immune stability and balance.
Insuffi ciency of the HPA axis/loop often leads to diseases
and sometimes even life-threatening pathological processes.
In the process of systemic immune/infl ammatory
responses, cytokines hormones in blood, through which sig-
nals are transmitted to the neuroendocrine system, are sig-
nifi cantly elevated. IL-1, IL-6, and TNF-α are the major
cytokines mediating an acute-phase response and they inter-
act with the central nervous system and many other organs
and tissues, and causing changes in the neuroendocrine and
cellular metabolism. α-MSH has antagonistic effects on
these infl ammatory cytokines and is known as the anti-fever
hormone. All in all, resistance to infection, trauma, and
shock depends largely on the function and state of the
neuroendocrine- immune network.
3.3.1.7 Changes in Cell Membrane During
the Burn Shock Stage
In addition to direct thermal damage to partial tissues and
cells, cell membrane antioxidant capacity in distant parts is
also reduced by the action of humoral factors. Researchers
have shown that the ratio of GSH-PX/LPO, as an indicator of
erythrocytic potential antioxidant capacity, progressively
decreases with the persistence of burn shock. The different
location induces the different fl uxionary changes caused by
lipid peroxidation. (Cross-linked proteins have less of an
impact on the superfi cial membrane and more on the deep
membrane. Therefore, for the superfi cial membrane, lipid
peroxidation mainly causes the breakage of the unsaturated
fatty acid chain and lipid degradation, thus resulting in an
increase in membrane fl uidity. On the contrary, as the deep
membrane is close to the membrane skeleton protein, cross-
linked proteins caused by peroxidation reduce membrane
fl uidity signifi cantly after a burn). SDS-PAGE electrophore-
sis has shown that membrane skeleton proteins would depo-
lymerize after peroxidation; membrane lipid peroxidation
could also induce an abnormality of anion-exchange proteins
and antigenic changes. A decrease in the intracellular ATP
content, a reduction of membrane sodium pump function, an
increase in membrane permeability, loss of intracellular
potassium and magnesium, intracellular sodium and calcium
overload, etc., are also induced [ 41 ].
3.3 Pathogenesis of Burn Shock

54
3.3.1.8 Acute Phase Response in Liver and Its
Signifi cance During the Burn Shock Stage
The acute phase response in liver is manifested mainly in the
synthesis of acute phase proteins [ 42 ]. Acute phase proteins
is a group of around 10 plasma proteins that would change
signifi cantly under the conditions of trauma or intense stress.
Acute phase protein mRNA expression in hepatocytes
changes signifi cantly within 2 h post-burn. Some acute phase
protein mRNA (for example, α-acid glycoprotein mRNA
and α-anti-trypsin protein mRNA) are regulated positively
and other mRNA (such as the transferring mRNA) is regu-
lated negatively. As the liver is the most important organ of
serum protein synthesis, the changes in acute phase protein
mRNA expression inevitably lead to changes in serum pro-
tein spectrum [ 43 , 44 ].
As these changes in hepatic acute phase response are not
caused by thermal injury directly, what mechanisms induce
them? Some researchers suppose that liver cells receive
information from skin cells at the burn site through some
mediators and this hypothesis has been confi rmed by in vitro
experiments. The basic design of these experiments is that:
1. Fibroblasts and hepatocytes are cultured in vitro
separately.
2. Pathological factors (e.g., bacterial endotoxin) are used to
activate fi broblasts.
3. Culture medium that contains activated fi broblast secre-
tion is used to culture liver cells in vitro.
4. Acute phase protein mRNA in in vitro hepatocytes is
measured.
The results have shown that acute phase protein mRNA
in vitro hepatocytes is similar to that in hepatocytes of
scalded animals, supporting the notion that the communica-
tion between the injured cells and cells in distant parts is
through factors/cytokines released from injured cells. IL-6
has been proven to be one of these cytokines. IL-6 has been
detected in supernatants of fi broblast culture medium and its
dose is proportional to the intensity of the injury (e.g., dose
of bacterial endotoxin) [ 45 ]. Because IL-6 is one of the most
important preinfl ammatory cytokines, these above results
strongly support the notion that burn is a post- traumatic
infl ammatory disease.
The changes in liver function are also manifested in glu-
cose metabolism. 13 C nuclear magnetic resonance spectrum
(NMR) techniques [ 46 ] are used to analyze carbon fl ow in
the tricarboxylic acid cycle (TAC), gluconeogenesis, and
anaplerotic reaction in the livers of burned rats and the results
showed that the liver plays an important role in maintaining
normal blood glucose levels after burn injury. If blood glu-
cose clearance increases, the liver can strengthen anaplerosis
and gluconeogenesis to ensure adequate energy substrate for
other important organs, while the liver cell reduces its own
TAC rate. In addition, acceleration of conversion from pyru-
vate to alanine has great signifi cance for protein synthesis in
liver cells.
The above has proved that the workload of liver
increases after burn injury. Multi-magnetic resonance spec-
troscopy in vivo (e.g., 31 P, 23 Na) is used to study hepatic
energy metabolism and ion distribution. The results show
that liver cells are in short supply of high-energy phos-
phate compounds after a burn injury, intracellular sodium
ions and hydrogen ions accumulate, and the sodium gradi-
ent on both sides of the cell membrane is reduced [ 47 – 49 ].
It is noteworthy that shortages of high-energy phosphate
compounds cannot fully explain intracellular Na + accu-
mulation, which suggests that there may be other infl am-
matory cytokines involved in the pathological process of
increased membrane permeability after a burn. Relaxation
time of 49 Na has shown that hepatic extracellular sodium
decreases, intracellular sodium increases, the percentage of
extracellular free sodium decreases (i.e., the percentage of
conjugated sodium increases), the percentage of intracel-
lular free sodium remains the same, whereas its absolute
value increases. It suggests that along with the increase in
intracellular sodium, intracellular sodium binding sites also
increase correspondingly. Liver plays a signifi cant role in
the burn course, but there is a lack of effective means of
detecting liver function. With the development of technol-
ogy, NMR may become an effective clinical tool for test-
ing liver metabolism and function in the near future. For
example, 31 P NMR provides information on hepatic energy
metabolism, intracellular pH, and magnesium ion metabo-
lism; NMR relaxation technique of 23 Na can provide infor-
mation on hepatocellular membrane function, intracellular
and extracellular distribution and status of sodium; 19 F NMR
provides relevant information on intracellular calcium over-
load and oxygen uptake in liver cells; 13 C NMR can provide
some data on selection and intake of hepatocellular meta-
bolic substrate, TAC, gluconeogenesis, anaplerosis, pen-
tose pathway, as well as the activity of enzymes that are
involved in the process of glycometabolism, lipid metabo-
lism, and amino acid metabolism. These examinations do
not cause any radioactive contamination or additional pain/
damage, and provide continuous dynamic data by repeated
measurements [ 50 , 51 ].
3.3.2
Theories on the Clinical Treatment
of Burn Shock
The understanding of the pathogenesis of burn shock has
gone through three major stages; namely, the “hypovolemia
theory”, the “microcirculation disturbance theory”, and the
“cellular energy dys-metabolism theory”. These three stages
refl ect the notion that the essential understanding of burn
shock is from macro to micro, from blood pressure, blood
volume, hemodynamic, and microcirculation to the cellular
and molecular levels [ 52 , 53 ]. This understanding that can
improve the clinical treatment of burn shock.
3 Burn Shock

55
3.3.2.1 Hypovolemia Theory
In 1921, Professor Underhill at Yale University detected the
hemoglobin, hematocrit, serous chloride concentration, and
protein content of blister fl uid from 20 burn cases and
believed that the loss of intravascular fl uid and protein
induced burn shock at an early stage. During the 1930s and
1940s, researchers gradually attained a more thorough
understanding of burn shock and the hypovolemia theory
was established and continuously improved on the basis of
increased vascular permeability and leakage of plasma com-
ponents to the wounds and tissue space, thereby resulting in
a lack of effective circulating blood volume and shock. As
the corresponding clinical treatment, vasoconstrictors and
volume replacement therapy were applied in the burn clinic.
Various fl uid replacement formulas were applied and schol-
ars in China also put forward formulas for burn shock accord-
ing to physiological characteristics and medical conditions.
Almost all the formulas predict the volume based on burn
size and body weight, and different formulas have different
ratios of colloid/crystals and different constants.
3.3.2.2 Microcirculation Disturbance Theory
In 1960s, the microcirculation disturbance theory was intro-
duced as a mechanism of burn shock. This theory emphasized
that the core of burn shock is the microcirculation distur-
bance and hypoperfusion of vital organs. Therefore, clinical
shock therapy should place great emphasis not only on fl uid
volume but also on its circulation. According to the microcir-
culation disturbance theory, the shock process can be divided
into three phases: the ischemic hypoxia phase, the stagnant
anoxia phase, and the MODS/MOF phase. The ischemic
hypoxia phase occurred in the early stages of shock. Because
of stimulation and compensatory mechanisms caused by
burn shock, the sympathetico-adrenomedullary system is
activated and catecholamine signifi cantly increased. Small
arteries, arterioles, metarterioles, and precapillary sphincters
contract in organs except for the brain and heart. With the
development of shock, stagnant anoxia phase occurs. In this
phase, the capillary perfusion fl ow decreases, tissue hypoxia
is exhibited, and the accumulation of metabolic products and
histamine released by mast cells leads to relaxation of metar-
terioles and precapillary sphincters. As the venules and small
veins have greater tolerance to hypoxia and acidosis and cat-
echolamine can induce spasticity of the venules, the post-
capillary resistance grows. In this way, the true capillaries
have enough infusion, but with little or no circulation. DIC is
induced by ischemia, slow, even stasis of the blood stream,
acidosis, endothelial injuries, and coagulation factor activa-
tion. Continuous DIC results in MODS/MOF. In the MODS/
MOF phase, microcirculation hypoperfusion deteriorates
progressively, severe hypoxia and acidosis stimulate the rup-
ture of lysosomal membrane and the proteolytic enzymes
overfl ow, consequently resulting in cellular autolysis, tissue
necrosis, and major organ failure, combined with secondary
hyperfi brinolysis, leading to a severe hemorrhagic tendency.
The microcirculation disturbance theory proposes that atro-
pine, anisodamine, lytic cocktail, etc., may be effective in
improving the microcirculation, and they were applied and
widely promoted in the clinical treatment of burn shock as
vaso-spasmolytic drugs to improve the microcirculation and
oxygen supply in organs and tissues.
3.3.2.3 Cellular Energy Dys-metabolism Theory
Since the 1980s, burn shock has been studied at the cel-
lular, subcellular, and molecular levels. Chinese scholars
established multinuclear magnetic resonance spectros-
copy in vivo to study the micromechanisms of burn shock
and fi rst revealed that vital organs have cellular energy
dys- metabolism, substrate utilization disorders, and
abnormal transmembrane ion gradients during the period
of burn shock. It includes a rise in intracellular pH, short-
ages of high-energy phosphate compounds, the intracel-
lular accumulation of sodium and calcium, an increase in
membrane permeability, a decrease in transmembrane ion
gradients, a decline in mitochondrial membrane calcium
ion pump-out function, and endoplasmic reticulum cal-
cium ion pump-in function, opening abnormalities of the
membrane ion channel. The application of fl uid replace-
ment and vasoactive agents cannot completely relieve
cellular injuries induced by burn shock. Based on the
above, membrane stabilizers are applied to improve cel-
lular energy metabolism, alleviate the inhibition of mito-
chondrial function caused by excessive free fatty acid, and
increase the cellular uptake of the substrate in the clinic,
and these treatments have further enhanced the control of
burn shock.
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3 Burn Shock

57
Z. Yang, Chinese Burn Surgery, DOI 10.1007/978-94-017-8575-4_4,
© Springer Science+Business Media Dordrecht and People’s Medical Publishing House 2015
4.1
Burn Wound Sepsis
Weishi Xu and Jie Liu
Different kinds of infection, such as invasive infection, gut
origin infection, and other infective complications such as
pneumonia, suppurative thrombophlebitis, and catheter-
related systemic infections can be derived from severe burn
injuries. Invasive burn infection is sepsis or sepsis with blood
stream infection in burns patients caused by the invasion of
the bacteria at the burn surface into the deep layers of the
eschar or even subjacent viable tissue, which is the unique
route of infection in burns and is identifi ed as burn
infection.
4.1.1
Concept of Burn Wound Sepsis
A puzzling problem when diagnosing some burns patients
with typical symptoms of septicemia but frequently negative
blood culture as “clinical septicemia,” an improper defi nition
that ignored the demanding element of diagnosing septice-
mia, had bothered burns surgeons for many years before
Teplitz et al. fi rst proposed the concept of “burn wound sep-
sis” [ 1 ].
In the early 1960s, Order established the burn wound sep-
sis model induced by Pseudomonas aeruginosa [ 2 ] and the
burns research department in Ruijin Hospital, Shanghai also
established the same model in the 1970s. Shaved on the back
and scalded for 10 s by 98 °C water, rats that had a third-
degree burn to about of 20 % of the total body surface area
(TBSA), the burn surface was immediately inoculated with
0.5 ml of a suspension of 2 × 10 8 Pseudomonas aeruginosa
per milliliter. This Pseudomonas aeruginosa strain was iso-
lated from the wounds of the burns patients. Then, 10–14
animals were killed after 24 h, on the 4th day, and on the 6th
day post-burn respectively for biopsy and microbial quantifi -
cation or counting in subeschar tissue. The average amount
of bacteria was 9.4 × 10 4 /g of subeschar tissue in the 24-h
post-burn group and a few bacteria colonies were found
around the hair follicles in superfi cial dermis according to
the biopsy. The bacteria count was 2.9 × 10 7 /g of subeschar
tissue on the 4th day post-burn, and amounts of bacteria were
found to have proliferated under the epidermis and around
the hair follicles, with invasion of the deeper layers of the
dermis, the local infl ammatory reaction was minor. On the
6th day post-burn, the amount of bacteria on the subeschar
tissue was 1 × 10 8 /g, while at biopsy, we found epidermis
necrosis, peeling off, and a large number of bacteria had
invaded into the dermis or muscular layers. Typical
Pseudomonas aeruginosa -induced vasculitis was observed
with infl ammatory cell infi ltration. The model indicated that
as time goes on, bacteria can not only colonize, proliferate
on the burn wound surface, but also invade the deep layers of
the eschar and subjacent unburned tissue through those
destructive hair follicles or subcutaneous lymphatic ducts
directly from the eschar. The toxins secreted by the invading
bacteria can be lethal to the patients. If the bacteria dissemi-
nated into the deeper vessels, the probability of systemic
infection via the blood steam would be increased, and bacte-
ria would develop in the blood culture. At the same time, the
burns department at Ruijin Hospital built up the method of
detecting bacterial quantity in subeschar tissue in burns
patients and evaluated its clinical signifi cance [ 3 ]. In their
study, 157 severely burned patients, from whom 996 sube-
schar tissue samples were collected during 220 cases of
escharotomy to perform quantitative culture of bacteria,
were included. Only 23.5 % samples were negative, while
41.4 % cases showed the quantitative culture result of 10 5
subeschar microorganisms per gram of tissue (Table 4.1 ).
The amount of bacteria in subeschar tissue increased as time
went on, 22.8 % of the specimens showed levels of greater
than 10 5 bacteria per gram of tissue on the 4th day post-burn
and the percentage increased to 46.3 % if the biopsies were
done after the 4th day post-burn (Table 4.2 ). The research
additionally suggested that bacteria could not only colonize
on the burn wound but also invade viable tissue underneath
the eschar; burn infection was the invasive infection that
Infection in Burns
Guangxia Xiao and Weishi Xu
4

58
arose from local burn wound infection and would probably
develop into burn wound sepsis. Chinese burns surgeons
generally accepted that early excision of necrotic tissue and
effective wound coverage served as the primary method of
preventing invasive infection in burns patients.
The term “burn wound sepsis” was initially defi ned as the
infection arising from burn wounds with bacteria counts of
more than 10 5 /g of subeschar tissue and evidence of invasion
of subjacent unburned tissue. Specialists working in the
burns center, Ruijin Hospital found that only 8.5 % of
patients manifested symptoms of burn wound sepsis when
bacteria exceeded 10 4 /g of subeschar tissue, while it increased
to 32.3 % with a quantitative count result of more than 10 5 /g
of subeschar tissue( p < 0.01). Furthermore, the incidence of
bacteria exceeding 10 6 /g of subeschar tissue was 16 out of
the 18 biopsy specimens from fi ve patients with erythema
gangrenosa, and the maximal count was 10 9 /g of subeschar
tissue. Although the probability of patients developing septic
symptoms was higher in those with a quantitative culture
result of more than 10 5 bacteria per gram of subeschar tissue,
it only counted for 32.3 % in this group of patients. Therefore,
the amount of bacteria in subjacent unburned tissue may cor-
relate with the incidence of burn wound sepsis, but this is not
necessarily the case (Table 4.3 ).
Marnin et al. also believed that quantitative culture results
of the bacteria proliferating in subeschar tissue could not be
the only evidence for the diagnosis of burn wound sepsis.
They found that about 30 % of patients showed no symptoms
of wound sepsis and their blood cultures were negative,
while bacteria levels of the subeschar tissue reached over
10 4 /g [ 4 ].
Meanwhile, the patients showed no symptoms of wound
sepsis, while the level of bacteria in subeschar tissue reached
10 5 /g, as high as 67.6 % in our study. Thus, a quantitative
culture result of 10 5 /g bacteria of subeschar tissue only
suggests a high risk of wound sepsis and the initial method of
wound treatment is ineffective. Furthermore, it is strongly
advised to reconsider the method of wound management,
such as a change in the topical agent or performing
escharotomy. Therefore, the probability of wound sepsis
increases when the level of bacteria in subeschar tissue
reaches 10 5 per gram, the amount considered to be the
threshold, but this is not necessarily the case when making
the diagnosis of burn wound sepsis. The diagnostic criteria
for burn wound sepsis are:
1. Burn wound biopsy with ≥10 5 viable bacteria per gram of
subeschar tissue
2. Histological evidence of viable tissue invasion
3. Clinical manifestation that indicates sepsis
McManus classifi ed burn infection into the following
three categories:
1. Burn wound infection, quantitative culture of bacteria in
subjacent viable tissue of >10 5 /g of tissue, but no evi-
dence of viable tissue invasion
2. Burn wound invasive infection, positive result of bacteria
invasion in biopsy specimen
3. Burn wound sepsis, the infection that manifests symp-
toms related to bacteria invasion of viable tissue [ 5 ].
Burn wound invasive infection is a histological diagnosis,
while burn wound sepsis is the systemic response that is out
of control of the host to bacteria; thus, it is necessary to have
the clinical manifestation of sepsis involved in its diagnosis.
However, it is probable that patients show no septic symp-
toms, but show histological evidence of bacteria invasion to
the viable tissue and a quantitative culture result of more
than 10 5 bacteria per gram of subeschar tissue, and vice
versa. In conclusion, the diagnosis of burn wound sepsis
must be based on the condition that patients develop a clini-
cal manifestation of sepsis.
Plasma endotoxin level increased after burn injury; never-
theless, endotoxemia should never be considered a synonym
for sepsis. We compared plasma endotoxin, tumor necrosis
factor (TNF)-ɑ levels, and interleukin 6 (IL-6) level in
patients complicated by burn wound sepsis with those of
patients who did not develop sepsis (Table 4.4 ), and these
Table 4.1 Results of quantitative culture for biopsy specimens
collected from 157 severely burned patients ( n = 996)
Amount of bacteria (per gram of tissue)
Specimens (%)
0
234 (23.5)
10 1 –10 4
349 (35.0)
10 5 –10 9
413 (41.4)
Table 4.2 Relationship between results of the quantitative culture for
biopsy specimens collected from 157 severely burned patients and the
date post-burn ( n = 996)
Post-burn day
Amounts of the bacteria in viable tissue
(per gram of tissue)
<10
10 1 –10 4
10 5 –10 6
10 7 –10 9
1–4
76 (36.9)
83 (40.3)
31 (15.0)
16 (7.8)
>4
158 (20.2)
266 (33.7)
265 (33.6)
101 (12.7)
Table 4.3 The relationship between the amount of bacteria subeschar in tissue and the probability of patients manifesting septic symptoms
Patients who manifested
symptoms of burn wound sepsis
Microorganism amount in subeschar tissue that lay before the eschar
<10 1
10 1
10 2
10 3
10 4
10 5
10 6
10 7
10 8
Positive (%)
0 (0)
0 (0)
1 (5.0)
6 (16.2)
5 (9.9)
8 (23.2)
11 (39.2)
3 (42.8)
1 (50)
Negative (%)
25 (100)
13 (100)
19 (95.0)
31 (83.8)
49 (90.1)
26 (76.8)
17 (60.8)
4 (57.2)
1 (50)
4 Infection in Burns

