Pathophysiological analysis of combined burn and smoke
inhalation injuries in sheep
Kazutaka
Soejima1,
Frank C.
Schmalstieg2,
Hiroyuki
Sakurai1,
Lillian
D.
Traber3, and
Daniel L.
Traber3
1 Department of Plastic and Reconstructive Surgery, Tokyo
Women's Medical University, Tokyo 162-8666, Japan; and
3 Department of Anesthesiology and 2 Department of
Pediatrics, University of Texas Medical Branch and Shriners Burns
Institute, Galveston, Texas 77555-0591
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ABSTRACT |
We investigated the pathophysiological
alterations seen with combined burn and smoke inhalation injuries by
focusing on pulmonary vascular permeability and cardiopulmonary
function compared with those seen with either burn or smoke inhalation
injury alone. To estimate the effect of factors other than injury, the
experiments were also performed with no injury in the same experimental
setting. Lung edema was most severe in the combined injury group. Our
study revealed that burn injury does not affect protein leakage from the pulmonary microvasculature, even when burn is associated with smoke
inhalation injury. The severity of lung edema seen with the combined
injury is mainly due to augmentation of pulmonary microvascular
permeability to fluid, not to protein. Cardiac dysfunction after the
combined injury consisted of at least two phases. An initial depression
was mostly related to hypovolemia due to burn injury. It was improved
by a large amount of fluid resuscitation. The later phase, which was
indicated to be a myocardial contractile dysfunction independent of the
Starling equation, seemed to be correlated with smoke inhalation injury.
pulmonary vascular permeability; lung edema formation; myocardial
depression
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INTRODUCTION |
MORE THAN 30% of
burn patients admitted to burn centers have a concomitant smoke
inhalation injury (5, 11, 18). Although the survival from
burn injury has increased in recent years with the development of
effective fluid resuscitation management or early surgical excision of
burned tissue, the mortality rate in this combination injury is still
high (5, 28, 36). In these fire victims, progressive
pulmonary failure associated with lung edema (acute respiratory
distress syndrome) and cardiac dysfunction are important
determinants of morbidity and mortality (5, 36).
In patients with extensive cutaneous burns in which the burned area
exceeds 30% of the total body surface area (TBSA), capillary hyperpermeability occurs not only at the injured site but also in
regions distant from the injury (4, 10, 34). This vascular hyperpermeability leads to a large amount of fluid flux from the circulating plasma to the interstitial spaces. The lung is especially affected by this phenomenon in the large-burn cases. The pulmonary microvascular permeability to water and small molecules increases after
major cutaneous burns alone (7, 10). This lung edema formation is even more severe when the thermal damage is combined with
inhalation injury (6, 20). Isago et al (13)
and Traber et al. (33) have previously reported
that smoke inhalation injury causes pulmonary microvascular
hyperpermeability to both fluid and protein. Although Sakurai and
colleagues (24, 25) have reported some of the
cardiopulmonary changes that occur with combined burn and smoke
inhalation, the pulmonary vascular permeability changes observed in
combined burn and smoke inhalation injury in sheep have not been
compared with those in sheep that had received either burn or smoke
inhalation injury alone.
Patients with massive cutaneous burns also suffer myocardial
contractile depression, which can be a serious complication, especially
in the early postburn period (8, 12). On the other hand,
our laboratory has demonstrated that smoke inhalation causes a delayed
onset of myocardial depression. Sugi et al. (30) reported that left ventricular contractility was significantly decreased 24 h after smoke inhalation. However, the time course and mechanism responsible for the cardiopulmonary hemodynamic alterations are still
unclear when cutaneous burn injury is associated with smoke inhalation injury.
In this study, we investigated the pathophysiological alterations seen
with burn and smoke inhalation combined injury by focusing on pulmonary
microvascular permeability and cardiopulmonary function compared with
those seen with either burn or smoke inhalation injury alone. To
estimate the effect of the factors other than injury, the experiments
were also performed with no injury in the same experimental setting.
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MATERIALS AND METHODS |
This study was approved by the Animal Care and Use Committee of
the University of Texas Medical Branch (Galveston, TX) and conducted in
compliance with the guidelines of the National Institutes of Health and
the American Physiological Society for the care and use of laboratory animals.
Surgical preparation.
