Introduction
Materials and methods
Instrumentation and surgical procedures
Experimental protocol
Hemodynamic monitoring and laboratory analyses
Immunohistochemical analysis and Western blots
Statistical analyses
Results
Baseline characteristics
Cardiovascular hemodynamics
Variable | Time point | sham | control | rhAT |
---|---|---|---|---|
CI
| BL | 6.1 (5.6; 6.7) | 5.9 (5.7; 6.7) | 6.8 (6.1; 7.8) |
(L/min/m
2
)
| 6 h | 6.7 (6.0; 7.5) | 6.2 (5.3; 7.2) | 6.7 (5.6; 7.5) |
12 h | 6.9 (6.4; 7.0) | 6.0 (4.7; 7.4) | 7.8 (6.9; 8.4) | |
24 h | 7.1 (6.6; 7.4) | 5.5 (5.0; 5.6)# | 8.0 (6.8; 8.8)† | |
36 h | 6.2 (5.4; 7.3) | 5.6 (5.3; 6.4) | 6.7 (6.3; 7.8) | |
48 h | 6.5 (6.4; 6.9) | 4.5 (4.4; 7.2) | 6.7 (5.8; 7.7) | |
MAP
| BL | 97 (93; 98) | 101 (93; 113) | 105 (96; 110) |
(mmHg)
| 6 h | 100 (94; 102) | 103 (99; 108) | 104 (96; 108) |
12 h | 95 (91; 104) | 100 (98; 109) | 102 (94; 102) | |
24 h | 92 (89; 98) | 102 (99; 107) | 95 (93; 106) | |
36 h | 92 (87; 98) | 100 (89; 104) | 103 (100; 108) | |
48 h | 93 (90; 98) | 101 (90; 111) | 101(99; 106) | |
CVP
| BL | 5 (5; 5) | 6 (5; 8) | 5 (4; 6) |
(mmHg)
| 6 h | 7 (6; 11) | 9 (7; 10) | 9 (8; 10) |
12 h | 9 (5; 10) | 10 (7; 11) | 9 (7; 9) | |
24 h | 8 (7; 10) | 12 (10; 14)*# | 7 (5; 11) | |
36 h | 10 (7; 11) | 13 (12; 14)*# | 7 (6; 10)† | |
48 h | 9 (9; 11) | 11 (7; 13) | 6 (5; 8) | |
LAP
| BL | 7 (6; 8) | 9 (8; 10) | 9 (9; 10) |
(mmHg)
| 6 h | 9 (9; 9) | 9 (7; 11) | 10 (8; 12) |
12 h | 12 (11; 12) | 11 (9; 13) | 11 (9; 12) | |
24 h | 11 (10; 12) | 12 (11; 13)* | 10 (9; 11) | |
36 h | 12 (9; 13) | 14 (13; 16)* | 10 (8; 14) | |
48 h | 11 (9; 13) | 17 (15; 18)*# | 8 (7; 9)† | |
LVSWI
| BL | 77 (67; 87) | 75 (67; 83) | 86 (73; 93) |
(g/m/m
2
)
| 6 h | 78 (57; 89) | 57 (45; 75) | 79 (64; 86) |
12 h | 66 (64; 72) | 50 (44; 60)* | 74 (60; 91) | |
24 h | 67 (59; 77) | 35 (34; 37)*# | 71 (56; 80)† | |
36 h | 71 (65; 76) | 35 (31; 43)*# | 73 (61; 86)† | |
48 h | 73 (72; 76) | 43 (42; 55)*# | 66 (63; 73)† | |
RVSWI
| BL | 13 (13; 14) | 12 (10; 15) | 13 (11; 15) |
(g/m/m
2
)
| 6 h | 13 (11; 17) | 13 (10; 15) | 13 (11; 17) |
12 h | 16 (14; 17) | 13 (11; 16) | 16 (14; 18) | |
24 h | 15 (15; 17) | 9 (8; 11)# | 15 (11; 17) | |
36 h | 16 (14; 17) | 8 (7; 12)# | 13 (13; 17) | |
48 h | 15 (13; 16) | 10 (9; 12) | 16 (11; 19) |
Vascular leakage and fluid accumulation
Variable | Time point | sham | control | rhAT |
---|---|---|---|---|
Hematocrit
| BL | 27 (22; 29) | 24 (23; 27) | 26 (21; 26) |
(%)
| 6 h | 23 (22; 26) | 27 (23; 29) | 25 (21; 26) |
12 h | 26 (23; 30) | 28 (24; 31) | 26 (24; 27) | |
24 h | 25 (24; 27) | 30 (27; 32) | 27 (22; 27) | |
36 h | 23 (23; 26) | 29 (28; 36)*# | 27 (27; 28) | |
48 h | 22 (21; 25) | 27 (24; 35) | 26 (24; 29) | |
Protein
| BL | 6.1 (6.0; 6.2) | 6.2 (5.8; 6.6) | 6.1 (6.0; 6.4) |
(g/dL)
| 6 h | 5.7 (5.6; 6.0) | 4.9 (4.6; 5.0)*# | 5.0 (4.6; 5.4)*# |
12 h | 6.1 (5.9; 6.4) | 4.5 (4.4; 4.6)*# | 4.9 (4.8; 5.0)*#† | |
24 h | 5.9 (5.8; 6.2) | 4.0 (4.0; 4.0)*# | 4.6 (4.6; 4.6)*#† | |
36 h | 5.9 (5.7; 6.2) | 3.6 (3.6; 3.9)*# | 4.7 (4.6; 5.0)*#† | |