59
levels at different time points of the development of burn
wound sepsis (Table 4.5 ). There was no signifi cant differ-
ence in plasma endotoxin level between the septic group and
the nonseptic group; nor did it signifi cantly increase as
patients showed septic symptoms. However, the plasma
TNF-ɑ and IL-6 levels in the septic group were signifi cantly
higher than those of the non-septic group, and those levels
were also signifi cantly elevated when patients showed septic
symptoms.
The results of these studies indicated that sepsis, the
patients’ reaction to the bacteria and their products, is deter-
mined by patients’ immunological status and the degree of
stress response post-burn, but does not defi nitely parallel the
plasma endotoxin level or the severity of burn wound infec-
tion, such as the density of the bacteria and the depth of bac-
teria invasion.
Infection factors like endotoxin and exotoxin released by
bacteria, cell wall products of Gram-positive cocci and
Candida albicans , viruses, and fungal antigens can activate
mono-nucleo-macrophages (MNP), neutrophils, and lym-
phocytes to release series of infl ammatory factors and prein-
fl ammatory cytokines. Trauma, including burns, acute
necrotic pancreatitis, and other non-infective factors, can
also stimulate MNP to release infl ammatory mediators and
proinfl ammatory cytokines. Under both circumstances,
patients may manifest fever, leukocytosis, tachycardia,
tachypnea, and infl ammatory markers such as IL-6 may be
detected in patients’ blood. The status is defi ned as systemic
infl ammatory response syndrome (SIRS) [ 6 ], and is the
moderate or excessive systemic response to infl ammatory
stimuli, but is under control. Sepsis is the systemic response
to infection-induced stimuli that surpasses the optimal level;
thus, infl ammatory mediators and proinfl ammatory cytokines
trigger the chain-like reaction to initiate the amplifi cation of
the response to a level that is out of control and causes
excessive systemic infl ammatory reaction leading to tissue
destruction and organ dysfunction. At this stage, the nature
of the infl ammation changes. Although SIRS and sepsis
share the same characteristic of systemic reaction to infl am-
mation, sepsis, in fact, is the excessive infl ammatory reaction
of the body to predisposing factors, the pathogenic microor-
ganisms and their products. Whether or not sepsis would
develop and the severity of sepsis are determined by the
response of the body. Large amounts of bacteria, higher
pathogenicity, and more severely impaired homeostasis,
could also induce an out-of-control response of the body to
those infections, and then sepsis occurs. Therefore, SIRS
could not be identifi ed as being the same as sepsis. In the
early stages post-burn, there is no bacteria colonization or
only local infection occurs that differs from the invasive
infection. Patients may manifest typical septic symptoms,
but cannot be diagnosed as having sepsis as the initial factor
of such a systemic response is not infection. In the two-hit
hypothesis, in most cases the initial burn injury primarily
induces and activates different kinds of infl ammatory cells;
thereafter, when the second insult occurs, these activated
cells release an enormous number of infl ammatory media-
tors, resulting in extensive systemic infl ammatory response
that may develop into multiple organic dysfunction
syndrome(MODS). Mainly, infection serves as the second
hit; hence, the diagnosis of sepsis in burns patients is
precise.
4.1.1.1 Diagnostic Signifi cance of the Clinical
Manifestation of Burn Wound Sepsis
Up to now, burns surgeons have not been able to reach a
consensus in proposing diagnostic criteria for burn wound
sepsis. Obviously, this may be a multicenter prospective
clinical study, which should contain an enormous, compre-
hensive database. Without imposing any clinical diagnostic
criteria, we now share some of the experience we have accu-
mulated since 1958.
Body Temperature
Body temperature suddenly rises up to above 40 °C for
several days, or there is a precipitous temperature drop below
36 °C. Hypothermia is characteristic of Gram-negative
bacilli infection, particularly Pseudomonas aeruginosa
infection or an indication of the critical condition of the
patient, but surgical, anesthetic, and environmental factors
should be ruled out fi rst.
Respiration
Change in the pattern of respiration is more indicative than
body temperature in diagnosing burn wound sepsis. Patients
are always in a status of hyperventilation, with shallow,
rapid breathing at >30/min, progressively developing into
Table 4.4 Plasma endotoxin, tumor necrosis factor (TNF)-ɑ and
interleukin (IL)-6 levels of the patients in the septic group and the
nonseptic group
Septic group ( n = 30) Nonseptic group ( n = 30)
Endotoxin (pg/ml)
43.96 ± 29.02
45.42 ± 33.39*
TNFα (pg/ml)
1160.11 ± 917.54
578.22 ± 537.98***
IL-6 (pg/ml)
124.40 ± 107.59
80.53 ± 61.87**
* p > 0.05; ** p < 0.05; *** p < 0.001
Table 4.5 Plasma endotoxin, TNF-ɑ and IL-6 levels of the patients
before development of sepsis, during sepsis, and post-sepsis
Endotoxin
(pg/ml)
TNF-α (pg/ml)
IL-6 (pg/ml)
Pre-sepsis
39.73 ± 27.01
721.48 ± 541.70
44.71 ± 18.49
During
sepsis
59.54 ± 31.82* 1459.67 ± 786.35** 221.45 ± 198.18**
Post-sepsis 42.40 ± 29.61
621.55 ± 531.37
40.73 ± 32.74
* p > 0.05; ** p < 0.05
4.1 Burn Wound Sepsis

60
expiratory dyspnea with prolonged expiration, and cannot be
explained by the airway factors, pulmonary diseases or
water, electrolytes, and acid–base disorders.
Consciousness
The majority of the septic patients manifest symptoms of
excitation or depression, such as irritability, delirium,
hallucination, and restlessness. The possibility of sepsis
should always be considered if irritability and restlessness
cannot be attributed to other causes.
Abdominal Distension
Reduced or absent bowel sounds, distended abdomen with a
drum-like appearance is due to paralytic ileus and brownish
gastric contents with numerous sloughing necrotic mucosal
fragments.
Edema: Delayed Absorption of Edema or
Reappearance of Subsided Edema
In the early stages post-burn, edema frequently subsides
along with high fever, hyperventilation, disturbance of con-
sciousness, such as delirious mania, abdominal distension,
and netrocytopnea, that are similar to symptoms of burn
wound sepsis. Meanwhile, there is also a signifi cant increase
in urine output and obviously subsiding infl ammatory infi l-
tration, not wound sepsis progressing from invasive infec-
tion, but a series of symptoms and signs occurring in the
re-absorption phase identifi ed as absorptive toxemia.
Appearance of the Tongue
Dark red or even purplish in color with a scorched yellow or
blackish coating, sometimes it may be “bare” (uncoated,
with the papillae fl attened or atrophied), fi ssured, and dry.
The appearance of the tongue carries valuable information
for an early diagnosis of sepsis; however, they seem to be of
little value in pediatric patients and in patients complicated
by systemic fungal infection.
Appearance of the Wound
The granulation tissue turns dark and dry, and the wound
becomes pus-free. Such an appearance of the wound could
be of signifi cant value in diagnosing burn wound sepsis.
Erythema Gangrenosa
Erythema gangrenosa (purplish-black hemorrhagic necrotic
patches), which appears at the site of the burn wound or on
the normal skin, gives the burn surgeons confi rmatory infor-
mation about the burn wound sepsis or the blood stream
infection, which is induced by Gram-negative bacilli, for
example, the Pseudomonas aeruginosa in most cases. This is
a high ranking symptom that suggests a lethal incident with
high mortality.
White Blood Cell Count
It is common to have neutrocytosis in post-burn patients;
nevertheless, we should keep an eye on the possibility of sep-
sis if white blood cell (WBC) count continues to exceed
20 × 10 9 /L for a period of days. WBC count less than 3 × 10 9 /L
suggests Gram-negative bacilli infection after the differential
diagnosis from the leukopenia related to medication. Low
white blood cell counts that coincident with hypothermia in
burns patients strongly indicate Gram-negative bacilli-
induced sepsis, especially that caused by Pseudomonas
aeruginosa . Consequently, the dynamic changes of the neu-
trophils should be paid special attention in burns treatment.
If fl uid therapy is adequate, symptoms of restlessness,
unstable blood pressure, oliguria remain, and wounds
retained a wet, greasy wound appearance with a special
putrid odor and extensive punctate hemorrhage, then there
should be a high degree of suspicion of early fulminating
Gram-negative bacilli sepsis or a systemic infection originat-
ing from the blood stream.
4.1.1.2 Principles of Prophylaxis and Treatment
for Burn Wound Sepsis
Sepsis Continues to Be the Dominant Lethal
Complication of Severely Burned Patients
Sepsis continues to be the dominant lethal complication of
severely burned patients and the main factor that leads to
prolongation of the period of hospitalization, to which a
waste of medical resources and a surge in its expenditure are
attributed, although Chinese burns surgeons have made great
achievements in burns treatment such as modifi cation of
fl uid therapy, the application of topical antimicrobial agents,
the early excision of necrotic tissue, optimal and effective
wound closure, broad acceptance of the necessity of gastro-
intestinal (GI) tract protection based on the awareness of gut-
originated bacterial translocation. Despite the fact that the
incidence of burn wound sepsis has decreased signifi cantly
nowadays, mortality remains high. Burns surgeons and
researchers all over the world are still making every effort to
fi nd a breakthrough in burn wound sepsis treatment.
Therefore, it is crucial to reduce the incidence of burn wound
sepsis so as to diminish burn injury mortality. In the 1970s,
statistical data collected in the burns department, Ruijin
Hospital, Shanghai, China, indicated that about 40 % of burn
wound sepsis occurred during the period of eschar separation
and later stages post-burn. Up to now, the occurrence rate of
sepsis during eschar separation or later stages post-burn has
been kept at a very low level since the techniques of early
operative procedures for deep wounds and optimal effective
wound recovery methods have been modifi ed.
In the study of the relationship between the animal course
of the hypovolemic phase and the probability of burn wound
sepsis in the early stages post-burn, we found that among
4 Infection in Burns

61
those patients suffering from extensive burn injuries more
than 80 % TBSA, 47 patients had an eventful course in their
early stages, including those 39 patients who developed burn
wound sepsis; while among the rest of the 35 uneventful
cases, 13 patients developed burn wound sepsis [ 7 ]. This
result suggested that for patients with impairment of homeo-
stasis induced by burn stress, hypovolemia, and tissue
hypoxia or ischemia, their probability of developing burn
wound sepsis when the burn wounds become infected is tre-
mendously higher than that of the others. Therefore, appro-
priate intervention during the early stages post-burn is the
key point in reducing the probability of burn wound sepsis
further.
The body promptly starts the potential stress response to
react to the intensive stimuli at the time of a severe burn:
elevating levels of stress hormones, initiating the infl amma-
tory reaction, releasing NF-κB to perform nuclear transloca-
tion (its migration into the nucleus) so as to upregulate gene
transcription of a variety of cytokines and chemokines,
resulting in the activation of infl ammatory cells, increasing
the levels of proinfl ammatory factors and infl ammatory
mediators [ 8 ]; elevation of cytokine levels of Th1/Th2, Th2
cells dominant [ 8 , 9 ] to suppress cellular immune function.
Inappropriate fl uid therapy, delayed resuscitation and event-
ful conditions during the early stages post-burn, etc., can
provoke a more intensive stress response and further impair-
ment of homeostasis. It is much easier for the infection to
progress into sepsis when burn wounds are colonized or
invaded by bacteria, the main cause of the high incidence of
patients developing burn wound sepsis during the early
stages post-burn.
In a study on the infl uence of reduced stress on infl amma-
tory response and Th1/Th2 in severely scalded rats, the
group treated by immediate fl uid resuscitation with modifi ed
lytic cocktail right after the burns. The results showed that
infl ammatory response was initiated, but in a delayed and
alleviated manner. Levels of plasma LPS, TNF-α, IL-1, IL-2,
IL-6, IL-8, and prostaglandin E2 (PGE2) were decreased, the
activation of peripheral monocytes was reduced, NF-κB
nucleus translocation was inhibited, Th1/Th2 was adjusted
by diminishing Th2 cytokines [ 9 ] to protect the cellular
immunity of the body. Furthermore, it was suggested in a
study on reduced stress response that it could be benefi cial to
the prevention of bacterial invasion. Results showed that in
those full- thickness burn wounds invaded by Pseudomonas
aeruginosa with reduced stress response, the 96-h survival
rate was signifi cantly increased from 33.3 % to 66.7 %
( p < 0.01), infl ammatory cell infi ltration and its destructive
effect were alleviated; while mRNA expression of Th1 cyto-
kines was magnifi ed in the test group, but mRNA expression
of IL-2 in the control group was decreased; on the other
hand, the increase in mRNA expression of Th2 cytokines in
the test group was less than that in the control group, which
indicated that Th2 cytokines were not dominant in the test
group and the body still retained an anti-infective capability
because of the changes in the Th1/Th2 ratio [ 10 ]. In conclu-
sion, these results suggest that early adequate fl uid resuscita-
tion combined with stress-reducing intervention might
downregulate
the
exorbitant
post-burn
infl ammatory
response, preserve the potential for cell-mediated immunity,
and reduce the probability of burn wound sepsis when there
is subsequent bacterial invasion. These phenomena are wor-
thy of further study and clinical validation.
The principle of the prevention and treatment of burn
wound sepsis is the combined application of operative
wound management, which removes necrotic tissue of deep
burn wounds by escharotomy or tangential excision so as to
reach the aim of wound closure, and antimicrobial
therapeutics.
Early excision of necrotic tissue, effective wound cover-
age, and prophylactic usage of antibiotics are necessarily
needed for the prophylaxis of burn wound sepsis. For those
wounds not yet removed, topical antibiotics should be
applied so as to minimize the density of bacteria (the amount
of colonized bacteria) and prevent them from invading to
deeper layers. Early surgical management (48 h post-burn)
could be considered as soon as the hemodynamic status is
stable; otherwise, the procedure should be fi nished within a
week post-burn. For those patients with extensive burns, if it
is impossible to remove all the necrotic tissue in one proce-
dure, it might be necessary to excise most of it so that the
residual does not trigger the occurrence of wound sepsis. The
quantity of necrotic tissue is defi nitely a more dominant fac-
tor than the amount of bacteria colonized on burn wounds in
the development of wound sepsis.
In any case, the key point of wound sepsis treatment is
focusing on removing pathogenic bacteria and controlling
any excessive infl ammatory response based on patients’
potential anti-infl ammatory ability. Systemic antibiotic ther-
apy is the fi rst choice for removing the pathogens, but wound
debridement and effective wound closure should still be
achieved promptly, especially infective foci that need fi rst-
time drainage or excision in order to cut off the bacterial
invasive pathway and clear out the origin of the infection.
Burn wound sepsis is critical, fast developing, life threaten-
ing, and correlates with the high mortality among burn
patients. The initial choice of antibiotic therapy is closely
related to its effi cacy. For that reason, systemic antibiotic
therapy should be optimized, i.e., when there are no micro-
biological data and sensitivity detection available or burn
wound sepsis occurs even though antibiotic agents have
already been administered, burns surgeons can make a choice
of initial antimicrobial agents according to the principle of
therapy experienced, based on the prevalent pathogens found
4.1 Burn Wound Sepsis