Twenty-four female sheep were surgically prepared for chronic study
under halothane anesthesia. The right femoral artery and vein were
cannulated with Silastic catheters (Intracath; 16 gauge, 24 in.; Becton
Dickinson Vascular Access, Sandy, UT). A thermodilution catheter
(Swan-Ganz model 131F7, Baxter, Edwards Critical-Care Division, Irvine,
CA) was introduced through the right external jugular vein into the
pulmonary artery. Through the left fifth intercostal space, a catheter
(Durastic silicone tubing DT08, 0.062-in. ID, 0.125-in. OD; Allied
Biomedical, Paso Robles, CA) was positioned in the left atrium. Through
the right fifth intercostal space, an efferent lymphatic vessel from
the caudal mediastinal lymph node was cannulated with a silicone
catheter (Alliedsil silicone tubing 1264/T056, 0.025-in. ID, 0.047-in.
OD; Allied Biomedical) with a modified method based on the technique of
Staub et al. (29). Ligation of the tail of the caudal
mediastinal lymph node and cauterization of the systemic diaphragmatic
lymph vessels removed the systemic lymph contribution. The animals were given 5-7 days to recover from the surgical procedure, with free access to food and water.
Measured variables.
Lung lymph flow (
lymph) was measured with a
graduated test tube and stopwatch. Lymph and blood samples were
collected in tubes containing EDTA. The total lymph protein
concentration (Clymph) was measured with a refractometer
(National Instrument, Baltimore, MD). For estimation of pulmonary
microvascular permeability to protein, net protein transvascular flux
in the lung (
lymph × Clymph; in
g/ml) was calculated.
Mean arterial (in mmHg), pulmonary arterial (in mmHg), left atrial
(LAP; in mmHg), and central venous (CVP; in mmHg) pressures were
measured with pressure transducers (model PX-1800, Baxter, Edwards
Critical-Care Division) that were adapted with a continuous flushing
device. The transducers were connected to a hemodynamic monitor (model
78304A, Hewlett-Packard, Santa Clara, CA). The pressures were measured
with the animals in the standing position. Zero calibrations were taken
at the level of the olecranon joints on the front leg of the animals.
Cardiac output was measured with the thermodilution technique with a
cardiac output computer (COM-1, Baxter, Edwards Critical-Care
Division). A 5% dextrose solution was used as the indicator. For
evaluation of cardiac function, cardiac index (CI; in
l · min
1 · m
2), left and
right ventricular stroke work indexes (LVSWI and RVSWI, respectively; in g · m · m
2), and
systemic and pulmonary vascular resistance indexes (SVRI and PVRI,
respectively; in
dyn · s · cm
5 · m
2)
were calculated with standard equations. Blood gases were measured with
a blood gas analyzer (model IL 1600, Instrumentation Laboratory, Lexington, MA). The blood gas results were corrected for the body temperature of the sheep. Oxyhemoglobin saturation and
carboxyhemoglobin concentration were analyzed with a CO-Oximeter (model
IL 482, Instrumentation Laboratory). Hematocrit (Hct) was measured in heparinized microhematocrit capillary tubes (Fisherbrand, Pittsburgh, PA). The airway blood flow was serially determined with colored microspheres (15 ± 0.1 µm; Interactive Medical Technologies,
Los Angeles, CA). Reference blood for the calibration of microsphere activity was withdrawn from the femoral arterial catheter at a constant
rate of 10 ml/min for 2 min while the microspheres were injected. The
color of the microspheres was changed with each injection.
Experimental protocol.
Twenty-four hours before the experiment, the vascular catheters were
connected to the monitoring devices, and maintenance fluid
administration (Ringer lactate, 2 ml/kg) via the femoral vein was
started. After baseline measurements and sample collections were
completed, the animals were randomized into four groups: a burn group
that received a 40% TBSA third-degree burn alone as described in
Burn and smoke inhalation injury (n = 6), a burn/smoke group that received both a 40% TBSA third-degree
burn and 48 breaths of smoke from burning cotton as described in
Burn and smoke inhalation injury (n = 6), a smoke
group that received 48 breaths of smoke from burning cotton alone as
described in Burn and smoke inhalation injury
(n = 6), and a control group that received no injury
(n = 6). Immediately after injury, anesthesia was
discontinued, and the animals were allowed to awaken but were
maintained on mechanical ventilation (Servo Ventilator 900C,
Siemens-Elema) throughout the 48-h experimental period. Ventilation was
performed with a positive end-expiratory pressure of 5 cmH2O and a tidal volume of 15 mg/kg. During the first
3 h after injury, the inspiratory O2 concentration was
maintained at 100% and respiratory rate was kept at 30 breaths/min to
induce rapid clearance of carboxyhemoglobin after smoke inhalation.