48 h | 5.6 (5.6; 5.8) | 3.8 (3.5; 3.9)*# | 5.0 (4.5; 5.3)*#† | |
Oncotic pressure
| BL | 19 (17; 20) | 19 (18; 20) | 20 (19; 22) |
(cmH
2
O)
| 6 h | 18 (16; 19) | 13 (12; 14)*# | 14 (13; 16)*# |
12 h | 18 (16; 20) | 12 (11; 13)*# | 14 (13; 15)*# | |
24 h | 19 (16; 20) | 10 (9; 10)*# | 13 (12; 14)*#† | |
36 h | 19 (16; 20) | 9 (9; 11)*# | 13 (13; 15)*#† | |
48 h | 17 (15; 18) | 9 (9; 10)*# | 13 (12; 15)*#† | |
Urine flow
| BL | / | / | / |
(mL/kg/h)
| 6 h | 7.7 (6.8; 8.3) | 3.4 (2.5; 4.3)# | 3.2 (1.6; 4.7)# |
12 h | 7.4 (4.5; 9.0) | 2.7 (2.0; 4.5)# | 2.7 (2.4; 3.8)# | |
24 h | 4.5 (2.7; 5.7) | 1.2 (1.1; 2.0)# | 4.0 (3.0; 5.2)† | |
36 h | 2.3 (2.0; 2.9) | 0.6 (0.3; 0.8)# | 4.1 (3.7; 5.4)#† | |
48 h | 2.4 (2.1; 2.5) | 0.8 (0.8; 0.9)# | 3.3 (2.6; 3.8)† | |
Creatinine clearance
| BL | / | / | / |
(mL/min)
| 6 h | / | / | / |
12 h | 105 (97; 129) | 89 (78; 141) | 78 (76; 124) | |
24 h | 88 (78; 176) | 84 (71; 94) | 100 (91; 115) | |
36 h | 107 (84; 135) | 104 (74; 122) | 120 (106; 134) | |
48 h | 102 (81; 112) | 91 (88; 94) | 96 (82; 115) | |
AT plasma level
| BL | 86 (83; 89) | 79 (72; 82) | 87 (73; 93) |
(mg/L)
| 6 h | 86 (81; 89) | 58 (57; 59)*# | 88 (83; 89)† |
12 h | 87 (83; 91) | 52 (50; 55)*# | 85 (81; 95)† | |
24 h | 86 (73; 88) | 45 (40; 50)*# | 83 (75; 84)† | |
36 h | 86 (76; 88) | 47 (40; 48)*# | 86 (80; 87)† | |
48 h | 83 (75; 88) | 52 (47; 54)*# | 84 (73; 87)† |
Gas exchange and global oxygen transport
Laboratory analyses
Immunohistochemical analyses and Western blots
Variable | sham | control | rhAT |
---|---|---|---|
Myeloperoxidase activity (U/mL)
| 105 (104; 106) | 132 (120; 139)# | 114 (105; 118)† |
p38-MAPK (arbitrary units)
| 2.3 (1.8; 3.5) | 6.1 (5.4; 6.5)# | 2.8 (2.3; 3.0)† |
TNF-α (arbitrary units)
| 2.1 (1.8; 2.1) | 2.7 (2.6; 2.8)# | 2.0 (1.6; 2.4)† |
IL-6 (arbitrary units)
| 1.4 (1.3; 2.0) | 4.0 (3.0; 4.6)# | 2.1 (1.9; 2.8)† |
Discussion
Conclusions
Key messages
-
Combined burn and smoke inhalation injury is associated with a marked myocardial dysfunction. To compensate for the reduced stroke volume, heart rate and eventually myocardial oxygen consumption are increased.
-
Impairment of myocardial function after burn and smoke inhalation injury is characterized by an activation of the p38-mitogen-activated protein kinase pathway, myocardial neutrophil accumulation and increased nitric oxide production.
-
The therapeutic infusion of recombinant human antithrombin restored myocardial function to the level of sham (not injured) animals, resulting in higher stroke volumes and reduced myocardial oxygen consumption.
-
The therapeutic infusion of recombinant human antithrombin reversed cumulative systemic fluid accumulation back to the level of sham animals at 48 h.
-
The attenuated inflammatory response, as suggested by a reduced activation of the p38-mitogen-activated protein kinase pathway resulting in lower cytokine release, less myocardial neutrophil accumulation and less nitric oxide production, presents a potential mechanism of action.