62
in the burns unit, bacterial resistance background, and the
condition of the patients at different stages of the burn. In the
early stages post-burn, the probability of Gram-negative
bacilli infection is higher than that of Staphylococcus aureus ;
thus, it is optimal to choose antibiotic agents with low resis-
tance whose spectrum includes Gram-negative bacilli, par-
ticularly Pseudomonas aeruginosa . Under the circumstance
that the resistance of the third-generation cephalosporins is
as high as 20–30 %, the fi rst choice of antibiotic agents is
carbapenem and the secondary is fourth-generation cephalo-
sporins. When pan-resistant strains are dominant, the fi rst
choice may be polymyxin B. Under the circumstance that
methicillin-resistant Staphylococcus aureus (MRSA) and
MRSE constitute 70–80 % of staphylococcus strains, vanco-
mycin for staphylococcus infection and enterococcus infec-
tion is preferred.
The cellular immunodefi ciency during the early stages
post-burn is the result of the exorbitant activation of Th1
cells, the process that activates and induces apoptotic cell-
induced death (AICD), and activated Th2 cells by feedback
so that Th2 cells are dominant in the body. IL-4 and IL-6 are
Th2-type cytokines, those that could inhibit the cascade
induced by proinfl ammatory cytokines, have the potential to
downregulate the infl ammatory response of the body; mean-
while, they also inhibit cell immunity and restrain patients’
capability to fi ght against infections. Furthermore, the
disturbance of patients’ immune system during the septic
stage also presents inhibited cell immunity, which is respon-
sible for the specifi c immune response, and the excessive
nonspecifi c infl ammatory response of the body. Under such
a circumstance, patients’ capability of controlling infection
is impaired; thus, sometimes the effective antibiotic therapy
may fail. This is why the mortality of burn wound sepsis still
remains at a high level, although we are in an era in which
antibiotics are omnipresent. Research focusing on immune
modulation therapy for sepsis is the pathway to helping
burns surgeons to reduce the incidence of wound sepsis dur-
ing the early stages post-burn and to improve the prognosis
of such lethal complications of burns. Our target for immune
modulation therapy is to restore patients’ cellular immunity
to control infections and re-balance the infl ammatory
response of the body. α1-Thymopeptide may be an inspiring
immune modulating agent. From an anti-infl ammatory point
of view, though, the application of mono-colonial antibodies,
antagonists, and soluble antibodies of proinfl ammatory cyto-
kines or infl ammatory mediators is disappointing. In other
cases, blocking the processes that deduce secondary tissue
impairment, such as the application of inhibitors of some
hydroproteases to inhibit the activation of the coagulation
system, may attenuate tissue and organ damage in sepsis,
prevent further septic progression, and improve the progno-
sis of burn wound sepsis. Moreover, there is also the need to
emphasize the importance of metabolic support and organ
protection in the treatment of septic patients. For more
details, please refer to the related items.
Pathogenic Bacteria of Burn Infection
Ecological Pattern of Bacteria on Burn Wound
It is interesting to fi nd that the bacterial ecology on the burn
wound has changed over time, when we review its history.
The main factor infl uencing the microbial distribution of a
burn wound is our choice of topical antimicrobial agents and
those systemically administered antibiotics. The most com-
mon strain identifi ed from a burn wound was Streptococcus
pyogenes before the era of sulfonamides and penicillin;
however, this spontaneously transferred to two main strains,
Staphylococcus aureus and Pseudomonas aeruginosa , after
the advent of penicillin. In the late 1960s, scientists developed
several topical antibacterial agents that are effective at con-
trolling Pseudomonas aeruginosa ; for that reason, the iden-
tifi cation of Pseudomonas aeruginosa from a burn wound
started to decrease, but the detection of Enterobacteriaceae
and Acinetobacter increased. However, in the 1990s, because
of the wide use of third-generation cephalosporins, the iden-
tifi cation rate of Staphylococcus aureus showed an upward
tendency, and MRSA increased signifi cantly.
The antibiotic selective pressure is refl ected by the
changes in the bacterial ecology of the wound, which show
the increasing tendency of resistant strains and continuously
selected the opportunistic pathogens. No matter what kind of
topical or systemic antibacterial agents is used, under such
pressure, bacterial resistance tends to grow, resulting in a
bacterial ecological pattern on the burn wound dominant
with multi-resistant strains.
For the different choices of topical or systemic antibacte-
rial agents in various burn centers, the wound bacterial eco-
logical pattern varies. In any case, it is necessary for the
pattern to change in accordance with the long-term use of
one kind of topical antibacterial agent, or the type usually
considered as the fi rst choice for systemic administration; or
in addition to the switch to a new topical agent or fi rst-choice
antibiotic.
At present, the bacterial ecological pattern of a burn
wound shows the following characteristics:
1. Gram-positive cocci are more often identifi ed than Gram-
negative bacilli.
2. The identifi cation rate of Staphylococcus aureus and
Staphylococcus epidermidis is increasing, and MRSA strains
constitute 70–80 % of identifi ed Staphylococcus aureus .
3. Pseudomonas aeruginosa ranks the fi rst among those
Gram-negative bacilli, when bacterial species is the only
concern.
4. There are two trends of Gram-negative bacilli. One
is that Pseudomonas aeruginosa decreases while
Enterobacteriaceae and Acinetobacter increase, mainly
the Enterobacter spp., Klebsiella pneumoniae , and
4 Infection in Burns

63
Acinetobacter baumannii . Another is that Pseudomonas
aeruginosa still increases, but with no change or decrease
in Enterobacteriaceae. Which pattern the wound bacte-
rial ecology might follow is mainly decided by the thera-
peutic effectiveness of the topical agents at controlling
Pseudomonas aeruginosa infection, and whether the bac-
teria have already developed resistance to the agents; or
it may be decided by the antibacterial activity of selected
systemic antibiotics to Pseudomonas aeruginosa and the
degree of resistance of Enterobacteriaceae.
The burn wound microbiological ecology changes at the
burns center, Ruijin Hospital, Shanghai, China, between
1970 and 2000 are shown in Table 4.6 , and those between
2004 and 2007 in Table 4.7 .
One percent silver sulfadiazine cream has been used as the
fi rst choice of topical agent since 1972 and the third- generation
cephalosporins have been considered the fi rst choice of sys-
temic antibiotics since the mid-1980s, especially ceftazidime,
which has specifi c antibacterial activity to Pseudomonas
aeruginosa . As a result, the signifi cant change in the bac-
terial ecology of burn wounds occurred in the mid1980s
compared with that of the early 1970s. The ratio of identi-
fi ed Pseudomonas aeruginosa was signifi cantly decreased;
however, the percentage of Enterobacteriaceae found on the
wound signifi cantly increased and Enterobacter cloacae was
found there, which was going to be an important pathogen of
burn infection. Although the identifi ed rate of Staphylococcus
aureus showed no change, MRSA constituted 73 % of those
identifi ed Staphylococcus aureus , while the proportions of
MRSA among Staphylococcus aureus found in the internal
medicine department and general surgery department were
31 % and 37 % respectively, during the same time period.
The unrestricted topical usage of oxacillin in late 1960s may
be responsible for the MRSA epidemic [ 11 ]. Nevertheless,
in the 1990s there was a signifi cant surge in Pseudomonas
aeruginosa with no change in Enterobacteriaceae [ 12 ], but
the identifi cation of Enterobacter cloacae increased signifi -
cantly. Moreover, the identifi cation rate of Staphylococcus
aureus jumped in late 1980s and the percentage of MRSA
among them rose from 73.4 % in the mid-1980s to 85.1 %
at the end of the 1990s [ 12 ]. Our research group in the
burns unit at Ruijin Hospital analyzed the homogeneity of
17 strains of MRSA identifi ed during December 2005 at a
molecular level by using random-amplifi ed- polymorphic
DNA technology; the result showed that they were all one
Table 4.6 Bacterial distribution
(%) of bacteria identifi ed from
burn wounds during four periods
Organisms
1970.1–1972.12 1985.1–1986.12 1993.2–1994.12 1999.1–2000.12
Staphylococcus aureus
26.62
23.13
22.33
28.36
Staphylococcus epidermidis
1.23
8.45
5.18
11.72
Enterococcus faecalis
3.85
3.43
1.10
6.62
D non-enterococcus group
–
3.55
2.09
2.01
Hemolytic streptococcus
5.23
2.08
2.59
2.11
Other G + cocci
2.70
5.02
6.28
1.35
Pseudomonas aeruginosa
35.08
11.26
23.33
18.90
E. coli
1.54
2.20
2.39
2.10
Citrobacter spp.
6.92
11.14
4.08
1.13
Enterobacter aerogenes
3.69
3.79
5.18
3.31
Klebsiella pneumoniae
–
3.06
6.18
4.32
Enterobacter cloacae
–
0.86
4.79
3.16
Proteus mirabilis
3.08
0.98
1.79
1.75
Proteus vulgaris
–
1.47
1.40
1.57
Bacillus alcaligenes faecalis
3.23
0.86
1.79
1.73
Serratia marcescens
–
0.98
1.10
1.34
Nitrate negative Acinetobacter
1.38
3.38
4.79
2.11
G ¯ other bacillus
–
1.47
0.70
3.16
Neisseria
–
0.61
1.69
1.01
Bacillus subtilis
5.10
5.63
1.20
1.24
Table 4.7 Bacterial distribution (%) of bacteria identifi ed from burn
wounds during the period 2004–2007
Organisms
2004
2005
2006
2007
Staphylococcus aureus
31.18
29.48
33.56
39.03
Staphylococcus epidermidis
6.46
5.58
6.44
6.93
Enterococcus faecalis
4.56
2.39
4.07
5.12
Other G + cocci
13.69
18.32
14.98
13.85
Pseudomonas aeruginosa
15.59
21.51
23.39
10.84
E. coli
4.56
3.19
5.08
5.72
Klebsiella pneumoniae
9.13
5.18
3.05
3.31
Enterobacter cloacae
4.18
3.19
2.37
3.31
Proteus mirabilis
–
0.80
1.70
2.41
Other G ¯bacilli
2.28
5.98
–
–
Neisseria sicca
–
–
–
1.01
Bacillus subtilis
–
–
–
1.24
Miscellaneous a
8.37
4.38
5.36
7.23
a Contained the strains identifi ed no more than 1 % of the total
4.1 Burn Wound Sepsis

64
type, indicating that cross-infection might be the cause of
the epidemic of MRSA in the ward [ 13 ]. Under the selective
pressure of the third-generation cephalosporins, the number
of third-generation cephalosporin- resistant Gram-negative
bacilli strains has already increased signifi cantly since early
1990s; thus, imipenem was often treated as the fi rst choice
of systemic antibiotics after 1993. However, its antibacte-
rial activity to Pseudomonas aeruginosa is not as effective
as that to Enterobacter in which the percentage of resistant
strains is 20 %. The ratio of ceftazidime-resistant strains of
Pseudomonas aeruginosa increased from 5 % in the mid-
1980s to 20 %. This may be related to the higher identifi -
cation rate of Pseudomonas aeruginosa on burn wounds in
the 1990s than that of the mid-1980s. Moreover, the topi-
cal application of silver sulfadiazine cream has been used
for more than 20 years; it is less effective on Pseudomonas
aeruginosa than it used to be. Since 2000, detection of
pan-drug- resistant strains of Pseudomonas aeruginosa
(pan-drug-resistant, PDR) has continued in the burns unit
at Ruijin Hospital. To study it by using random-amplifi ed
polymorphic DNA analysis, we found that 28 PDR strains
originated from one type. There were 26 strains of A1 type,
2 strains of A2 type, and 9 strains of non-PDR, which were
classifi ed as types B, C, D, E, and F, identifi ed from different
patients, but only one type on one patient. This result sug-
gested that PDR Pseudomonas aeruginosa originated from
one colonial strain. It was at the end of 1990 that the inci-
dence of identifying Gram-positive cocci surpassed that of
Gram-negative bacilli. On this list, Staphylococcus aureus
occupied the fi rst place, while the identifi cation rates of
Staphylococcus epidermidis and Enterococcus faecalis were
11.72 % and 6.62 % respectively. The identifi cation rate of
Staphylococcus aureus continues to increase, reaching 39 %,
in the twenty fi rst century. Such a change might be related
to two factors: fi rst, the third-generation cephalosporins and
imipenem were selected as the fi rst choice for systemic anti-
bacterial treatment in burn wards; second, the most common
topical antibacterial agent, sulfadiazine, is less effective for
Gram-positive cocci. On the other hand, at the end of the
1990s Stenotrophomonas maltophilia was identifi ed on the
burn wound as imipenem had been widely used since the
mid-1990s. The identifi cation rate of Stenotrophomonas
maltophilia is still very low, even though imipenem has been
used for more than 10 years.
Staphylococcus aureus and Pseudomonas aeruginosa
continues to dominate in the bacterial ecosystem of the burn
wound along with the emergence of MRSA and multi-
resistant and pan-resistant Pseudomonas aeruginosa . Burns
surgeons should keep an eye on another kind of popular
strains, the Amp-C enzyme producing Enterobacteriaceae,
Enterobacter cloacae , and Acinetobacter baumannii , the
strain that is capable of producing metalloenzyme. In the
burns center at Ruijin Hospital, Acinetobacter baumannii
was ranked 7th of those bacteria identifi ed on a burn wound
in 2003, but it ranked 4th and 3rd in 2004 and 2005 respec-
tively. Among them, there were 11 strains of PDR
Acinetobacter baumannii that were classifi ed as B type orig-
inating from the same clone according to the result of pulse-
fi eld gel electrophoresis, while the popular Acinetobacter
baumannii strains in the emergency intensive care unit
(EICU) and the surgical intensive care unit (SICU) were type
A [ 14 ]. A research group in Jishuitan Hospital, Beijing,
China, reported that their average identifi cation rate of
Acinetobacter baumannii found on burn wounds, in blood,
on venous catheters, and in urine or fecal specimens col-
lected from burns patients was 9.1 % [ 15 ]. This may relate to
its mechanism of drug resistance.
Last but not the least, burn surgeons should defi nitively
understand the pathogenesis of common pathogens identi-
fi ed on burn wounds and their clinical signifi cance.
Furthermore, someone should be responsible for the epide-
miological study of bacteria on burn wounds to gather pri-
mary information on the categories of common pathogenic
bacteria and the prevalent strains found in burns wards.
4.1.1.3 Pathogenesis of Common Pathogens
in Burn Infection Centers and Their
Clinical Signifi cance
Burn infection is a kind of nosocomial infection and its
pathogen is usually opportunistic bacteria that might be
inconsistently sensitive to antibiotics, some of which might
be naturally resistant strains. Under antibiotic pressure, it is
not rare to have resistant, multi-resistant or even pan- resistant
strains of bacteria in burns wards. Shortly after the patient is
admitted to hospital, his or her original normal fl ora is inevi-
tably replaced by those drug-resistant strains.
Burn wounds could be contaminated not only by exoge-
nous bacteria living in the surrounding environment, but also
by endogenous bacteria inhabiting in our bodies. In addition
to bacterial infection, it is also possible to have fungal or viral
infections. However, no reports of burn patients suffering spe-
cifi c infections, such as toxoplasmosis, Pneumocystis carinii ,
infections that are common among immune defi cient patients.
Staphylococcus aureus
Staphylococcus aureus is widely distributed in our environ-
ment. Its resistance to the external environment is strongest
among spore-forming bacteria and it can survive in dry con-
ditions. Staphylococcus aureus attaches to dust particles
and desquamated epithelia so that hygienic cleansing, bed
sorting, and dressing changes initiate its airborne spread. It
is ubiquitous in the environment and is one kind of normal
fl ora living inside of the body. It is very common to be a
Staphylococcus aureus carrier in the population and the most
common colonizing sites are the nasal vestibule mucosa
and skin surface. Hospital staff who carry the bacteria may
4 Infection in Burns

65
mediate cross-infections; for that reason, it is mandatory to
wash hands after contact with patients.
Staphylococcus aureus is one of the bacteria that primarily
colonize on a burn wound. Among those patients who are
admitted and suffer minor or moderate burns, or those who
are treated in outpatient clinics, Staphylococcus aureus is
predominant in the early stages post-burn, whereas exten-
sively burned patients easily develop Staphylococcus aureus
infection in the later stages post-burn. It always occupies the
fi rst place in the list of bacteria identifi ed on burn wounds or
ranks second only to Pseudomonas aeruginosa .
Coagulase-positive Staphylococcus aureus , not neces-
sarily to be gold in appearance of the colony, produces
numbers of exotoxins and extracellular enzymes so that
its pathogenicity is strong. The exotoxins include cytolytic
toxin, leukotoxin, enterotoxin, epidermolytic toxin, toxic
shock toxin I (toxic shock syndrome toxin, TSST-1), and
rash toxin. Among those toxins, enterotoxin and TSST-1
show the characteristics of superantigen, which carries a
strong potential to stimulate the antigens, for example, with
the concentration of 1–10 ng/ml it can activate a large num-
ber of T cells to produce cytokines, such as TNF-ɑ, inter-
feron (IFNγ), etc. Fifty percent of strains of Staphylococcus
aureus , which causes clinical infection, produce enterotoxin
and/or TSST-1 and the most common types of enterotoxin
are types B and C. TSST-1 is not lethal, but it signifi cantly
increases hosts’ sensitivity to the attack induced by endo-
toxins. Enterotoxin generating lethal synergy to activate a
large number of T lymphocytes to induce IFNγ production,
upregulate the expression of proinfl ammatory cytokines, and
other infl ammatory mediators such as TNF-ɑ and nitric mon-
oxide (NO). The activation of broadly distributed intestinal
T lymphocytes engenders enterotoxin, which plays a prob-
ably important role in mediating intestine mucosal injury,
including intestinal barrier impairment, increased intestinal
permeability, and causes intestinal endotoxin translocation.
Moreover, enterotoxin bears signifi cant hepatotoxicity [ 16 ].
Extracellular enzymes include coagulase, lipase, hyaluroni-
dase, and heat-resistant nuclease. Cell wall components of
Staphylococcus aureus , peptidoglycan and teichoic acid, are
also important pathogenic factors. They can induce mono-
phagocytes to synthesize and release amounts of TNF-ɑ,
IL-1 (interleukin-IL), NO, and other pro-infl ammatory fac-
tors and infl ammatory mediators. The ability of peptido-
glycan and teichoic acid in deducing human monocytes to
release IL-1 is 100 times and 10,000 times that of endotoxin
respectively. A-protein produced by Staphylococcus aureus
could combine with the IgG Fc segment to compete with
phagocytes to show its antiphagocytosis.
Patients infected with Staphylococcus aureus may
develop scarletinoid rashes, or be complicated with scalding
skin syndrome and toxic shock syndrome. Although it is rare
to develop toxic shock syndrome in burns patients when they
suffer Staphylococcus aureus infection, there have been case
reports documented in the medical journals. Severe wound
infection caused by Staphylococcus aureus can lead to fail-
ure of the skin graft.
Staphylococcus aureus can be classifi ed into two types of
strains according to its capability of producing penicillinase,
an enzyme-producing strain and a non-enzyme producing
strain. Penicillinase can hydrolyze penicillin G, ampicillin,
carbenicillin, and ureidopenicillins; thus, S. aureus is resis-
tant to these antibiotics. This is a plasmid-mediated mecha-
nism that induces the drug resistance of bacteria and 90 % of
the strains isolated from the patients belong to this enzyme-
positive category. MRSA strain was fi rst identifi ed in 1961.
It should be cultivated at 30 °C on the plates with a pH value
of around 7.0 and contains 5 % sodium chloride. MRSA
drug resistance is chromosome-mediated, which produces a
mutant penicillin-binding protein 2a (PBP2a), a variation of
PBP2. MRSA is also resistant to oxacillin and cephalospo-
rins, but sensitive to vancomycin, vancomycin demethyl-
ation, and teicoplanin. The proportion of enterotoxin
produced by MRSA is signifi cantly higher than that of
methicillin- sensitive Staphylococcus aureus (MSSA). Up to
now, MRSA has been one of the important pathogens, and
can give rise to nosocomial infection.
Staphylococcus epidermidis
Staphylococcus epidermidis is the normal fl ora of the human
body, colonizing on skin and mucous membrane. It is coagu-
lase negative and does not produce ɑ-hemolysin or A pro-
tein, but only δ-toxin instead. In recent years, scientists have
found that coagulase-negative bacteria, for instance,
Staphylococcus epidermidis , can produce extracellular adhe-
sives that tightly bind to the cell surface to form a biofi lm and
are capable of antiphagocytosis, cell-mediated immunity
suppression, and prevention of antibiotics penetration.
Biofi lm is a crucial factor that determines the pathogenicity
of the bacteria and its formation is related to the tendency of
the bacteria to adhere to some materials, such as plastics. In
addition, this adhesive substance prevents vancomycin and
teicoplanin from penetrating the cell wall so as to greatly
reduce the antibacterial activity of antibiotics. We used to
consider Staphylococcus epidermidis to be the contaminated
microbe; however, at present its pathogenicity inevitably
catches our attention. Staphylococcus epidermidis has
already been one of the most important pathogens of nosoco-
mial infections, traumatic infections, catheter-related infec-
tions, and infections caused by artifi cial prosthesis for the
wide application of broad spectrum antibiotics and invasive
medical apparatus. Severe burns provide a seriously diseased
backdrop, which coincides with immune disturbance; for
that reason, there is the potential to develop Staphylococcus
epidermidis -induced sepsis. Its identifi cation rate is showing
an upward tendency in burns wards; thus, it should not be
4.1 Burn Wound Sepsis