Then the ventilation was adjusted according to blood gas analysis to
maintain arterial O2 saturation > 90% and
PCO2 between 25 and 30 mmHg. The burn and the
burn/smoke groups received fluid resuscitation during the experiment
with Ringer lactate solution following the Parkland formula (4 ml · %burned surface area
1 · kg body
wt
1 for the first 24 h and 2 ml · %burned
surface area
1 · kg body wt
1 for the
next 24 h). One-half of the volume for the first day was infused
in the initial 8 h, and the remainder was infused in the next
16 h. Because the mechanical ventilation and/or fluid resuscitation itself might affect the physiological parameters, even
the control group received the identical amount of fluid resuscitation
following the Parkland formula and underwent the same ventilatory
support as the injured animals during the whole experimental period.
The smoke group was mechanically ventilated with the same setting as
the other groups but was not resuscitated following the Parkland
formula. The animals in the smoke group received maintenance fluid
resuscitation (Ringer lactate solution, 3 ml · kg
1 · h
1) to mimic the
clinical situation. Previously, Schenarts et al. (26) have
demonstrated that the fluid requirement to maintain LAP at ±2 mmHg and
mean arterial pressure at ±5 mmHg of the baseline values after smoke
inhalation injury alone is an average of 3 ml · kg
1 · h
1 of Ringer
lactate. During this experiment, the animals were allowed free access
to food but not to water to accurately measure fluid intake.
For airway blood flow determination, 5 million colored microspheres
were injected into the left atrium before and 3, 6, 12, 24, and 48 h after injury. The lymph and blood samples for determination of total
protein concentration were collected 3, 6, 12, 18, 24, 36, and 48 h after injury in all groups. Hemodynamic variables and blood gases
were obtained 3, 6, 12, 18, 24, 30, 36, 42, and 48 h postinjury in
all groups. Forty-eight hours after injury, animals were killed
after an injection of ketamine followed by saturated KCl. Immediately
after death, the entire right lung was harvested for measurement of
blood-free wet weight-to-dry weight ratios (an index of pulmonary
edema) as described by Pearce et al. (21). The lower part
of the trachea just above the carina (to which blood is supplied only
by the bronchial artery) was harvested to determine airway blood flow
(23, 26).
Burn and smoke inhalation injury.
Before the injury, a tracheostomy was performed under ketamine
anesthesia (Ketaset, Fort Dodge Animal Health, Fort Dodge, IA) and a
cuffed tracheostomy tube (10-mm diameter; Shiley, Irvine, CA) was
inserted. Then anesthesia was continued with halothane. Thereafter, the
animals in the burn group were subjected to a 40% TBSA third-degree
burn. After the wool was shaved, a 20% TBSA flame burn was made on one
side of the flank with a Bunsen burner until the skin was thoroughly
contracted. After this procedure, another 20% TBSA third-degree burn
was made on the remainder of the flank. The burn/smoke group received
both a 40% TBSA third-degree burn and smoke inhalation from burning
cotton. The smoking procedure was performed between the series of 20%
thermal injury (17). Smoke inhalation was induced
with a modified bee smoker. The bee smoker was filled with 40 g of
burning cotton toweling and then attached to the tracheostomy tube via
a modified endotracheal tube containing an indwelling thermistor from a
Swan-Ganz catheter. Four sets of twelve breaths of smoke (total 48 breaths) were delivered, and the carboxyhemoglobin level was determined
immediately after each set. The temperature of the smoke was not
allowed to exceed 40°C during the smoking procedure
(14). The smoke group received only smoke inhalation with
the same procedure as the burn/smoke group. In the control group, the
tracheostomy was performed under ketamine anesthesia, and then the
animal was connected to the mechanical ventilator.
Statistical methods.