66
considered a contaminating microbe if we identify
Staphylococcus epidermidis on burn wounds.
The
clinical
manifestations
of
Staphylococcus
epidermidis - induced sepsis are similar to those of sepsis
induced by Staphylococcus aureus . Most Staphylococcus
epidermidis strains are enzyme-producing and methicillin-
resistant Staphylococcus epidermidis (MRSE) strains consti-
tute about 76 % of the total [ 17 ]. It is mandatory to test the
sensitivity of these detected strains to antibiotics.
Streptococcus pyogenes
Streptococcus pyogenes has a wide distribution. The naso-
pharynx and skin of healthy people can carry bacteria.
Streptococcus pyogenes shows a beta-hemolytic reaction on
the blood plate; thus, in the past it was named beta-hemolytic
streptococcus. Now, it is categorized as Streptococcus pyo-
genes
according
to
the
biochemical
classifi cation.
Considering the polysaccharide antigens of streptococcus, it
can be divided into 18 subtypes A, B, C, D, E, F, G, H, K, L,
M, N, P, O, Q, R, S, and T, and Streptococcus pyogenes refers
to the A subtype. Spreading from patients’ own laryngophar-
ynx to the wounds, it is the major pathway of Streptococcus
pyogenes infections. Another pathway is the cross-infection
among patients mediated by hospital staff.
Streptococcus pyogenes produces roseola toxin, hemoly-
sin, hyaluronidase, streptokinase, etc., which relate to its
pathogenicity to cause scarletinoid rashes on patients’ skin
and has a strong capability to invade tissue, disseminate
among tissue prone to inducing cellulitis or along lymphatic
vessels to initiate erysipelas.
M-protein on the cell wall of Streptococcus pyogenes has
the capability for antiphagocytosis; however, as it is defi cient
in catalase and cannot neutralize or inhibit lysosomal enzymes,
it can be killed rapidly once it is phagocytosed by neutrophils.
Burn wounds infected by Streptococcus pyogenes may
show the manifestations of surgical scarlet fever, with a
broad and remarkable infl ammatory infi ltration boundary
and excretion of thin pus. While infecting the donor sites or
burn wounds with grafts, Streptococcus pyogenes may not
induce an intense systemic response, but the grafts on those
burn sites slough off, followed by the skin graft failure.
When the donor site becomes infected, it may change from a
superfi cial wound into a deep one, or even a wound with full-
thickness skin loss. Streptococcus pyogenes is capable of
invading healthy granulation tissue. Scar skin of the lower
extremities formed after deep burns is prone to developing
erysipelas owing to the repetitive infection induced by this
microorganism.
Most Streptococcus pyogenes infections occur within a
week after the burn injury; this is the reason why the special-
ists prescribe penicillin G to the patients in the early stages
post-burn. While the wound swabs or throat swabs detect
Streptococcus pyogenes , it is necessary to administer penicil-
lin G systemically until it tests negative. For patients who
have had it detected recently, prophylactic systemic penicil-
lin G administration is also advised before and after the
grafting operation.
The best way to prevent Streptococcus pyogenes infection
is the microbiological surveillance of bacteria in burns
patients according to the results of periodic throat and wound
swabs cultures of admitted patients (at the time of admission,
periodic collection during the patients’ stay in the burns
ward).
Up to now, penicillin G has been the fi rst choice for
Streptococcal pyogenes infections, while the resistance rates
of erythromycin and clindamycin reach 78.6 % and 73.8 %
respectively [ 18 ]. Streptococcus pyogenes is naturally resis-
tant to antibiotics of the aminoglycoside class.
Genus Enterococcus
This microbe used to be classifi ed as D-type streptococcus.
In 1986, it was categorized as an independent genus,
Enterococcus , according to its biological characteristics.
Enterococcus belongs to the optional anaerobic bacteria and
is widely distributed in nature. It has a strong capability to
adapt to the environment and survive for several weeks.
Enterococcus can grow in the environment with temperature
10–45 °C and bears a super sound, the acids and alkali. The
sodium azide and concentrated cholates cannot kill entero-
coccus. The microbe is part of the normal fl ora that resides in
the intestinal tract, or it may colonize in the skin, upper respi-
ratory tract, and urogenital tract. Among 20 % of the healthy
population, there is the chance to isolate enterococcus from
the oral cavity and the vagina; thus, it is an opportunistic
pathogen. The main pathway of the nosocomial infection
caused by enterococcus is the hands of staff or the medical
instruments. Multiresistant enterococcus that co-habits in a
patient’s intestinal tract could be the origin of the infection.
Among the enterococcus species that could be identifi ed,
E. faecalis and E. facecium are the most common types.
Enterococcus is the common pathogen that induces trau-
matic infections, the most common infection only after uri-
nary infection. In humans, the infection caused by E. faecalis
constitutes about 60 % of enterococcal infections; E. faecium
constitutes about 30 %, and other enterococcus species con-
stitute about 10 %. The main enterococcus species identifi ed
on burn wounds is E. faecalis. E. faecalis colonized in the
intestinal tract can translocate to other sites to induce infec-
tions under some circumstances. When anaerobes and other
aerobes in the intestinal tract are inhibited, infections caused
by E. faecalis might be enterogenous. The Enterococcus
genus bears the character of inherent and acquired multire-
sistance. The percentage of nosocomial infections caused by
vancomycin-resistant enterococcus (VRE) strains has gradu-
ally increased over the years. Among such VRE strains, E.
faecium strains are more common than E. faecalis . The ceph-
alosporin widely used in burns wards is responsible for the
escalating tendency in its isolate identifi cation rate.
4 Infection in Burns

67
Pseudomonas aeruginosa
The bacterium that belongs to the nonzymophorous type and
it is a representative of the genus Pseudomonas . Also widely
distributed in nature, it colonizes in soil, air, polluted water,
on skin, and in the open tracts of the human body, such as the
intestinal tract and respiratory tract. It is seldom identifi ed at
home, but is easy detected in hospitals; thus, Pseudomonas
aeruginosa is an important pathogen that induces nosoco-
mial infections. Pseudomonas aeruginosa is easy to repro-
duce in a humid environment and survives for a long time.
Open wounds that are moist are optimal for its growth, but it
also shows a high resistance to a dry environment.
Pseudomonas aeruginosa is the opportunistic pathogen
colonized in the human body with low pathogenicity and
maintains the balance with other bacteria on the site. Its
pathogenicity is mainly determined by the host’s immune
status and internal bacterial ecological balance. Pseudomonas
aeruginosa becomes a very important pathogen for immune-
impaired patients, such as those suffering burns, receiving
organ transplantation, with acute leukemia, and with can-
cers. It could induce self-infection or be transmitted among
burn patients by cross-infection. Pseudomonas aeruginosa is
the main pathogen that causes burn infection and the mortal-
ity from the infection induced by this bacterium is higher
than that of Staphylococcus aureus .
Pseudomonas aeruginosa produces two kinds of pig-
ments, pyocyanin and pyoxanthine. Pyocyanin, the specifi c
green pigments produced by Pseudomonas aeruginosa , has
the capability to kill bacteria that have corresponding recep-
tors. However, for the wide usage of antibiotics, mutant
strains have lost their ability to synthesize pyocyanin, so that
wounds infected by Pseudomonas aeruginosa cannot be
green. Pyoxanthine, also named as pyoxanthine fl uorescent,
shows the color of yellow–green or yellow–brown, is
fl uorescent.
Besides endotoxin, Pseudomonas aeruginosa produces
several substances relating to its toxicity, for example, exo-
toxin- A, proteolytic enzyme, hemolysin, leukocidin, and
extracellular enzyme-S. The toxicity of exotoxin-A produced
by Pseudomonas aeruginosa is tens of thousands times
higher than that of endotoxin. Extracellular enzyme-S is the
crucial pathogenic factor required for the bacterium to infect
human beings. Thus, the mortality of the infections induced
by strains producing both exotoxin A and extracellular
enzyme-S is signifi cantly higher than that of the strains that
produce exotoxin A or extracellular enzyme-S only [ 19 ]. The
burn infection model (mice) also confi rms that infections
induced by extracellular-enzyme-positive strains are more
severe than those induced by those extracellular-enzyme-
negative strains [ 20 ]. The toxicity of mutant strains that are
extracellular-enzyme-negative is 2,000 times lower, the
bacterial capability to disseminate to other organs is also sig-
nifi cantly reduced with a bacteria count 102–101 less than
that of the original strain [ 21 ]. The antibody of extracellular
enzyme-S can prevent enzyme-positive strains from
disseminating.
Pseudomonas aeruginosa is multi-resistant. The mecha-
nism of its resistance is extremely complicated, and includes
outer membranous porin-D2 defi ciency, enhanced function of
active drug effl ux pumps, production of several β-lactamases
(broad spectrum enzymes, plasmid-mediated Amp-C
enzymes and carbapenem enzymes), aminoglycoside-
modifying enzyme, changing of target sites, and biofi lm for-
mation. Usually, it is the combined effect of several
mechanisms that causes the multidrug resistance of the strains.
Up to now, we have isolated pan-drug-resistant strains from
burns patients.
Enterobacteriaceae
A class of spore-forming Gram-negative bacilli with similar
biological characteristics, Enterobacteriaceae is the subtype
of enterobacillus, which is the opportunistic pathogen that
inhabits the intestinal tract and could also be identifi ed from
various places. Enterobacteriaceae, the main source of auto-
infection, induce burn wound infection often originating
from autogenous colonies of patients, the main source of
autoinfection.
The
fact
that
dominant
strains
of
Enterobacteriaceae isolated from patients in burn wards dur-
ing certain periods can switch from one to another suggests
that it might also be originating cross-infection. In recent
years, the identifi cation rate of Pseudomonas aeruginosa
identifi ed from burn wounds has tended to decrease, while
that of Enterobacteriaceae has increased.
The cell wall structure of Enterobacteriaceae is closely
related to its pathogenicity. The outer membrane of the cell
wall contains endotoxin, the lipopolysaccharide that is com-
posed of polysaccharide and lipid A. Polysaccharide can be
further divided into O-specifi c polysaccharide side chain and
core oligosaccharide. Lipid-A is the active part of endotoxin,
which combines with endotoxin-specifi c polysaccharide
chain (O antigen) through 2-keto-3deoxy-D-mannooctulose
acid. O-specifi c polysaccharide enables bacteria to resist
phagocytosis and the lytic effects of complements. In addi-
tion to endotoxin, the bacteria also produce exotoxin with
pathogenicity and invasiveness.
There is a wide range of Enterobacteriaceae, and the vari-
ety is unceasingly increasing and the categories are also
being changed. At present, it is classifi ed as Genera
Escherichia, Shigella, Salmonella, Citrobacter, Klebsiella,
Enterobacter, Owen, Serratia, Hafnia, Edwardsiella,
Proteus, Providencia, Morganella , Yersinia . The common
Enterobacteriaceae identifi ed from burn wounds are
Klebsiella and Enterobacter .
4.1.1.4 Klebsiella pneumoniae
The microbe that belongs to the genus Klebsiella , exists in
water and soil and in the intestinal and upper respiratory
tracts in the normal fl ora. It could be isolated from the
4.1 Burn Wound Sepsis

68
respiratory tracts and feces of 5–10 % of the healthy popu-
lation, and serves as the main pathogen of nosocomial
infections. One of the consequences induced by the wide
usage of topical antibacterial agents, such as sulfamylon
and silver sulfadiazine, for burn wounds is the increasing
identifi cation rate of Klebsiella pneumoniae , while its iso-
lation from burn wounds was rare before such treatment. In
1983, strains producing SHV-2 were identifi ed from the
patients. Today, strains that produce extended-spectrum
β-lactamases (ESBLs) account for 32 % [ 22 , 23 ], and such
strains reaches 84 % among those Klebsiella Pneumonia
isolated from burn wards [ 24 ]. Its resistance to third-gener-
ation cephalosporins is attributed to these plasmid-medi-
ated ESBLs.
4.1.1.5 Enterobacter
Enterobacter are saprophytic bacteria existing in water, soil,
the human respiratory tract, and the intestinal tract and serves
as the normal fl ora or the opportunistic pathogen in the
human body. Enterobacter contains 11 subtypes, among
which E. aerogenes , E. cloacae , E. sakszakii , and E. agglom-
erans could be identifi ed from specimens isolated from
patients. E. sakszakii are similar to E. cloacae except for
their ability to produce yellow pigment. Enterobacter agglo-
merans are rare in specimens collected from patients.
Until the early 1980s, E. cloacae had not been identifi ed
from burn wounds and E. aerogenes was not yet the main
strain in burn wounds. However, the identifi cation rate of E.
aerogenes or E. cloacae from burn wounds has climbed to
the fi rst rank in Enterobacteriaceae at present.
Enterobacter cloacae are the typical bacteria that produce
chromosome-mediated AmpC enzymes. For the selective
pressure induced by antibiotics, the identifi cation rate of E.
cloacae from burn wounds and biopsies of subeschar tissue
has reached 3–4 % since the mid-1980s and has increased in
recent years. The epidemic of E. cloacae with AmpC genes
in burn wards might be responsible for the resistance of
Gram-negative bacilli to third-generation cephalosporins.
4.1.1.6 Proteus
The bacteria that are identifi ed from burn wounds are indole-
positive Proteus vulgaris and indole-negative Proteus mira-
bilis . They are widely distributed in nature and serve as
important opportunistic pathogens. Usually, Proteus mirabi-
lis is sensitive to antibiotics but resists polymyxin, while
Proteus vulgaris is multi-resistant. The main strains of
Proteus that are identifi ed from burn wounds are Proteus
mirabilis .
In the former category, indole-positive Proteus morgani
and Proteus rettgeri were also included; nevertheless,
Proteus morgani is classifi ed as an independent genus,
Morganella ; and Proteus rettgeri is included in Providencia ,
named Providencia rettgeri .
4.1.1.7 Providencia
This bacteria used to be included in the Proteus genus,
named Proteus inconstans , but now it is classifi ed as an inde-
pendent genus. Although the bacteria of this genus show sev-
eral characteristics that are similar to those of Proteus , they
bear no “swarming” pattern on the agar surface, which is
different from Proteus . Furthermore, they are indole-positive
bacteria and can be classifi ed as four species, Providencia
rettgeri , Providencia alcalifaciens , Providencia stuartii , and
Providencia rustigianii , all of which are multidrug-resistant
and can cause infections with extremely high mortality.
Topical application of Sulfamylon on burn wounds induces
ecological environment change to those colonized bacteria
so that the identifi cation rate of Providencia increases.
Isolation of such bacteria indicates cross-infections exist
among burn patients.
Providencia stuartii and Providencia alcalifaciens are
urease-negative, the crucial characteristic that differentiates
them from Proteus , Providencia rettgeri , and Morganella .
4.1.1.8 Acinetobacter
A group of Gram-negative bacteria that belongs to the
Neisseria family, bear the features of being capsule, nonmo-
tile, strictly aerobic, nonfermentative, and pair-arranging.
They look very much like Neisseria , but have the character-
istics of polymorphism, the phenomena of being rod-like
during a fast-growing phase and coccus-like in a stable
period. They can be sub-divided into Acinetobacter bauman-
nii , Acinetobacter calcoaceticus , Acinetobacter lwoffi i ,
Acinetobacter haemolyticus , etc. Being oxidase-negative
and nitrate-negative, Acinetobacter can be distinguished
from bacteria of Neisseria and Enterobacter respectively.
Acinetobacter baumannii is the most common species in this
genus.
These bacteria are also widely distributed in nature, exist-
ing in water and soil and suited to a humid environment, such
as a humidifi er, washbasin, tub, and so on. For humans,
Acinetobacter constitute the group of normal fl ora coloniz-
ing skin, mucosa, at the nasopharynx, in the respiratory tract,
intestinal tract, urogenital tract, etc., with low pathogenicity,
and serve as opportunistic pathogen. Not long after the set-
ting up of burns wards in Ruijin Hospital, Shanghai in 1958
Acinetobacter were identifi ed from the wounds, named
nitrate-negative bacilli. For a long period of time, the identi-
fi cation rate of Acinetobacter did not increase signifi cantly,
remaining within the range 2–3 %. However, they have
shown their power to be the prominent bacteria, increasing
rapidly. Some burns centers reported it climbing up into the
top three on the list.
Contaminated medical equipment and the hands of hospi-
tal staff are signifi cant carriers of nosocomial infections.
Acinetobacter are multidrug-resistant or pan-drug-resistant,
while carbapenem antibiotics might be the most effective,
4 Infection in Burns

69
but Acinetobacter baumannii can produce OXA-23 car-
bapenemase. In recent years, the number of carbapenem-
resistant strains that are isolated from the patients has
increase. Acinetobacter are quite sensitive to sulbactam.
4.1.1.9 Stenotrophomonas maltophilia
Initially named Pseudomonas maltophilia and grouped
under the genus Xanthomonas in 1983, named Xanthomonas
maltophilia , Stenotrophomonas maltophilia cannot produce
the typical yellow pigment and can only use a narrow spec-
trum of substrates. For these reasons, they were renamed and
classifi ed as the subtype of the genus Stenotrophomonas in
1993.
Stenotrophomonas maltophilia are exclusive aerobic, fer-
mentative Gram-negative bacilli. Widely distributed in water,
soil, and plant roots, they can also be isolated from the human
body and animals. They are opportunistic pathogens and
induce nosocomial infections. Strains identifi ed from respi-
ratory tracts are most commonly temporary colonizing bac-
teria. This type of bacteria is capable of producing elastase,
lipase, mucopolysaccharidase, hyaluronidase, DNase, and
hemolysin.
Stenotrophomonas maltophilia are multidrug-resistant,
and the low permeability of the outer membrane is one of the
mechanisms that are responsible for their inherent resistance
to a broad spectrum of antibiotics [ 25 ], including β-lactamase,
quinolones, and aminoglycosides. The bacteria can produce
at least chromosome-encoded metallo-β-lactamase (Bush 3)
and serine-β-lactamase (Bush 2f), which can be induced by
one kind of β-lactam antibiotics at the same time and increase
the amount hundreds of times. Carbapenems are not effec-
tive in controlling S. maltophilia infections, but it is most
easy to induce β-lactamase; thus, it is prone to causing super-
infection of the bacteria during the treatment. There had
been no reports of identifying S. maltophilia from burn
wounds before the 1990s, but there were cases to isolate such
bacteria resulting from the frequent usage of imipenem in
burn wards. It is not appropriate to choose carbapenems to
treat the infections if S. maltophilia is highly suspected
clinically.
There are two pathways of burn infection: one is auto-
infection, the other is cross-infection. Pathogens of auto-
infection mainly colonize on patients’ skin, in hair follicles,
sweat glands, oral cavity, throat, respiratory tract, intestinal
tract, and around the anus; pathogens of cross-infection
mainly come from infected burn wounds. Bacteria present in
the local environment may contaminate the burn wound
through direct contact. Common sources are contaminated
dressings, medical instruments, necessary items and air,
contaminated hands of staffs, overalls, medical masks and
caps, etc. An open burn wound serves as the main reservoir
of bacteria, contaminating and colonizing bacteria on burn
wounds transferred from one patient to another through the
air, medical instruments, and the hands of medical personnel
to cause cross-infection and initiate the spread of drug-resis-
tant strains. Cleaning of wards, dressing changes, frequent
ward –access, and lack of appropriate room ventilation are
the main reasons for indoor air pollution; the most serious
scenario is the time of dressing changes. Those dressings,
clothing, mattresses, necessary items, and medical instru-
ments have a high carrier rate, and usually carry the popular
drug- resistant strains in the wards. The hands of members of
staff are the major carriers for cross-infection; according to a
sample survey carried out by the researchers of the burns
center, Ruijin Hospital, in the 1980s, the carrier rate was up
to 85 % and 50 % for the anterior part of overalls.
In order to prevent auto-infection, normal skin hygiene,
dirt cleaning, shaving, trimming of nails should be done
when the patient is fi rst admitted; during hospitalization,
patients suffering facial burns need nursing for eyes, nose,
ears, and the oral cavity. For those who have burns on the
buttocks and perineal area, they need a disinfected toilet and
normal saline washing every time.
To avoid cross-infection, the key point is to implement a
terminal disinfection system of the wards, and to establish a
practical system for disinfection and isolation. A terminal
disinfection system is the procedure that is carried out to
sterilize the air, all necessary items in the room to reach the
sterilization standard, and it should be administered after the
patient’s death, discharge, transfer to other departments, or
room re-arrangement. The key point of disinfection and iso-
lation is to prevent cross-infection mediated by the hands of
members of staff or that happens during dressing changes.
Hand-washing is mandatory before or after staff contact with
patients, or after contact with contaminated apparatus. All
staff should be required to wear a disposable gown, mask,
and medical cap before entering the patient’s room.
Moreover, every patient’s room should have its dedicated
medical supply system and those medical supplies and
equipment need effective sterilization.
In burns centers, admitting severely burned patients into
the laminar fl ow rooms, which provide positive ventilation,
can help to decrease patients’ infection rate and prevent the
cross-infection of drug-resistant strains.
4.1.2
Antibiotics Treatment for Burns
4.1.2.1 Concept of “Prophylactic Treatment”
The types and total amounts of antibiotics that are prescribed
in the burns department always remain at the top of the sta-
tistical list in the hospital’s administrative database as the
burns ward suffers most with the problem of drug-resistance
strains. Under selective pressure, bacteria obtain drug resis-
tance to the novel antibiotics at an earlier time, with rapid
development and greater severity. So that the model of drug
4.1 Burn Wound Sepsis

70
resistance of the bacteria identifi ed from the burns ward
always indicates those drug resistance patterns of other
departments in the near future, the severity of bacterial drug
resistance presses burns surgeons to switch to new antibiot-
ics: semi-synthesized penicillin, the third or the fourth gen-
eration of cephalosporins, carbapenems, β-lactamase
inhibitor compound, vancomycin, norvancomycin, etc., were
usually fi rst used clinically in burns departments. Under such
circumstances, the third generation of cephalosporins were
widely used in some burns centers in the 1980s, with ceftazi-
dime mostly the fi rst choice to be prescribed. As a result, it
was
not
uncommon
to
identify
third-generation
cephalosporin- resistant bacteria in burns centers in the mid-
1990s [ 26 ]; thus, imipenem was always the fi rst-choice anti-
biotic. Selective pressure induced by the wide use of
third-generation cephalosporins is not only related to the
production of ESBLs, but also enhanced MRSA strains,
which constituted 80 % of the Staphylococcus aureus identi-
fi ed from burns centers. Furthermore, the induction of genes
that encoded β-lactamase transformed from the induced type
to the stable depressive constructive type (cephalosporinase
containing a mutant strain), and that of the persistent produc-
tive chromosomal type-I β-lactamase (Amp-C enzymes),
such as super-resistant Enterobacter cloacae , are related to
Amp-C enzymes. The wide use of carbapenems, such as imi-
penem, detected Stenotrophomonas maltophilia , while it had
never been detected from burn wounds [ 27 ]. The usage of
β-lactamase compound caused the development of the 2br-
type β-lactamase strain, which is resistant to those enzyme
inhibitors; thus, cefoperazone/sulbactam resistance of the
bacteria identifi ed from burns wards increased signifi cantly
[ 13 ]. Apparently these are the necessary results that can be
attributed to unlimited use of antibiotics to control severe
infection in burns patients. Another consequence is the mali-
cious cycle between resistance of the bacteria and applica-
tion of antibiotics with the results of multiresistant
Gram-negative bacilli and MRSA becoming the main patho-
gens of burn infections, and the diffi culty in choosing opti-
mal antibiotics for sepsis treatment. In conclusion, how to
decrease the bacterial resistance and postpone its appearance
must be considered in burns treatment. The key points to
alleviate the selective pressure include minimizing the total
amount of antibiotics used in the burns ward, reducing the
number of days of systemic antibiotic treatment, and avoid-
ing prescribing one type of antibiotics for a certain amount
of time. Therefore, it is necessary for us to discuss the indica-
tion for systemic antibiotic treatment for severe burns in
addition to the treatment for sepsis and the complications of
infections.
Being a nosocomial infection, burn infection is caused by
opportunistic pathogens that show incongruity in antibiotic
sensitivity, including some naturally resistant strains. Under
the selective pressure in burns wards, there often exist
resistant or even multiresistant strains, and now there are
pan- resistant bacteria. Not long after patients’ admission,
their normal fl oras are quickly replaced by resistant strains.
Burn wounds are open wounds that become contaminated
or colonized by bacteria so easily. The local environment is
good for the proliferation of the bacteria colonizing the site,
which leads to the rapid increase of bacteria in a short period
of time. Moreover, the immune system is disturbed after
severe burns. All these factors promote the possibility of
local infection developing into sepsis. According to the data-
base of 26 burn centers collected from 1993 to 1998, the
incidence of systemic infection was 17.73 % among the
patients whose burn surface area was more than 50 % of the
TBSA, while it jumped to 39.96 % among those who also
had third- degree burns in this group [ 28 ]. Hence, it is not
diffi cult to make a deduction that patients with more than
50 % of the body surface area burned or the those suffering
third-degree burns on more than 30 % of the body surface
area are at a high risk of developing sepsis. The administra-
tion of prophylactic antibiotics is aimed at preventing local
infection from developing into sepsis. As local infection is
inevitable, we should not consider the indication for admin-
istering antibiotic therapy in burns treatment as “preventive
usage,” but “prophylactic treatment.” The results of a multi-
center clinical trial concerning prophylactic treatment by
using piperacillin/tazobactam [ 29 ] showed that: 47 burn
cases with TBSA of 57.0 ± 20.17 %, in which 46 cases had
third-degree burns. Among these 46 cases, there were 27
patients with TBSA of more than 50 %, 43 with third-degree
burns that exceeded 30 % of the TBSA and an average of
43.1 ± 20.1 %. It showed that 45 patients (95.7 %) with local
infection did not develop wound sepsis. The incidence of
sepsis was 7.40 % in the group of 27 patients suffering burns
of more than 50 % of the TBSA. The result suggested that
prophylactic antibiotic treatment, aimed at dominant bacte-
ria related to burn wound infection, might reduce the inci-
dence of burn sepsis occurring in the early stages post-burn.
Another key point regarding the rational usage of antibiotics
for burn patients is the timing of its application. As we know,
there is a process for local infection to develop into burn
sepsis and the potential risk of sepsis starts to exist when
such an infection reaches a certain degree. Clinically, early-
stage sepsis usually occurs at around a week post-burn
because of patients’ early admission with optimal fl uid
resuscitation and topical use of effective antibiotics such as
1 % SD-Ag cream. On the 4th day post-burn, the quantitative
counts of subeschar bacteria have not reached the threshold
of 10 5 /g. It is usually on the 4th day post-burn that systemic
administration of antibiotics is initiated to prevent local
infection from developing into sepsis. Moreover, at that time
when the interstitial fl uid starts to be reabsorbed, necrotic
tissue should be debrided by surgery. Thus, the prophylactic
treatment and perioperative usage of antibiotics can be com-
bined. In any case, early excision of the necrotic tissue and
effective wound closure are fundamental treatments for
4 Infection in Burns

71
preventing sepsis. We recommend removing most or all of
the necrotic tissue according to the area of deep burns during
the fi rst surgery so as to close the wound effectively and
eliminate the potential risk of sepsis. In this way, antibiotics
could be disabled on the second or third day post-operation
so that the total course of prophylactic treatment can be lim-
ited to 5–7 days to reduce the selective pressure of the anti-
biotic agent applied in burn wards, to postpone the appearance
of drug-resistant strains, and to decrease their proportion.
For those patients with an eventful clinical course of shock
or early eschar excision within 24–48 h post-burn, there is no
doubt about applying systemic antibiotics within 24 h or
48 h.
Other indications for prophylactic antibiotic treatment
are: perioperative use of penicillin-G for patients who receive
skin grafting to prevent Streptococcus pyogenes infection;
patients suffering deep burns and electric burn injuries that
result in a great deal of muscle necrosis to prevent anaerobic
infection; eschar separation stage or later stage with a larger
area of exposed granulation tissue; circumstances that induce
a variety of severe complications with impaired anti-
infectious ability. Prophylactic antibiotic treatment for sys-
temic infection developed from bacterial translocation is a
project that still needs to be studied. We need to know the
potential risk of sepsis that happens in severe burns patients
who are suffi ciently resuscitated during the hypovolemic
stage but develop systemic infection because of intestinal
bacterial translocation at the time of 24–48 h post-burn;
common pathogens relating to gut-originating infection and
the resistance of bacteria, so as to ensure whether there is an
indication to apply prophylactic antibiotic treatment, the
kind of antibiotics to be prescribed, and what the optimal
dosage and course of the treatment are.
On the other hand, although potential risk of developing
sepsis when severely burned patients have most of their
wounds re-covered, it is impossible for the white blood cell
(WBC) count and body temperature to return to normal.
Even if the open wounds are treated with effective topical
agents, it is not rare to have positive results of the bacterial
culture. Therefore, high temperature, elevation of WBC
count, and a positive wound culture are not indications for
systemic antibiotics if the patients have no clinical manifes-
tation of burn sepsis.
Optimization of Antibiotic Therapy
The purpose of the optimization of antibiotic therapy is to
eliminate pathogens (bacteria), to control the infection,
reduce drug-resistant strains, and to minimize adverse
reactions. Therefore, burns surgeons should optimize antibi-
otic treatment in accordance with the pharmacokinetics (PK)
and pharmacodynamics (PD) principles in order to ensure
that there is suffi cient concentration of optimal antibiotics at
the site of infection, enough time for it to clear those patho-
gens and concurrently prevent bacteria from being exposed
to low minimum inhibitory concentration (MIC) levels,
thereby reducing the drug-resistant strains.
Antibiotics selected for prophylactic treatment should be
those whose spectrum covers prevalent strains found in
burns wards and their sensitivity to antibiotics. The treat-
ment for sepsis should follow the principles of antibiotic
application, and every effort should be made to ensure
microbial diagnosis and sensitivity of the bacteria. Usually,
bacteria identifi ed as pathogens of invasive infection are in
accordance with those found on infected wounds; however,
the wound surface culture is far less reliable than that of sub-
eschar tissue culture. For sepsis induced by factors other
than wound infection or other septic complications, their
pathogens are usually the same as those isolated from burn
wounds.
When the results of wound culture and bacterial sensitiv-
ity still remain unknown, burns surgeons should follow the
principles of empiric use of antibiotics. During the early
stages post-burn, the incidence of Gram-negative bacilli
infection is much higher than that of Staphylococcus aureus
infection; thus, we should choose antibiotics whose spec-
trum covers Gram-negative bacilli, including Pseudomonas
aeruginosa , and those with the lowest resistant rate. With a
background of a resistance rate of more than 20–30 % among
the third-generation cephalosporins, carbapenem could be
the fi rst choice followed by the fourth-generation cephalo-
sporins. At a time of pan-drug-resistant strains being preva-
lent in wards, polymyxin B is preferred. During a time when
MRSA and MRSE rates reach 70–80 %, the preferred treat-
ment for both staphylococcal infection and enterococcal
infection is vancomycin or linezolid.
When the antibiotic can just kill those sensitive strains, it
is very likely to select drug-resistant strains. While it was
able to not only kill sensitive bacteria but those resistant
strains as well, such a medication is able to prevent bacterial
resistance caused by microbial mutation. Under these cir-
cumstances, the concentration of the antibiotics is named the
mutant prevention concentration (MPC). The variation of
concentration levels between MPC and MIC is called the
mutant selection window (MSW), where it is easy to induce
drug resistance of the strains. Therefore, the key point of
antibiotic treatment is to ensure the drug concentration to
achieve MPC so as to prevent it from falling into the MSW
and inducing resistant strains.
According to their characteristics of antibacterial activ-
ity, antibiotics can be divided into two classes, time-depen-
dent and concentration-dependent. β-lactam antibiotics
belong to the time-dependent type, which means a time of
blood concentration exceeding the MIC level (T>MIC) is
the main parameter of predicting the effi cacy of the medica-
tion. Usually, free serum concentration should be main-
tained over MIC for at least 40–50 % of the dosing interval,
that is, %T>MIC is 40–50 %. For that reason, multiple
intravenous guttae of the antibiotics would be the better
4.1 Burn Wound Sepsis

72
choice to maximize its T>MIC. For severe burns patients,
we should also consider increasing %T>MIC when
providing a dosage regimen because of the patients’ immune
suppression. However, aminoglycoside antibiotics are con-
centration-dependent with a long post-antibiotic effect
(PAE); thus, their therapeutic effects are related to the ratio
of maximum concentration (Cmax) to MIC, which should
be at least 8–10, and daily administration is able to maxi-
mize Cmax/MIC. However, in severe burns patients, its
peak concentration is lower than usual because of faster
clearance [ 30 , 31 ]; therefore, the multiple dosage regimen is
the better choice. Fluoroquinolones are also concentration-
dependent antibiotics whose PAEs are about 1.5–2.5 h.
Their bactericidal effects correlate with the area under the
concentration time curve (AUC) or the ratio of Cmax to
MIC. Cmax/MIC and AUC/MIC are PK/PD parameters that
are able to predict the effi cacy of antibiotics. AUC24/MIC
or Cmax/MIC of the antibiotics that are chosen to treat
Gram-negative infections should be higher than 125 or 8
respectively.
The capability of the antibiotics to induce bacteria to
release endotoxin varies widely. For this reason, we prefer
to choose those with less endotoxin-releasing capability
among the sensitive list. An in vitro study of bacteria-
induced endotoxin releasing carried out by the Fujian
Institutes of Burns found that a combination of β-lactamase
and aminoglycosides can reduce the amounts of endotoxins
released by bacteria. Clinically, it is very common for the
effi cacy of β-lactamase regimen for severe Gram-negative
infections to not be as good as that of a combined β-lactamase
and aminoglycosides regimen. Apart from the synergic
effects of both agents, it may also relate to the lesser release
of bacterial endotoxins. In conclusion, a combination regi-
men could be a rational choice for the treatment of Gram-
negative sepsis.
When patients show early septic symptoms, there should
be no hesitation of the doctors to prescribe sensitive antibiot-
ics according to the results of the wound culture, subeschar
tissue culture, and their antibiotic sensitivity, intravenously
administered guttae; otherwise, good timing has passed.
4.1.3
Antibiotic Treatment Regimens
4.1.3.1 Principles
1. For minor to medium burns, it is necessary to use penicil-
lin G to prevent Streptococcus pyogenes infection for the
fi rst 3 days post-burn.
2. For extensive burns, especially deep burns, on the 4th day
post-burn, it is recommended to apply broad- spectrum
antibiotics (the spectrum including Pseudomonas aerugi-
nosa ) to treat Gram-negative bacilli. The entire course
should be restricted to within 5–7 days.
3. For patients who have an eventful course during the early
stages post-burn, who have had a long journey to be deliv-
ered to hospital, who have been involved in an explosion
or who have wounds with bleeding spots, sloughing
debris, combined with infl ammatory infi ltration and other
severe infection signs, it is mandatory to use antibiotics
within 24–48 h post-burn. As the main pathogens of early
invasive infection are Gram-negative bacilli, we should
choose antibiotics that are effective for Gram-negative
bacilli, including Pseudomonas aeruginosa and antibiot-
ics whose antibacterial spectrum includes Gram-positive
cocci. It is common to apply a combination regimen of
two types of antibiotics for about 2–3 days. Afterward, if
there is no sign of sepsis, the antibiotic therapy should
cease; while there are still indications for antibiotic treat-
ment, burns surgeons can select a sensitive antibiotic
according to the results of the bacterial sensitivity test, if
it is available at that time.
4. When there are signs of sepsis emerging, burns surgeons
can prescribe sensitive antibiotics in accordance with
the results of wound culture and subeschar culture.
If there are no available microbial data and the patho-
gen could not be decided upon, the combination regimen
should include broad spectrum antibiotics (covering
Pseudomonas aeruginosa ) and antibiotics that are effec-
tive to Gram-positive cocci. The application of antibiotics
should be stopped as soon as the sepsis is under control.
On the other hand, if it is non-effective 24–48 h after the
fi rst dose, then we should make another choice.
5. For perioperative antibiotic treatment around escharot-
omy, tangential escharotomy, debridement, and auto-
skin- grafting, the initial dosage of sensitive antibiotics
should be started 24 h before the operation and last
continuously for 3 days. Patients who have an early
escharotomy within 48 h post-burn, antibiotics whose
antimicrobial spectrum covers Pseudomonas aeruginosa
must be prescribed within 24 h post-burn.
6. If Streptococcus pyogenes has been detected at the wound,
application of a high dosage of penicillin-G is mandatory
before auto-skin-grafting.
7. In later burn sepsis 1 month post-burn, sepsis is mainly
caused by Staphylococcus aureus , and so it is a non-
invasive infection-originating sepsis or blood stream
infection. We prefer to choose staphylococcal-sensitive
antibiotics. Norvancomycin or vancomycin is the better
choice, and serves as fi rst choice when MRSA is preva-
lent in the wards. However, we could not ignore Gram-
negative bacilli infection, even though Staphylococcus
aureus mainly causes later stage infections in burns
patients. When vancomycin or linezolid could not control
sepsis development, it is compulsory to adjust the regi-
men, changing to the use if Gram-negative bacilli-
sensitive antibiotics.
4 Infection in Burns