Summary statistics of data are expressed as means ± SE. In the
burn and burn/smoke groups, data were analyzed with analysis of
variance (ANOVA) for a two-factor experiment, with repeated measures on
time. The two factors were experimental group (burn and burn/smoke) and
time. Another two-way ANOVA was also performed in the smoke and
burn/smoke groups. In the control group, data were analyzed with ANOVA
for a one-factor experiment, with repeated measures on time. Fisher's
least significant difference procedure was used for multiple
comparisons (or post hoc analysis). The differences in the wet
weight-to-dry weight ratios of the right lung among groups were
evaluated by means of Student's unpaired t-test. A
P value < 0.05 was considered to be significant.
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RESULTS |
All animals in all groups survived the 48-h experimental period.
The arterial carboxyhemoglobin levels immediately after the smoke
exposure were 69.6 ± 4.1% in the burn/smoke group and 72.1 ± 9.2% in the smoke group. There was no significant difference between these values.
Airway blood flow.
The tracheal blood flow in the smoke and burn/smoke groups dramatically
increased immediately after injury (1,666 ± 168 and 1,671 ± 360% of the baseline values in the smoke and burn/smoke groups,
respectively, 3 h after injury; P < 0.05). The
burn-alone group showed a mild but significant increase in tracheal
blood flow at 48 h (545 ± 151% of baseline value at 48 h; P < 0.05; Fig. 1).
The airway blood flow consists of two blood supplies, the systemic and
pulmonary circulations (23, 28, 33). The lower trachea
harvested in the present study is supplied by the bronchial arteries
from the systemic circulation. These vessels of the airway circulation
anastomose with each other and empty into the pulmonary circulation
(bronchopulmonary shunt). Previous studies conducted in our
laboratories (23, 24) have demonstrated that airway blood
flow increases after either smoke-alone or burn/smoke combined injury.
This augmented blood flow, associated with inflammation in the airway,
contributes to the development of lung tissue damage by diffusing
inflammatory mediators from the injured airway to the pulmonary tissue
through the bronchopulmonary shunt (1, 23). The increase
in the airway blood flow seen at the end of the experiment after burn
injury alone indicates that inflammatory events occurred in the airway
to which blood was supplied via the bronchial artery from the systemic
circulation.

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Fig. 1.
Changes in airway blood flow. Control, group that
received no injury; smoke, group that received 48 breaths of smoke from
burning cotton toweling; burn, group that received a 40% total body
surface area 3rd-degree burn; burn/smoke, group that received both burn
and smoke injuries. The burn/smoke and smoke groups showed significant
increases immediately. The burn group showed a mild but significant
increase 48 h after injury. * Significant difference between
burn and burn/smoke groups, P < 0.05. Significant difference from baseline value, P < 0.05.
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Pulmonary vascular permeability.
The burn group did not show a significant increase in
lymph during the 48-h experimental period.
However, the
lymph in the burn group tended to be
higher than in the control group 12 h after injury (Fig.
2). It has been demonstrated that major
burn alone can increase pulmonary microvascular permeability to water (7). The burn/smoke group and smoke-alone group showed
significant increases in
lymph after injury. In the
smoke-alone group, the
lymph increased more slowly
than in the combined injury group and reached significance 24 h
after injury (9.8 ± 2.0 ml/h at baseline; 35.4 ± 8.0 ml/h
at 24 h; P < 0.05; Fig. 2). This delayed onset of
pulmonary microvascular hyperpermeability seen with smoke inhalation
injury has been demonstrated to be due to the progress of inflammation
from the injured airway to the lung tissue subsequent to a marked
increase in airway blood flow (1, 23). The
lymph tended to be higher in the burn/smoke group
than in the smoke group throughout the experiment (by 69.3% at 30 h), although there was no significant difference between the groups.
This result suggests that burn injury contributes to the augmentation
of transvascular fluid flux in the pulmonary microvasculature when
smoke inhalation injury is associated with burn injury. Net protein
transvascular flux in the lung (
lymph × Clymph) increased significantly in both the burn/smoke and
smoke groups; however, there was no significant difference between the
groups (Fig. 3). In the burn-alone group, the net protein flux in the lung was relatively constant but tended to
be lower than the control group (Fig. 3). These data suggest that burn
injury does not affect protein leakage from the pulmonary microvasculature. The blood-free wet weight-to-dry weight ratios of the
right lung, an index of lung edema, were burn/smoke > smoke > burn > control. The values were 5.52 ± 0.37, 4.30 ± 0.08, 3.68 ± 0.16, and 3.09 ± 0.40, respectively (Fig.