73
8. Polymyxin B can be used to treat pan-drug-resistant
Gram-negative bacilli infections; if the treatment is not
as effective as desired, Proteus infection is highly
suspected; thus, the third-generation cephalosporins and
fl uoroquinolones are preferred.
9. High doses of penicillin-G are usually prescribed for
patients suffering electrical burns, thermal crush inju-
ries, and deep burns with large amounts of necrotic
muscle to prevent clostridial infection. Clindamycin,
cefoxitin, and metronidazole are the antibiotics of choice
if Bacteroides infection is suspected.
10. Oral antifungal agents are required simultaneously when
the patients have been treated with broad spectrum
antibiotics for more than a week.
4.1.3.2 Antibiotic Regimen
The key point of the principles of antibiotic treatment is to
administer sensitive antibiotics according to the results of
bacterial sensitivity. For severe burns patients who are
immune-suppressed, sepsis develops from the infection of
extensive open wounds. It is critical, progresses rapidly, and
is related to the high mortality among severe burns patients.
Early diagnosis of sepsis and early effective antibiotic treat-
ment have the potential to save lives. Nevertheless, during
the early stage of sepsis, if there is no available wound cul-
ture and its bacterial sensitivity data or the sepsis is devel-
oped when antibiotics have already been administered,
empirical treatment should be applied and the initial treat-
ment is closely related to the effi cacy of antibiotic treatment.
Regimens of empirical treatment are based on the knowledge
on the dominant bacteria of the burn infection, the currently
popular strains found on burn wards, and their resistance
background to ensure the optimal choice of antibiotics. It is
thus important and necessary to survey the ecological
changes in bacteria isolated from burn wounds and their
resistance pattern.
An antibiotic regimen made for invasive infection treat-
ment must be modifi ed in accordance with the change in bac-
terial resistance and development of novel antibiotics. Next,
we are going to discuss the antibiotics available for burns
treatment. For the variety of bacterial resistance in different
hospitals, the following arrangements of antibiotic regimens
are based on the author’s clinical experience and knowledge
of long-term survey database of bacterial resistance found in
the burns center, Ruijin Hospital.
β-lactamase
(a) Penicillins
1. Penicillin-G: Streptococcus pyogenes is still sensitive
to penicillin-G, with a resistance rate of 4.1 % [ 18 ].
Most Gram-positive aerobic bacteria are also sensi-
tive to penicillin-G. The indication for burn patients
to use penicillin-G is to prevent Streptococcus
pyogenes infection and Clostridium perfringens
infection. Every 100 million units of penicillin-G
contain about 1.0–1.5 mEq of potassium, while for a
high- dose intravenous injection and patients with the
complication of acute renal failure, penicillin sodium
may be the substitute.
Procaine penicillin-G is water-soluble and slowly
released after intramuscular injection. Its blood con-
centration can be maintained about 12–24 h after the
injection of one bolus; thus, the dosing interval could
be every 12 h. As its serum peak concentration only
reaches a small proportion of the same dosage of pen-
icillin-G, it is only chosen for the treatment of mild or
moderate infections caused by these highly sensitive
bacteria, and is quite suitable for outpatients.
2. Piperacillin/tazobactam
Currently, Gram-negative bacilli resistance to piper-
acillin is increasing dramatically. The major mecha-
nism of resistance is the production of β-lactamase.
Tazobactam is the derivative of sulbactam, which irre-
versibly competitively inhibits the action of staphylo-
coccally generated penicillinase, β-lactamases, those
produced by Gram-negative bacilli, such as TEM
OXA SHV, and PSE plasmid- mediated β-lactamases,
including ESBL-β- lactamases; and part of the chro-
mosome-mediated AmpC enzymes. Its enzymatic
inhibitory effect is stronger than that of clavulanic acid
and sulbactam. As a result, piperacillin/tazobactam
can restore bacterial sensitivity of those piperacillin-
resistant strains that contain ESBLs. Seventy to eighty
percent of piperacillin-resistant Enterobacteriaceae
strains could restore sensitivity; however, the restora-
tion rates of resistant Pseudomonas aeruginosa and
Acinetobacter baumannii are only 29 % and 36 %
respectively [ 18 ]. The ratio of piperacillin to tazobac-
tam is 8:1. The product could be one of the options
for antibiotic treatment for ESBL-producing strain
infections.
Dosing intervals and mode of administration are
18–13.5 g per day, every 6–8 h intravenously admin-
istered in a slow manner. For those whose creatinine
clearance is less than 20 ml/min, dosing adjustment
is needed every 12 h. Maximum dose for hemodial-
ysis patients is 9 g per day, and a complementary
dose of 2.5 g after the hemodialysis. For patients
with impaired hepatic function, there is no need to
adjust dosage because of minor changes in drug
metabolism under these circumstances.
(b) Cephalosporins
According to the development order and certain charac-
teristics, such as antibacterial activity, the antibiotics
spectrum, and its stability when acting with β-lactamase,
cephalosporins can be divided into four generations,
4.1 Burn Wound Sepsis

74
fi rst, second, third, and fourth, although there is no defi -
nite border line among the different generations.
The antibacterial effect of fi rst-generation cephalospo-
rins against Gram-positive cocci is signifi cantly higher
than that of third-generation cephalosporins; when con-
sidering their effect against Gram-negative bacilli, it is the
reverse. Third-generation cephalosporins are subdivided
into two categories, those with good antibacterial activity
and those with poor activity, according to their effects
against Pseudomonas aeruginosa . The former class
includes cefoperazone and ceftazidime; the latter involves
cefotaxime, ceftizoxime, and ceftriaxone. The antibacte-
rial spectrum of the third-generation cephalosporins is
broader than that of fi rst-generation and second-genera-
tion cephalosporins, including Gram- negative bacilli,
which are resistant to the earlier generations of cephalo-
sporins. However, their antibacterial activity against
Gram-positive cocci is not as effective as that of the other
two generations. They are also unstable to ESBLs and
AmpC enzymes. Moreover, third- generation cephalospo-
rins, except for cefoperazone, are capable of penetrating
the blood–brain barrier. Fourth- generation cephalosporins
have the characteristics of a low affi nity to AmpC, high
activity against Citrobacter and Acinetobacter , similar
activity against Pseudomonas aeruginosa to that of
ceftazidime and better effects on Gram-positive cocci than
that of third-generation cephalosporins. Moreover, some
cephalosporins containing N-methyl-tetrazole side chain,
such as cefoperazone, may induce a disulfi ram-like reac-
tion and occasionally bleeding complications.
Cephalosporins are time-dependent and have no
PAE. Their antibacterial activity depends on the time of
blood concentration above MIC, hence, it is required that
the time of blood concentration above MIC should at least
be 40–50 % of the dosing interval (%T>MIC for 40–50 %)
for antibacterial treatment, while for bacteriological cure
the %T>MIC should be 85 %. Apart from some long half-
life cephalosporins, such as ceftriaxone, administration is
required to be every 6–8 h. Cephalosporins are unstable at
room temperature; thus, the solution should be prepared
just before the application and administered via a fast intra-
venous drip. One dose of medication can be added to 100–
250 ml 5 % glucose solution to be administered within 1 h.
1. Ceftazidime: Gram-negative bacilli are quite sensitive
to ceftazidime, even though those strains that are resis-
tant to fi rst- and second-generation cephalosporins, but
Enterobacter cloacae is relatively resistant to it. Its
antibacterial activity against Pseudomonas aeruginosa
is the strongest among third-generation cephalosporins
and its minimal bactericidal concentration (MBC)
against most strains is no more than twice the MIC
[ 32 ], nor is its antibacterial activity against
Acinetobacter . While concerning its effi cacy with
regard to Gram-positive cocci, it ranks behind other
third-generation cephalosporins and imposes no effects
on most anaerobic bacteria, except carboxyl spp.,
Peptostreptococcus and certain types of Bacteroides .
Currently, dominant pathogens isolated from the
wounds of severely burned patients are Gram-negative
bacilli, with the main strains of Pseudomonas aerugi-
nosa whose resistance to ceftazidime remains around
20–30 %. Therefore, ceftazidime is one of the fi rst
choices for the treatment of infections occurring in
severely burned patients. However, for those patients
being treated in the wards with popular strains of pan-
drug-resistant Pseudomonas aeruginosa , it is not rec-
ommended as the fi rst-choice antibacterial agent since
ceftazidime is included in the resistance spectrum of
those strains. Its plasma protein combination rate is the
lowest among third-generation cephalosporins, about
17 %; thus, most ceftazidime in serum has a free status,
which has a bactericidal effect.
Dosing intervals and mode of administration are a
total of 4 g per day, administered equally every 6 h
via intravenous drips. For severely infected patients,
it could be increased to 6 g per day, equally adminis-
tered every 8 h. For patients with moderate to severely
impaired renal function, the daily dose should be
decreased into 0.5–1.0 g.
2. Cefoperazone/sulbactam: Sulbactam is the irreversible
broad-spectrum β-lactamase inhibitor, which prevents
the ring of β-lactam from being destroyed by β-lactamase
to ensure the antibacterial activity of the antibiotics fac-
ing with those β-lactamase-producing pathogens. ESBLs
produced by drug-resistant strains are the main mecha-
nism of bacteria in resisting third- generation cephalo-
sporins. The activity of most ESBLs can be inhibited by
sulbactam; therefore, combined with sulbactam, cefo-
perazone is able to recover its antibacterial activity,
which is blocked by β-lactamase [ 33 ]. When administra-
tion of cefoperazone/sulbactam was started in our burns
center, it was able to recover the sensitivity of 60 % of
third- generation cephalosporin-resistant Enterobacter
isolated from burn wounds [ 34 ]. At the same time, the
sensitivity rate of Pseudomonas aeruginosa to this com-
pound was 86 %, but it fell to 53.7 % in 2005, while the
rate to cefoperazone was just 44.4 %. Moreover, it
extends the antibacterial spectrum of cefoperazone to
cover the insensitive strains of Acinetobacter and
Bacteroides fragilis . For its effects against Gram-positive
cocci, the compound shows the same antibacterial spec-
trum and activity as that of cefoperazone alone. In
conclusion, cefoperazone/sulbactam can be used as
the fi rst choice for infections caused by pathogens of
Pseudomonas
aeruginosa ,
Acinetobacter ,
and
Enterobacter resistant to third- generation cephalospo-
rins, especially for infections occurring in wards in which
strains resistant to third- generation cephalosporins are
4 Infection in Burns

75
popular. However, for those populated with pan-drug-
resistant Pseudomonas or Acinetobacter baumannii , it is
not recommended as the choice of initial empirical
therapy.
The ratio of cefoperazone to sulbactam is 1:1. The
pharmacokinetics of cefoperazone is not infl uenced
by sulbactam, the form that is excreted mainly by the
kidneys. Adverse reactions of the compound are the
same as those for cefoperazone.
Dosing intervals and mode of administration are
4–8 g per day, administered equally every 12 h via
intravenous drip. The maximum recommended dos-
age of sulbactam is 4 g.
3. Cefepime is a fourth-generation cephalosporin
with the chemical structure of the introduction of
N-methylpyrrolidine moiety into the C3 point of pivoxil
triazene. It is highly water-soluble and easy to penetrate
the outer membrane of the bacteria through membra-
nous pores. It has a high affi nity to penicillin binding
protein and a broad antibacterial spectrum includ-
ing those strains that are resistant to third- generation
cephalosporins, aztreonam, piperacillin/tazobactam,
and aminoglycoside-resistant Gram- negative bacilli.
For the low affi nity with plasmid- mediated or chro-
mosome-mediated AmpC enzymes, cefepime is not
easy to hydrolyze and its ability to induce β-lactamase
is lower than that of third- generation cephalosporins.
AmpC-producing Enterobacter and Pseudomonas
aeruginosa are sensitive to cefepime.
Its antibacterial activity against Pseudomonas aeru-
ginosa is similar to that of ceftazidime, and so is its
bacterial sensitivity. Concerning its antibacterial activ-
ity against AmpC enzymes producing Gram- negative
bacilli, it is better than that of third- generation cepha-
losporins and aztreonam. To MSSA, penicillin-
sensitive or -resistant Streptococcus pneumoniae ,
which is sensitive to it, its antibacterial activity is
higher than that of ceftazidime. However, Enterococcus
and MRSA are resistant to it. As third- generation
cephalosporin resistance of the bacteria isolated from
burn centers is becoming a serious problem, cefepime
could be one choice for initial empirical treatment.
Dosing intervals and mode of administration are
4 g per day, equally administered every 12 h via intra-
venous drip.
Carbapenem
(a) Imipenem is a compound of imipenem and cilastatin, at a
ratio of 1:1. Cilastatin is the inhibitor of renal dehydropep-
tidase 1, which protects imipenem from being destroyed
by the enzyme. It is extremely stable to chromosome-
mediated and plasmid-mediated β-lactamase produced
by Gram-negative bacilli. As this group of bacteria lacks
the permeable barrier to hinder imipenem penetrating the
cells, the medication is easy to reach at the target site. It
has a high affi nity with penicillin- binding protein, espe-
cially to PBP2. As imipenem acts with bacteria, only a
small number of bacteria split up, while most of the bac-
teria transform into spherical form which is the inactive
form; thereby, its ability to induce Gram-negative bacilli
to release endotoxin is minor [ 35 , 36 ]. Its antibacterial
spectrum is broader than that of third-generation cepha-
losporins and fl uoroquinolone antibiotics, including
almost all important pathogens found in burns wards.
Enterobacter are highly sensitive to it, including those
strains that are resistant to third- generation cephalospo-
rins and aminoglycoside antibiotics. Up to now, imipe-
nem-resistant strains of Enterobacter have comprised less
than 5 % of the total and Acinetobacter are quite sensitive
to it. Nevertheless, there is the tendency of burns wards to
be populated with multi-resistant and pan-drug-resistant
Acinetobacter baumannii in recent years; the identifi ca-
tion rate of imipenem-resistant strains reaches 53.2 %
[ 15 ]. The antibacterial activity against Pseudomonas aeru-
ginosa is poorer than that against Enterobacteriaceae. In
recent years, its resistant strains appeared so fast, account-
ing for 20–30 %. Stenotrophomonas maltophilia is not
sensitive to it, but to act with MSSA, Staphylococcus epi-
dermis and Enterococcus faecalis , it shows good effects.
Moreover, it also obtains the ability to control anaerobic
infections. Chromosome and plasmid-mediated zinc-
containing metalloenzymes (carbapenem enzyme) and
plasmid- mediated A group 2f β-lactamase can inactivate
imipenem. Fortunately, the proportion of clinically iso-
lated strains producing these two kinds of β-lactamases is
not currently very high. However, the change of penicillin
binding protein and loss of mosaic proteins on the outer
cell membrane engender bacteria to develop imipenem
resistance because the pathway of the antibiotics to pen-
etrate bacteria no longer exists. Thus, there is currently
an ascending tendency of resistant strains isolated clini-
cally. However, no strains have been found to be cross-
resistant to both imipenem and cephalosporins. In order
to avoid selective pressure and the appearance of resistant
strains induced by imipenem, it should be used as the last
choice of antibiotics, while for burns centers populated
with third-generation resistant strains; imipenem could be
the fi rst choice of initial empirical antibiotic treatment for
Gram-negative infection. Imipenem is able to impose PAE
on both Gram-negative bacilli and Gram-positive cocci.
Adverse reactions of the CNS, such as convulsions
and headaches, are relatively common among patients
with impaired renal function and CNS diseases.
Dosing intervals and mode of administration are
1.5–2 g per day, equally administered every 8 or 12 h
intravenously and the time of infusion more than 3 h for
every dosage should ensure that %T>MIC reaches the
maximum effect. For severe infections, Pseudomonas
4.1 Burn Wound Sepsis

76
aeruginosa
infection
and
infection
caused
by
Staphylococcus aureus , the dose could be increased to 4 g
per day, equally administered every 6 h. For patients with
minor renal function impairment its daily dose should not
exceed 2 g, 1.0–1.5 g per day for moderate renal function
impairment, equally administered every 8–12 h, and 0.5–
1.0 g per day for patients with severe renal function
impairment, equally administered every 12 h.
(b) Meropenem: introducing methyl base into the 1β site of
carbapenem, meropenem’s stability to dehydropeptidase-
1 increases signifi cantly. As a result, there is no need
for it to be used with cilastatin. It has a high affi nity to
PBP 2 and induces minor release of endotoxin produced
by Gram-negative bacilli. Most Gram-positive cocci, and
aerobic and anaerobic Gram-negative bacilli, are quite
sensitive to meropenem because of its broad antibacte-
rial spectrum. As it is stable to chromosome- mediated
and plasmid-mediated β-lactamase, which is produced
by Gram-negative bacilli, meropenem shows excellent
antibacterial activity against multidrug- resistant aero-
bic Gram-negative bacilli. Comparing its antibacterial
activity with that of imipenem, meropenem is more
effective on Enterobacteriaceae, Pseudomonas aeru-
ginosa , and has similar effects on Acinetobacter , while
Stenotrophomonas maltophilia is insensitive to merope-
nem. However, on Staphylococcus and Enterococcus ,
the antibacterial activity of imipenem surpasses that of
meropenem. For burn centers populated with third-gener-
ation-resistant strains, it is the fi rst choice of initial empir-
ical treatment for Gram-negative infections. Mechanisms
of bacteria for developing drug resistance are their ability
to produce carbapenemases, OprD loss, and hyperexpres-
sion of the MexAB-OprM effl ux system. For this reason,
there is not only cross- resistance between meropenem
and imipenem but also between meropenem and other
kinds of antibiotics. To ensure its vitality in treating infec-
tions, it should be retained as a fi nal choice of antibiotic
therapy. Adverse CNS reaction induced by meropenem is
much less severe than that induced by imipenem.
Dosing intervals and mode of administration are
2–3 g per day, equally administered every 8–12 h via
intravenous drip. The maximum dose is 6 g per day,
equally administered every 6–8 h.
Aminoglycosides
Aminoglycoside antibiotics have a broad anti-aerobic spec-
trum with a PAE, but do not cover anaerobic bacteria.
Although they are toxic and ototoxic to the kidneys, some-
times burn surgeons have to choose aminoglycosides to treat
severe Gram-negative bacilli infections. The combination of
β-lactam and aminoglycoside antibiotics produces a synergic
effect in controlling infections.
The nephrotoxicity of aminoglycoside antibiotics is not
related to its peak concentration in serum, while the ototoxicity
decreases when the dosing interval has been prolonged.
However, their antibacterial activity is concentration- dependent,
i.e., correlated with the serum peak concentration, and so is the
duration of their PAE. When the ratio of serum peak concentra-
tion to MIC is more than 10:1, this demonstrates the perfect
effects of treating infections caused by clinically sensitive
strains. The recommended once-daily dosage regimen reaches
a higher serum concentration than multiple dosage regimens,
which improves the antibacterial effect and minimizes the
potential nephrotoxicity and ototoxicity. Moreover, patients
should receive their blood concentration surveillance and indi-
vidualization of therapy should be advocated.
(a) Amikacin is the derivative of kanamycin A, which has
similar pharmacokinetics to that of the latter. Although
6 of the 17 known aminoglycoside inactivate enzymes
could inactivate amikacin, only AAC(6)-I among those
modifying enzymes produced by Gram-negative bacilli
could render amikacin inactivated. At the same time,
AAC(6)-I could also inactivate gentamycin, tobramycin,
and netilmicin; therefore, amikacin-resistant strains are
resistant to these antibiotics simultaneously. However, for
those amikacin-resistant strains with decreased permeabil-
ity of the outer bacterial membrane, they may be sensitive
to other aminoglycosides, i.e., under these circumstances,
such bacteria are not resistant to all of the aminoglycoside
antibiotics. Currently, the resistance rate of amikacin is the
lowest among those of the aminoglycoside antibiotics.
Pseudomonas aeruginosa can produce AAC(6)-I, and the
percentage of resistant strains isolated clinically is
20–30 %. MRSA and Enterococcus are resistant to amika-
cin. For the signifi cant increase in gentamycin-resistant
and tobramycin-resistant strains found in burns wards,
amikacin could be the fi rst choice of aminoglycoside anti-
biotics to treat infections before the results of the antibiotic
sensitivity test are available. The combination of amikacin
and third-generation cephalosporins could be a better regi-
men for severe Gram- negative bacilli infections.
As the amikacin-resistant rate of Gram-negative
bacilli, including Pseudomonas aeruginosa , isolated
from some of the burns centers has increased signifi -
cantly since the twenty fi rst century (reaching about
50–60 %), we prefer not to use amikacin alone to treat
Gram-negative bacilli infections.
Clinical manifestation of the nephrotoxicity of ami-
kacin are changes found in the urination routine, increas-
ing blood urea nitrogen and creatinine, salt-losing
nephritis characterized by loss of salts, etc. There’s the
possibility of developing salt-losing nephritis if the
patient has been continuously treated with amikacin for
1 week; thus, patients’ 24-h urinary volume and urinary
output of electrolytes should be monitored.
Serum peak concentration of amikacin should reach
20–30 mg/L for the treatment of severe infection. Daily
dosage for burns patients is 30 mg/kg per day, equally
4 Infection in Burns

77
administered every 6 h. As its serum peak concentration
in burns patients is 29.8 ± 9.9 mg/L, and in the normal
control group it is 37.5 ± 4.9 mg/L lower, its average half
life, which is 1.4 h shorter than in the normal control
group [ 31 ], it is recommended to have the daily dosage
administered in multiple doses.
Dosing intervals and mode of administration are 1.2 g
per day, equally administered every 8 h via intravenous
drip with a time of no less than 1 h. The dosage should
be modifi ed if the patient’s renal function is impaired.
(b) Netilmicin is the semi-synthetic derivative of gentamy-
cin with a similar chemical structure to the latter. It has
the same pharmaceutical characteristics and antibacte-
rial spectrum as gentamycin. Its N1 ethyl site could not
be inactivated by ANT(2) and AAC(3)-I, III, which are
produced by Enterobacteriaceae and Pseudomonas
aeruginosa ; thus, these gentamycin- and tobramycin-
resistant bacteria are sensitive to it. Furthermore, MSSA
is included in its antibacterial spectrum, but MRSA and
Enterococcus are resistant to it.
Among 120 strains of Pseudomonas aeruginosa
isolated from patients in the burns department, Ruijin
Hospital, between 1998 and 2000, only seven (5.83 %)
are resistant to netilmicin, while among 95 strains of
Enterobacteriaceae 53 (55.79 %) are resistant. Therefore,
netilmicin could be the fi rst-choice antibiotics for
treating infections when multidrug-resistant strains of
Pseudomonas aeruginosa , which are simultaneously
sensitive to netilmicin, are popular in the burns center
Dosing intervals and mode of administration are
300 mg per day, equally administered every 8 h via intra-
venous drip. The dosage should be modifi ed if the
patient’s renal function is impaired.
Polymyxins
Polymyxins are a group of lipo-peptide antibiotics iso-
lated from Bacillus polymyxa , containing the structure
of polypeptides and showing strong antibacterial activity
against a broad spectrum of Gram-negative bacilli, includ-
ing Enterobacteriaceae, nonsugar-fermented bacteria, such
as Pseudomonas aeruginosa , Acinetobacter baumannii ,
and Stenotrophomonas maltophilia . However, Proteus ,
Morganella , Providencia , and Serratia are resistant to them.
Polymyxins are fast bactericides, which interact with lipo-
polysaccharides existing within the outer membrane of
Gram-negative bacteria. They are concentration-dependent
antibiotics, with the antibacterial activity most probably
related to AUC/MIC, the parameter of PK/PD. Moreover,
they are also toxic to the kidneys. Only polymyxin B and
polymyxin E are used clinically.
(a) Polymyxin B has excellent antibacterial activity against
Gram-negative bacilli isolated from burn wounds,
except for Proteus . Its sensitivity is 90 % (Table 4.8 ),
while Serratia is resistant to it. Polymyxin B imposes no
antibacterial activity effects on Gram-positive cocci and
sensitive bacteria do not easily develop drug resistance.
From the fi rst case of a severe burns patient adminis-
tered polymyxin B in 1958, over the next 20 years, poly-
myxin B sensitivity of Pseudomonas aeruginosa fl uctuated
years by year, but it remained at around 90 % (Table 4.9 ).
Currently, there are the pan-drug-resistant Gram-
negative bacilli, such as Pseudomonas aeruginosa ,
Acinetobacter baumannii , against which almost no anti-
biotics can be used in burn centers. This is the reason
why polymyxins have returned to surgeons’ list of anti-
biotics to serve as the last choice for multidrug-resistant
or pan-resistant Gram-negative bacilli infections. Before
the application of third-generation cephalosporins,
polymyxin B was the main antibiotic used to treat inva-
sive infections in burns patients. Up to now, the resis-
tance of Pseudomonas aeruginosa , Enterobacteriaceae,
and Acinetobacter , which are isolated from burns wards,
to polymyxin B has not increased signifi cantly. It may be
the fi rst-choice antibiotic for the initial empirical treat-
ment of infections occurring in those wards populated
with pan-resistant Pseudomonas aeruginosa and
Acinetobacter baumannii , which are resistant to antibi-
otics, such as carbapenems, third- and fourth-generation
cephalosporins, monocyclic, semi-synthetic penicillins
and β-lactamase inhibitor compounds, aminoglycosides,
Table 4.8 Sensitivity of gram-negative bacilli isolated from burn
wounds to polymyxin B (1966–1978)
Bacteria
Sensitivity (%)
Pseudomonas aeruginosa
94.8
Escherichia coli
86.9
Escherichia paracolon a
88
Klebsiella pneumoniae b
92.5
Proteus
35.6
Enterobacter aerogenes
90
Alcaligenes
91
Nitrate-negative bacilli c
95
a Citrobacter after 1973
b Data collected 1978–1987
c Acinetobacter
Table 4.9 Polymyxin B sensitivity of Pseudomonas aeruginosa iso-
lated from burn wounds (1964–1979)
Year
Number
of strains
Sensitive
strains (%)
Year
Number
of strains
Sensitive
strains (%)
1964
862
332 (91.7)
1972
99
88 (89)
1965
151
141 (93.3)
1973
54
49 (90.7)
1966
35
33 (94.3)
1974
102
102 (100)
1967
29
29 (100)
1975
111
91 (82)
1968
47
45 (95.7)
1976
39
34 (87.2)
1969
39
39 (100)
1977
122
112 (91.8)
1970
99
96 (97)
1978
80
79 (98.9)
1971
59
54 (91.5)
1979
45
39 (86.6)
4.1 Burn Wound Sepsis

78
and fl uoroquinolones. In addition to its good antibacte-
rial activity against Gram-negative bacilli, polymyxin B
can also neutralize endotoxins.
The nephrotoxicity of polymyxin B manifests as pro-
tein urea, granular particles in the urine, elevation of
blood urea nitrogen and blood creatinine levels, and salt-
losing nephritis. The renal damage is reversible; renal
function may be recovered when the medication is
stopped. Therefore, there is no need to strictly restrict
the number of days on the treatment. The total number of
days of polymyxin B treatment in 14 surviving severely
burned patients whose TBSA exceeded 80 % and more
than 50% third-degree burns reached 20 days during the
fi rst month post-burn. Among this group of patients,
there was a one who received continuous treatment for
17 days and no irreversible renal damage occurred. Salt-
losing nephritis is the most common form of renal dam-
age, an adverse reaction that would unavoidably occur in
patients who had been treated for more than 1 week.
Daily urine output of the patients may reach 4–5 L or a
negative water balance may even occur. Electrolyte con-
centrations in urine almost reach their serum levels and
daily potassium and sodium loss in urine is almost 20 g.
Thus, it is very important to keep an eye on patients’
water and electrolyte balance, monitor the total volume
of input and output precisely, test the electrolyte output,
for example, chloride, sodium, and potassium in daily
urine, monitor serum electrolytes, and supply those lost
water and electrolytes. If administration via an intrave-
nous drip is too fast, it will inhibit respiration when the
serum level reaches 30 mg/L. Other adverse reactions
are paresthesia, such as lip numbness, formication, but
these disappear fast when the medication is stopped. The
oral intake of polymyxin B could be used as a selective
intestinal disinfectant because of its non-absorbable
characteristics.
Dosing intervals and mode of administration are
2–3 mg/(kg·day), equally administered every 8 h via
intravenous drip. Delivery duration should be maintained
at 1–1.5 h. Maximum adult dosage should not exceed
0.2 g per day, equally administered every 6 h. For patients
with impaired renal function, the fi rst day’s dosage is
2.5 mg/kg. Subsequent dosage depends on the patient’s
renal function, and is 1 mg/kg, once a day, every other
day or every other 2 days; even once a week might be
possible. Polymyxin B cannot be dialyzed. To treat intes-
tinal Pseudomonas aeruginosa infection, the dosage is
0.1 g/day, taken equally every 6 h via the oral route.
(b) Colistin: there is only one amino base different in the
chemical structure of colistin compared with polymyxin
B; thereby, their antibacterial spectrums are the same,
but less antibacterial activity and less nephrotoxicity are
found in colistin (Table 4.10 ).
Dosing intervals and mode of administration are
2.5–5 mg/(kg·day) of colistin, equally administered
every 8 h via intravenous drip.
Glycopeptide Antibiotics
Glycopeptide antibiotics are those with the chemical
structure of glucose and peptide chains, which are the
bactericides with a narrow antibacterial spectrum, high
antibacterial activity, and various degrees of nephrotoxicity.
(a) Vancomycin and norvancomycin. Norvancomycin has
the same antibacterial spectrum and antibacterial
activity as vancomycin. It works against Gram-positive
cocci with speed and strength, but has no effect on
Gram- negative bacilli, while showing good antibacterial
activity against anaerobic Gram-positive bacilli. Its
mechanism of inhibiting bacterial cell wall synthesis is
earlier than that of β-lactamase, without competitive
binding.
Vancomycin-sensitive
bacteria
include
Staphylococcus , Streptococcus pyogenes , Streptococcus
pneumoniae , and Enterococcus . Bacteria do not
easily develop resistance to vancomycin; however,
vancomycin- resistant enterococci and vancomycin-
resistant coagulase- negative staphylococci had already
been isolated clinically. Simultaneously, the intermedi-
ate strains of Staphylococcus aureus appeared; in some
regions, people even found vancomycin-resistant
Staphylococcus aureus . There is no cross-resistance
Table 4.10 Comparative in vitro
antibacterial activity of
polymyxin B and colistin against
Gram-negative bacilli
Bacteria
Number
of strains Antibiotics
Accumulated inhibited % of strains with MIC μg/ml
0.5
1
2
4
6
10
Pseudomonas
aeruginosa
45
Polymyxin B 13.3
55.6
86.7
100
100
100
Colistin
2.2
2.2
13.3
17.8
33.3
51.1
Citrobacter
26
Polymyxin B 84.6
88.5
88.5
88.5
88.5
88.5
Colistin
38.5
38.5
53.9
57.7
62.0
71.1
Klebsiella
pneumoniae
20
Polymyxin B 65.0
85.0
95.0
95.0
95.0
95.0
Colistin
15.0
30.0
40.0
55.0
70.0
70.0
Enterobacter
aerogenes
24
Polymyxin B 83.3
91.7
100
100
100.0
100.0
Colistin
12.5
25.0
50.0
54.2
58.3
83.3
E. coli
18
Polymyxin B 100
100
100
100
100
100
Colistin
46.2
69.2
77.0
84.6
92.3
100.0
Nitrate
negative bacilli
7
Polymyxin B 100
100
100
100
100
100
Colistin
14.3
28.6
57.1
57.1
71.4
71.4
4 Infection in Burns

79
between vancomycin and nonglycopeptide antibiotics.
MRSA and methicillin- resistant coagulase-negative
staphylococci (MRCNS) are sensitive to it. In 1987, 58
strains of MRSA isolated from burn wounds had an
MIC90 of 2 mg/L. The percentage of MRSA isolated
from burns wards is signifi cantly higher than those
found in internal medicine wards or general surgery
departments. Furthermore, MRSA isolated from some
burns centers even reached 70–80 %. As cephalosporins
have been widely used, infections caused by enterococci
are increasing against a background of the multiresis-
tance of enterococci. Nevertheless, vancomycin is effec-
tive at controlling these infections. Among 15 strains of
Enterococcus faecalis isolated from burn wounds,
14 strains were sensitive to vancomycin. In conclusion,
vancomycin and norvancomycin are the fi rst-choice
antibiotics for the initial empirical treatment of Gram-
positive cocci infections in MRSA-prevalent burns
wards. Moreover, vancomycin shows good antibacterial
activity against the anaerobic Clostridium diffi cile , the
pathogen of antibiotic-related colitis; thus, it is effective
for treating antibiotic-associated colitis.
Vancomycin has low nephrotoxicity, but it becomes
signifi cant when it is used together with aminoglycoside
antibiotics or loop diuretics, or in patients with basic
renal diseases. In the 1960s, literature reports of severe
nephrotoxicity induced by vancomycin were related to
those impurities contained in preparations. Now, the
preparation of vancomycin has reached a high level of
purity, which signifi cantly decreases its nephrotoxicity.
When the patient’s renal function is impaired, its high
serum level leads to a high incidence of ototoxicity.
Vancomycin is a time-dependent antibiotic with a
PAE, and AUC24/MIC is the PK/PD parameter for pre-
dicting drug effi cacy. With half-life of 6 h, Vancomycin
cannot be dialyzed. In patients who have no urine output,
its half-life is prolonged to 216 h. The plasma protein
binding rate of vancomycin is 10 %.
Norvancomycin has one methyl base less than vanco-
mycin, but has similar antibacterial activity, nephrotox-
icity, and main adverse reactions.
Dosing intervals and mode of administration for
vancomycin are 1.5–2 g per day, equally administered
every 6–8 h via intravenous drip, with no more than
15 mg of the medication delivered into the body within
1 min. When treating antibiotics-associated colitis, 2 g
per day, with equal oral intake every 6 h. The dosage of
norvancomycin is 1.2–1.6 g per day, equally adminis-
tered every 6–8 h via intravenous drip. Fast intravenous
infusion or an excessive level of blood concentration may
induce histamine release into the human body, causing
“red man syndrome” or “red neck syndrome” clinically.
(b) Teicoplanin works against bacteria via the same mecha-
nism as vancomycin. It also has a similar antibacterial
spectrum and antibacterial activity to vancomycin, as
are its effects on MRSA, MSSA, Staphylococcus epi-
dermidis , enterococci and Streptococcus pneumoniae .
Its antibacterial activity against aerobic and anaerobic
Gram-positive cocci is strong, but most coagulase-
negative Staphylococcus hemolysis is resistant to it.
For its incapability to induce vancomycin B-type
resistance protein, vancomycin B-type resistant strains
of enterococci are sensitive to teicoplanin, but resistant
to vancomycin. Therefore, it is preferable to choose tei-
coplanin. Vancomycin A-type resistant strains of entero-
cocci are resistant to both vancomycin and teicoplanin.
The half-life of teicoplanin is considerably longer
(47 h) and its protein binding rate nears 90 %. Thus, after
the administration, the serum level reaches its stable
concentration. Hemodialysis or peritoneal dialysis is not
effective at clearing teicoplanin.
There is a lower incidence of adverse reactions
induced by teicoplanin, compared with that of vancomy-
cin. Nephrotoxicity and ototoxicity are rare. Teicoplanin
and vancomycin have a cross allergic reaction, but less
possibility of developing “red man syndrome” in patients
treated with teicoplanin.
Dosing intervals and mode of administrations are
400 mg per day for the fi rst day of administration, then
200 mg once daily via intravenous drip. For severe infec-
tions, the dosage could be doubled, i.e., 800 mg per day
for the fi rst day, equally administered every 12 h, and
then 400 mg per day equally administered every 12 h.
Fluoroquinolone Antibiotics
The main mechanism of fl uoroquinolone antibiotics to work
against bacteria is inhibiting microbial DNA synthesis so as
to kill the bacteria quickly. It imposes its action on DNA
gyrase or topoisomerase IV, resulting in the enzyme–DNA
complex breaking down and ceasing of DNA replication.
Two times the MIC value leads to its bactericidal effect and
it is able to kill those “static” bacteria. Fluoroquinolone
antibiotics have a PAE. When combined with other types of
antibiotics, they do not antagonize antibacterial activity.
Moreover, they are active even when existing in pus. They
have a broad antibacterial spectrum: they show their good
effects on Gram-negative bacilli, including Pseudomonas
aeruginosa , and lower but real antibacterial activity against
Gram-positive cocci. The concentration needed to inhibit
streptococcus in some species is higher than its serum con-
centration. Most fl uoroquinolone antibiotics are not able to
inhibit anaerobic bacteria. Their antibacterial activity is
related to the AUC. The ratio of AUC24 to MIC of more than
125 should be established for Gram-negative bacilli infec-
tion treatment and to prevent bacteria from successfully
developing drug resistance.
The main pharmacological characteristics of this type of
antibiotics are their excellent bioavailability; good oral
absorption; their capability of being absorbed less when
taken together with mg 2+ , Ca 2+ , A1 3+ , and Fe 2+ ; and a long
4.1 Burn Wound Sepsis