4). The wet weight-to-dry weight ratios
in the smoke and burn/smoke groups were significantly higher
than in the control group. The burn/smoke combined injury group showed
significantly higher wet weight-to-dry weight ratios compared with
either the smoke-alone or burn-alone injury group. These data suggest
that the severity of lung edema seen with burn and smoke combined
injury is mainly due to augmentation of pulmonary microvascular
permeability to fluid, not to protein.

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Fig. 2.
Changes in lung lymph flow ( lymph).
There was slight increase in lymph in the burn-alone
group compared with that in the control group. In the burn/smoke group,
the lymph was significantly increased compared with
the burn group. The lymph tended to be higher
in the burn/smoke group than in the smoke group. * Significant
difference between burn and burn/smoke groups, P < 0.05. Significant difference from baseline value,
P < 0.05.
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Fig. 3.
Net protein transvascular flux in the lung was increased
in both the burn/smoke and smoke groups; however, there was no
significant difference between the groups. There was no increase in the
burn group. * Significant difference between burn and burn/smoke
groups, P < 0.05. Significant difference from
baseline value, P < 0.05.
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Fig. 4.
Blood-free wet weight-to-dry weight ratios of the right
lung were burn/smoke > smoke > burn > control. The
burn/smoke group showed significantly higher wet weight-to-dry weight
ratios compared with either smoke-alone or burn-alone injury group.
* Significant difference from the burn group, P < 0.05. Significant difference from the control group,
P < 0.05. Significant difference from the smoke
group, P < 0.05.
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Cardiac functions.
Hemodynamic variables are summarized in Tables
1 and 2.
Although a large amount of fluid was administered rapidly, both the
burn and burn/smoke groups showed hemoconcentration as evident from the
significant increase in Hct immediately after injury (Fig.
5) due to fluid loss from the circulating
plasma to the systemic interstitial space. In the burn group, it peaked
3 h after injury and recovered to the baseline value within
12 h, whereas in the burn/smoke group, hemoconcentration was
significantly worse than in the burn group. However, the Hct in the
burn/smoke group peaked 24 h after injury and then improved, which
suggests that hemoconcentration was not sustained after 24 h even
when the burn injury was associated with the smoke inhalation injury. The smoke and control groups did not show significant changes in the
Hct during the study.

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Fig. 5.
Changes in hematocrit (Hct). The burn and burn/smoke
groups showed a significant increase in Hct immediately after injury.
The smoke and control groups did not show a significant change in Hct
during the study. * Significant difference between burn and
burn/smoke groups, P < 0.05. Significant
difference from baseline value, P < 0.05. Significant difference between smoke and burn/smoke groups,
P < 0.05.
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The burn and burn/smoke groups showed a significant decrease in CI
immediately after injury (71.1 ± 3.9 and 69.0 ± 3.7% of the baseline values in the burn and burn/smoke groups, respectively, 3 h after injury; P < 0.05; Fig.
6A). In the burn-alone group, a trough in CI was observed 3 h after injury. Thereafter, it
recovered smoothly and returned to near baseline level within 6 h,
whereas hemoconcentration was restored by fluid resuscitation. In the burn/smoke group, the CI improved slightly 6 h after injury but remained depressed for >36 h and then gradually returned toward baseline. There was a significant difference between the burn and
burn/smoke groups during the 24-30 h after injury. The CI in the
smoke-alone group decreased slowly and reached significance 12 h
after injury (82.4 ± 6.1% of the baseline value;
P < 0.05; Fig. 6B). The control group did
not show significant changes in CI throughout the experimental period
(Fig. 6). This result indicates that the depressed CI seen in the later
phase after burn and smoke combined injury correlates with the smoke
inhalation injury.

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Fig. 6.
Changes in cardiac index (CI). A: burn and burn/smoke
groups showed a significant decrease in the CI immediately after
injury. B: in the smoke group, the CI decreased gradually.
* Significant difference between burn and burn/smoke groups,
P < 0.05. Significant difference from baseline
value, P < 0.05. Significant difference between
smoke and burn/smoke groups, P < 0.05.