80
half-life, usually 3–7 h. Recently developed species, such
as gatifl oxacin and moxifl oxacin, have a longer half-life;
thus, they could be administered once a day; their serum
concentration level could be maintained over MIC and
MBC for a long time; with a 14–30 % plasma binding rate;
distribute widely into organ and infection sites with a
higher, or at least, the same concentration as that in serum.
Drug concentration in tissue and cerebrospinal fl uid may
reach an effective level. Most species of fl uoroquinolone
antibiotics are cleared by the kidney, but some are partly
metabolized in the liver, such as pefl oxacin, ciprofl oxacin,
and enoxacin.
The main adverse reactions of fl uoroquinolone antibiotics
are gastrointestinal and CNS reactions. Since the observance
of articular cartilage damage occurring in weight-bearing
joints in baby animals, fl uoroquinolone antibiotics have not
been recommended for children and pregnant women.
The antibacterial spectrum of fl uoroquinolone antibiotics
includes common pathogens of burn infection, but
Escherichia coli , Pseudomonas aeruginosa , and MRSA eas-
ily develop resistance. In the last 10 years, bacterial resis-
tance to fl uoroquinolones has increased signifi cantly, over
40 % among E. coli , and 80 % and 50 % in MRSA and
Pseudomonas aeruginosa respectively. This is all related to
the abuse of this type of medicine. To avoid bacterial resis-
tance developing in the short term, it is forbidden to use fl uo-
roquinolones as topical agents.
(a) Ofl oxacin and levofl oxacin: Enterobacteriaceae are
extremely sensitive to these species of antibiotics, while
Pseudomonas aeruginosa and Staphylococcus aureus
are intermediately sensitive; the sensitivity of strepto-
coccus is less than that of staphylococcus. Antibacterial
activity
against
Pseudomonas
aeruginosa
and
Enterobacteriaceae of ofl oxacin is weaker than that of
ciprofl oxacin, but its MIC90 is higher than that of
ciprofl oxacin. Therefore, ofl oxacin is not the main
antibiotic that was used to prevent burn infection.
Antibacterial activity of levofl oxacin is twice as high as
that of ofl oxacin. Its bioavailability reaches 95 %, and it
may be absorbed completely by oral intake. After a dos-
age of 400 mg per os, its serum peak concentration is
4 mg/L, and concentrations in body fl uid and tissue are
two to four times those of the drug in the same category.
Levofl oxacin has the highest distribution in the lungs,
bronchial mucosa, and sputum. Ofl oxacin imposes no
infl uence on theophylline clearance. If the patient should
be treated together with theophylline, we prefer to
choose ofl oxacin in the category of fl uoroquinolone
antibiotics.
Dosing intervals and mode of administration are
ofl oxacin 600–800 mg/day, equally administered every
8–12 h via intravenous drip; levofl oxacin 500 mg admin-
istered once daily via intravenous drip.
(b) Ciprofl oxacin has a similar antibacterial spectrum
to ofl oxacin. Its N-1 cyclopropyl base enhances its
antibacterial activity against Enterobacteriaceae and
Pseudomonas aeruginosa , with stronger effects against
the former. More or less, its activity against Pseudomonas
aeruginosa ranks at the top of the fl uoroquinolone
antibiotics. Recently, the main Gram-negative bacilli,
such as Klebsiella pneumoniae , Enterobacteriaceae,
Acinetobacter , and Pseudomonas aeruginosa , isolated
from burn wounds that were resistant to ciprofl oxacin
at a rate of about 60–70 %. In 1987, MIC50 and MIC90
of the 58 MRSA strains isolated from burn wounds were
1 mg/L and 4 mg/L respectively; the resistance rate was
only 12 %. However, sensitive strains isolated between
1993 and 1995 only comprised 7 of the 100, and the
resistance rate was as high as 93 %. Ciprofl oxacin-
resistant rate of Enterococcus faecalis was as high as
40–60 %. Therefore, ciprofl oxacin should not be used as
for the initial empirical treatment of burn infections. Its
bioavailability is 70 %, average serum peak concentra-
tion 2–4 mg/L after oral intake of 500 mg of medication.
It may infl uence the metabolism of theophylline.
Dosing intervals and mode of administration are
400–800 mg per day, equally administered every 12 h
via intravenous drip. For patients with severe renal dam-
age whose creatinine clearance rate is less than 20 ml/
min, the dosage should be 50 % less.
New generation of fl uoroquinolone antibiotics, such
as gatifl oxacin and moxifl oxacin, have much stronger
antibacterial activity against Streptococcus pneumoniae ,
Streptococcus pyogenes , and Staphylococcus aureus than
ofl oxacin and ciprofl oxacin owing to the chemical recon-
struction of the drug, especially against those that are peni-
cillin-intermediate, and penicillin-resistant Streptococcus
pneumoniae is still sensitive to these drugs. However, it is
poor at working against MRSA, MRSE, and enterococci.
Because its MIC90 locates the main pathogens of burn
infections, for instance, Pseudomonas aeruginosa ,
Acinetobacter , Enterobacteriaceae, Citrobacter , and
Proteus mirabilis , are between 4 and 16 mg/L, a param-
eter of PK/PD, AUC/MIC, cannot reach 100, and Cmax/
MIC is less than 8, the new generation of fl uoroquinolone
antibiotics are no better than the traditional ones at treat-
ing burn infections.
4.2
Gut-Origin Infection in Burns
Guangxia Xiao
Gut-origin infection is a phenomenon in which the indige-
nous gut bacteria or endotoxin cross the intestinal wall and
spread to the extraintestinal tissue, such as the mesenteric
4 Infection in Burns

81
lymph nodes, liver, spleen, lungs, and systemic circulation.
It is now suspected to be one of the sources of systemic
infection and of multiple system organ failure in critically
burned patients. We fi rst had the idea in 1962 from an exten-
sive clinical analysis, which was then proved by serial ani-
mal experiments in the early 1980s. We termed this process
“gut- origin infection,” and it was commonly accepted by
Chinese colleagues. Its meaning is similar to “bacterial
translocation” or “gut-derived infection” now being used
around the world.
4.2.1
How the Idea Emerged
and Was Followed by Evidence
in Animals
Early in 1962, in an extensive review of 312 cases of
bacteremia in burned patients, we were surprised at the
result that stated that about 30 % of patients had early bac-
teremia in which no bacteria were even recovered with use
of extensive wound cultures (eight samples were taken daily
from different portions of the wound) [ 37 – 46 ]. An early
bacteremia emerged, with bacteria normally contained
within the intestinal tract. The idea of a gut origin infection
was thus formed. In that era, patients were always hospital-
ized late because of long-distance transportation. Delayed
resuscitation with severe shock followed by early fulminat-
ing systemic sepsis and multiple organ failure became a
general pattern of the clinical course. The shock state was
always diffi cult to reverse with adequate fl uid resuscitation;
thus, early fulminating bacteremia with a non-identifi ed
source of infection prompted us to study the role of the gut.
Over the next 20 years, serial animal experiments were
carried on:
1. A rational number of fl uorescein-labeled microbes includ-
ing aerobic (represented by Pseudomonas aeruginosa ),
anaerobic (represented by Bacteroides fragilis ), fungus
(represented by Candida albicans ) were introduced into
the GI tract of separate groups of animal sustained with a
full-thickness burn of 25–30 % of the TBSA; the labeled
microbes were traced in visceral organs at various
post- burn hours.
2. Radioisotope ( 125 I)-labeled endotoxin was introduced to
burned or non-burned animals; endotoxin levels were
detected from the plasma of portal and caval veins.
Radioautography of liver sections was performed.
3. Lymphatic fi stula of animals was created both in burned
and in non-burned animals; dynamic changes of lymph
fl ow endotoxin and TNF were measured.
4. The expressions of TNF mRNA in the main organs were
demonstrated by in situ hybridization.
The results showed that the labeled microbes could be
demonstrated from various internal organs’ homogenates,
some of which began to translocate across the intestinal
mucosa at 1–3 h post-burn; systemic dissemination reached
a peak around 12–24 h post-burn (Fig. 4.1a–d ). The translo-
cation of endotoxin even is earlier than that of bacteria
(Figs. 4.2 , 4.3 , and 4.4 ).
a
b
Fig. 4.1 Bacterial translocation in Wistar rats sustained with 30 % of
the total body surface area (TBSA) with full-thickness burns. ( a ) Gut
fl ora penetrating the impaired intestinal mucosa (HE × 640). ( b ) Club of
bacteria demonstrated from submucosal lymphatic duct (hematoxylin–
eosin [HE] × 640). ( c ) The fl uorescein-labeled candida from the gut
were demonstrated from liver homogenate (FM × 400). ( d ) Further
information proved by biopsy showed the existence of fungal spores
and fi laments in the liver (periodic acid Schiff [PAS] × 400)

4.2 Gut-Origin Infection in Burns

82
4.2.2
The Intestinal Lymph Flow Was Another
Portal for Translocation
The lymphatic fi stulas from the small intestine were created
both in burned and in non-burned animals (Fig. 4.5 ). Special
cages were designed to restrain the rats and dynamically
collect the lymph fl ow for detection (Fig. 4.6 ).
The results showed that the levels of intestinal lymph
endotoxin, the positive rate, and bacterial counting were
evidently increased in burned animals. This suggested
that the intestinal lymph circulation might be one of
the important portals for endotoxin and microbial
translocation.
Endotoxin is a strong activator for the release of
inflammatory mediators. In our model of gut origin
7
125I-LPS Content (cpm/ml)
6
Portal V,
Vena Cava
Control
Control
5
4
3
2
1
0
0
0.25
0.5
1
3
6
12
24
48
72 h
Fig. 4.2 Endotoxin
translocation in Wistar rats
sustained with 30 % TBSA
full-thickness burns. The level of
radioisotope 125 I labeled
endotoxin detected from the
portal vein began to ascend from
15 min post- burn, reaching a
peak around 6 h post-burn, and
maintained higher than the level
of the vena cava
Fig. 4.3 Radioautography of a liver section showed the labeling of
endotoxin granules revealed in macrophages and hepatocytes. Black
arrow is showing the labeling endotoxin granules reveal in hepatocyte.
Red arrow is showing the labeling endotoxin granules reveal in
macrophage
c
d
Fig. 4.1 (continued)


4 Infection in Burns

83
endotoxemia, we found that there were three organs
(intestine, liver, and lung) and three kinds of cell (macro-
phages, vascular endothelium, and polymorphonuclear),
which showed significant expression of TNF mRNA
(Fig. 4.7 ).
4.2.3
The Clinical Signifi cance of Gut Origin
Infection
Since the recognition of the gut origin infection, it has
reminded us of at least three aspects:
1. Take more care with regard to the potential septic source
from the gut.
2. In some cases of hypovolemic shock, from which the
patient could not be resuscitated by fl uid replacement, the
early interference of septic factors from the gut should be
considered.
3. Breakdown of the gut mucosal barrier may induce
the passage of enteric fl ora and bacterial toxin to extrain-
testinal sites; thus perhaps becoming the motor of sepsis
and even MODS: the two-hit theory of the development
of MODS is quite suited to critically burned patients.
Fig. 4.4 Using macromolecular horseradish peroxidase straining, the
macromolecular substance could cross the tight junction of the epithe-
lium and appear in the submucosal medium, ×640
Fig. 4.5 Diagram illustrating the established model of mesentery
lymphatic fi stulas
Fig. 4.6 Special cages for restraining rats



4.2 Gut-Origin Infection in Burns

84
The fi rst hit comes from burn injuries and hypovolemic
shock, which induce the fi rst wave of systemic
infl ammatory response, but in general the patient can be
resuscitated by timely, proper fl uid replacement. The seri-
ous threat of the development of MODS is followed by an
early endogenous infection from the gut, which always
occurs before the invasive infection from the burn
wounds; the systemic infl ammatory response is thus
amplifi ed and progressive organ failure occurs [ 47 , 48 ].
Since we drew attention to gut origin infection, a number
of cases with early positive blood cultures (within 6–24 h
post-burn) have been reported. Before that, taking blood
for bacterial culture early in the post-burn period was
rare.
4.2.4
Factors Pre-disposing to the Gut-Origin
Infection
The human intestinal tract contains a great number of
bacteria. The bacterial count per 1 g of feces may exceed 1012
[ 48 ]. During the proliferation or lysis of the bacteria, a large
amount of toxin, such as lipopolysaccharides (LPS, endo-
toxin), may be derived; therefore, we consider the intestinal
tract to be the largest “bacterial reservoir” and “endotoxin
storeroom” within the human body.
Under normal conditions, the host defense, including the
mucosal barrier and local immune system, known as
gut- associated lymphoid tissues (GALT), can prevent the
invasion of bacteria and pathogenic molecules, but under
certain circumstances the translocation of bacteria and
endotoxin may occur.
4.2.4.1 Physical Disruption to the Mucosal
Barrier
In hypovolemic shock, the host response to hypoperfusion
and hypoxia is to preserve oxygen delivery to the heart and
brain by selectively diverting blood fl ow from other tissues,
particularly the skin, subcutaneous tissues, and the gastroin-
testinal tract. The splanchnic circulation is especially
vulnerable to this redistribution of blood fl ow with a pre-
dominantly vasoconstrictive effect. Thus, despite normal
blood pressure, ongoing ischemia may occur in the intestine.
Mucosal ischemia and cellular hypoxia may lead to the dis-
ruption of the normal epithelial cell barrier and increase the
gut’s permeability. The consequence is to allow enteric fl ora
or bacterial toxins to translocate across the gut wall and
invade the host via lymphatic or portal venous routes.
a
b
c
Fig. 4.7 Early expression of tumor necrosis factor (TNF) mRNA in visceral organs of rats with gut-origin endotoxin model of rats via in situ
hybridization, 6 h post-burn. ( a ) Intestinal lamina propria. ( b ) Liver Kupffer cells × 400. ( c ) Lung, vascular endothelial cells × 1,000

4 Infection in Burns

85
4.2.4.2 Chemical Barrier of the Intestine
Normal physiological secretions of the GI tract consist of
many factors that direct against the invasion of microbes,
such as gastric acid, pancreatic enzymes, and bile.
The intestinal epithelium is a monolayer of enterocytes
covered with mucus and secreted immunoglobulin A (sIgA).
It is a chemical barrier separating the luminal contents of the
bowel from the internal milieu, lubricating the surface of the
mucus from mechanical and chemical injuries. The mucus or
mucoprotein can mix with the enteric fl ora or endotoxin and
then be expelled with the feces. All of the physiological
secretions may be inhibited following burn injuries and
shock. This is why we recommend the early use of enteral
feeding.
4.2.4.3 The Biological Barrier of the Intestine
The human gastrointestinal tract contains more than 400
species of microorganism. Among them, anaerobic bacteria
account for 95 %. This indigenous microfl ora exerts an
important infl uence in preventing colonization with exoge-
nous pathogens, called colonization resistance; obligate
anaerobic bacteria may be the principal inhibitors of the
translocation of potentially pathogenic bacteria. The ecologi-
cal balance of fl ora can be disturbed by many factors, such as
bowel motility, ileus, the suppression of physiological secre-
tion, especially in long-term antibiotic therapy, which may
inhibit some benefi cial fl ora and promote the overgrowth of
some pathogens.
4.2.4.4 Immunological Barrier of the Intestine
Critical illness is often associated with immunocompromise,
including cellular and humoral immunities. Under healthy
conditions, a small amount of translocating bacteria or endo-
toxin can be phagocytosed before reaching the mesenteric
lymph nodes, but under immunocompromised conditions
further invasion may occur. In athymic mice the spontaneous
incidence of gut-origin infection reached 50 %. Bacterial
translocation is also promoted by injection with immuno-
suppressive agents. In Berg’s studies (1983), after the injec-
tion, the host can no longer confi ne the translocation of
bacteria only to the mesenteric lymph node; it spreads sys-
temically to the spleen, liver, kidney, and even the blood
stream.
4.2.5
The Clinical Strategies for Gut-Origin
Infection
For a long period, people considered the gut to be merely
an organ of digestion, absorption, and excretion, and rarely
took account of its potential changes following critically
illness. Thus, initially after severe trauma, stress, and
shock, people paid attention to the organs such as the heart,
lungs or kidney, and regarded the gut as something of a
“bystander.” In fact, following severe burns, with the result
of blood fl ow redistribution, the gut is one of the fi rst
organs to be compromised. Even if the systemic blood
pressure and cardiac output turned out to be normal, there
still exists a concealed ischemia in the gut due to the
selective constriction of arterioles. The local hypoperfu-
sion and cellular hypoxia may lead to the loss of mucosal
integrity, bacterial/endotoxin translocation, and induce
local and systemic infl ammation. For these reasons, the gut
has been termed the motor of irreversible shock and
MODS. Therefore, recognition of this deep placed patho-
genesis and its possible consequences should be empha-
sized immediately.
4.2.5.1 Timely and Appropriate Resuscitation
from Shock
In our animal experiments, a model of hemorrhagic shock
created in Wistar rats with blood pressure at 30 mmHg, when
the state of hypotension was maintained for 30 min, the
labeled gut microbes could reach the mesentery lymph
nodes; when it was maintained for 90 min, labeled microbes
reached the liver, spleen, and even the blood stream, which
indicated the close relationship between the hypotension
time interval and bacterial translocation.
However, depending only on the massive fl uid replace-
ment, this may sometimes not completely correct the isch-
emia of the gut, owing to the selectively local constriction of
arterioles in the gut. The overloading of fl uid may also induce
other complications such as abdominal compartment syn-
drome, which may also promote the translocation of bacte-
ria/endotoxin. To discover how to correct the disorder of the
microcirculation of the gut requires more studies to be
undertaken.
4.2.5.2 Early Enteral Feeding
There is now a consensus that early enteral feeding after
burns is better than restricted feeding and the use of total
parenteral nutrition (TPN). A number of animal experiments
showed that the latter was always associated with mucosal
atrophy. We studied the intestinal permeability in 22 severely
burned patients. The enteral group started feeding within
6–18 h post-burn. In the TPN group the enteral feeding was
delayed until 48 h post-burn. Intestinal permeability was
assessed by quantifi cation of urinary lactulose/mannitol.
Lactulose and mannitol are water-soluble molecules, which,
after oral ingestion, are not metabolized in the body and are
excreted intact in the urine. Mannitol is thought to be pas-
sively absorbed via the transcellular route, while lactose is
absorbed via the paracellular route (tight junctions between
intestinal epithelial cells). The results showed that the levels
of lactulose were signifi cantly higher in the TPN group,
which suggested that the intestinal permeability might be
increased, thus predisposing to bacterial translocation in the
TPN group.
4.2 Gut-Origin Infection in Burns

86
Certain nutrients have specifi c effects on gut function;
glutamine is known to be the preferred fuel source of small
intestine enterocytes. However, in standard total parenteral
nutrition the solution did not include glutamine as it belongs
to “conditionally essential” amino acids. When the demand
for glutamine increases after a burn, it cannot be met by
mobilization from other tissue stores. Glutamine can increase
villous height, mucosal thickness, and sIgA secretion, thus
strengthening the intestinal barrier, and may reduce the rates
of translocation, which had been proved in our animal stud-
ies. In addition, the early enteral feeding could improve the
portal and intestinal mucosal circulation, promoting the phys-
iological secretions of the gastrointestinal tract, all of which
suggested the benefi cial effects of early enteral feeding.
4.2.5.3 Selective Decontamination
of the Digestive Tract
Selective decontamination of the digestive tract (SDD) is the
administration of oral nonabsorbable antibiotics such as
polymyxin B or neomycin to reduce the number of aerobic
Gram-negative bacteria in the digestive tract, which are the
major pathogens in translocation; but in fact it is not practi-
cable, because the SDD is time-consuming, frequently
requiring 5–7 days [ 49 ]. The mechanical cleansing of the
colon had been suggested by the provider of acute pancreati-
tis, and the results still require further studies.
4.2.5.4 Early and Short-Term Use of Antibiotics
The early state of severe burns is a critical phase for bacte-
rial/endotoxin translocation, as damage to the intestinal bar-
rier is common.
Under normal conditions, the regeneration of intestinal
epithelium takes place every 3 days; therefore, a short-term
use of proper antibiotics may be of benefi t to prevent early
fulminating sepsis. If we follow this with early escharectomy
and grafting, the antibiotics also serve as a perioperative
measure, but long-term use of antibiotics should be
prevented.
Conclusion
Severe trauma is really a multiple organ disease.
Recognizing the “shock kidney” led to dialysis therapy;
recognizing the “shock lung” led to ventilator support.
Now, caring for the “shock gut,” the resuscitation of
severe trauma may hopefully be raised to a new level.
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