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In the burn/smoke group, the LVSWI significantly decreased immediately
after injury (45.8 ± 3.8% of the baseline value at 3 h;
P < 0.05). It showed slight improvement transiently
and then deteriorated again, and it remained depressed throughout the
remainder of the experimental period (Table 2). The burn-alone group
also showed a rapid fall in LVSWI (52.7 ± 11.3% of the baseline
value at 3 h; P < 0.05), but it recovered
smoothly toward the baseline value in a later phase (Table 2). There
was a significant difference in the LVSWI between the burn and
burn/smoke groups during the 18-42 h after injury. The smoke group
showed a significant decrease in LVSWI in only the later phase, during
the 18- to 48-h period (72.1 ± 9.2% of the baseline value at
18 h; P < 0.05; Table 2). The LAP and CVP
(preload) increased rather than decreased in all groups after injury,
with a large amount of fluid resuscitation and mechanical ventilation
with positive end-expiratory pressure (Table 1). The relationships
between preload and stroke work (LAP and LVSWI; CVP and RVSWI) are
shown in Fig. 7 as indexes of myocardial
contractility. The values for the burn/smoke group are clearly shifted
downward and to the right. This result indicates that this cardiac
dysfunction seen in the burn/smoke group was due to myocardial
contractile depression independent of the Starling mechanism.

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Fig. 7.
Relationship between preload and stroke work.
A: left atrial pressure (LAP) vs. left ventricular stroke
work index (LVSWI). B: central venous pressure (CVP) vs.
right ventricular stroke work index (RVSWI). Nos. in symbols, index of
myocardial contractility. The values for burn/smoke group are clearly
shifted downward and to the right.
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Vasoconstriction after injury.
Both the burn and burn/smoke groups showed a rapid increase in PVRI and
SVRI (Table 2). In contrast, in the smoke-alone group, the increase in
the PVRI and SVRI was delayed in onset. Each reached significance
18 h after injury (Table 2). In the burn-alone group, these
vascular constrictions improved smoothly with fluid resuscitation. However, in the burn and smoke inhalation combined group, recovery from
the initial vasoconstriction was considerably delayed. This vasoconstriction seen in the later phase seems to be correlated with
smoke inhalation injury.
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DISCUSSION |
It is well known that morbidity and mortality risk increases when
thermal injury is associated with inhalation injury (5, 28,
36). The present study reproduced the typical response to this
combination injury. In the burn and smoke combined injury group, a
pulmonary failure associated with more severe lung edema formation,
increase in fluid requirement, and prolonged cardiac depression were
noted compared with those in the burn-alone group.
The results confirmed that lung edema formation and secondary pulmonary
failure are much more severe when thermal injury accompanies smoke
inhalation injury. However, the results revealed that burn injury does
not contribute to the increase in protein leakage from the pulmonary
microvasculature. Demling et al. (7) and Harms et al.
(10) reported that major thermal injury alone caused a
selective increase in pulmonary microvascular permeability only to
water and small solutes but not to protein. Our results are in
agreement with their work. In our study, the smoke group showed a
significant increase in
lymph, the ratio of lymph to
plasma protein content, and net protein flux from the pulmonary
vasculature in the lung. In contrast, in the burn/smoke group, the
lymph was significantly increased and to a somewhat
greater degree. On the other hand, the increase in protein flux was no
greater than that observed in the group with smoke inhalation alone.
The edema formed in the combined injury group, which was over and above
what was seen with smoke injury alone, is probably due to changes in
permeability to small molecules. More exacting techniques such as
measurement of the reflection coefficient and filtration coefficient
need to be utilized in these models to make a final confirmation of
this hypothesis. Isago et al. (13) from our laboratory
previously showed that the reflection coefficient decreased and the
filtration coefficient increased in the pulmonary microvasculature after smoke inhalation injury. These findings suggested that pulmonary vascular permeability to both water and protein increased after smoke
inhalation through both transcellular and paracellular pathways. The
present study suggests that burn injury does not affect the paracellular pathway even when the burn is associated with smoke inhalation injury. Again, this will have to be confirmed by further investigation. Interestingly, our findings are not in agreement with
results reported in rats by Till and Ward (32). They have shown that there is an increase in pulmonary microvascular permeability to protein after burn injury. The difference in experimental model and
the degree of resuscitation of the animals may relate to the results.
The burn wound in their rat model was second degree (partial thickness)
as opposed to the third-degree burns in our studies and those of
Demling et al. (7) and Harms et al.
(10). We are unable to study second-degree burns
in our ovine model because the injury is painful. In third-degree
burns, animals feel no pain because the nerve endings are destroyed.
Inadequate resuscitation may result in lung damage secondary to
reperfusion injury (31).
The cardiac dysfunction seen in the burn/smoke group seemed to consist
of two phases. An initial depression characterized by a significant
decrease in CI and stroke work index was observed within 3 h after
injury in both the burn and burn/smoke groups. The depression
correlated with the hemoconcentration evident from the significant
increase in Hct and the increase in SVRI. These phenomena may be
explained by a hypovolemia resulting from a large amount of fluid loss
from the circulation due to vascular hyperpermeability because the
burn-alone group showed a smooth recovery of cardiac function with
fluid resuscitation. The increased peripheral resistance could be the
result of sympathetic stimulation. Although there is still controversy
over what is the main cause of cardiac depression after thermal injury,
hypovolemia or the circulating cardiac depressant factor (2, 8,
19, 27), our results are consistent with hypovolemia as the
primary contributor. However, analysis of the relationship between
preload and stroke work index revealed that the depressed myocardial
contractility in both the burn and burn/smoke groups occurred
independent of the Starling mechanism, which may support the existence
of a myocardial depressant factor released from the burn wound. We
speculate that burn wounds release vasoactive mediators that contribute
to the alteration of vascular permeability and vasoconstriction
immediately after thermal injury. However, the mediator might be
inactivated by the administration of large amounts of fluid. The
duration of release and the amount of mediator released from the burn
wound may also depend on the depth of the thermal injury.
On the other hand, the left side-dominant myocardial depression seen in
the later phase in the burn/smoke and smoke groups cannot be explained
by hypovolemia. It was observed beginning 18-24 h after injury. In
this regard, the Hct in the burn/smoke group peaked 24 h after
injury and then improved, which suggests that hemoconcentration was not
sustained beyond 24 h. The delayed-onset cardiac depression seen
in the burn and smoke combined injury group is likely related to the
smoke inhalation and subsequent progressive lung tissue inflammation.
Recent investigations (3, 9, 22) have demonstrated that
proinflammatory cytokines are circulating myocardial depressant
substances during inflammatory conditions such as septic shock,
ischemia-reperfusion injury, or burn. In addition, induction of
inducible nitric oxide (NO) synthase (iNOS) and the subsequent
overproduction of NO has been suggested as a myocardial depressant
factor as well as the inflammatory cytokines (3, 15, 22,
35). Recently, we (Traber, unpublished data) have found
a significant increase in plasma concentrations of nitrite/nitrate
(metabolites of NO) beginning 24 h after burn and smoke combined
injury in a sheep experimental model. It is unlikely that iNOS-NO
affects the initial cardiac depression seen with burn injury because
iNOS is not expressed before cell activation by inflammatory cytokines
and expression takes several hours to occur (16). However,
it is possible that NO plays some role in the cardiac dysfunction seen
in the later phase with burn and smoke inhalation combined injury.
In the present study, the airway blood flow was determined in each
group. The smoke and burn/smoke groups showed a significant increase in
blood flow immediately after injury. This augmented airway blood flow,
associated with inflammation in the airway, contributes to development
of the lung tissue damage seen with smoke inhalation injury by
transporting inflammatory mediators from the injured airway to the
pulmonary tissue through the bronchopulmonary shunt, which is a
communication between the systemic circulation supplying the airway and
the pulmonary microcirculation (1, 23). On the other hand,
the burn-alone group showed a significant increase in tracheal blood
flow 48 h after injury, which indicates that inflammatory events
occurred in the airway to which blood is supplied via the bronchial
artery from the systemic circulation. This result may support the
hypothesis that burn wounds release cytotoxic mediators, which play a
role in the pulmonary failure seen in the later phase of extensive
cutaneous burn injury.
In summary, the acute pathophysiological alterations observed after
combination injury with burn and smoke inhalation may be mostly related
to burn injury. The effect of the additional smoke inhalation was
observed later than 18-24 h after injury as progressive pulmonary
failure, with more severe edema formation and sustained left
side-dominant myocardial dysfunction. The lung edema formation was most
severe when the burn injury was associated with smoke inhalation
injury. The severity of lung edema seen with the combined injury is
mainly due to augmentation of pulmonary microvascular permeability to
fluid, not to protein.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: K. Soejima, Dept. of Plastic and Reconstructive Surgery, Tokyo Women's Medical Univ., 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan (E-mail: kasoejim{at}prs.twmu.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 28 March 2000; accepted in final form 16 January 2001.
 |
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