Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Hemorrhagic Shock and the Microvasculature

Ivo Torres Filho

10.1002/cphy.c170006

Source: Volume 8, Issue 1, January 2018

Published online: December 2017

Full Article on Wiley Online Library



ABSTRACT

The microvasculature plays a central role in the pathophysiology of hemorrhagic shock and is also involved in arguably all therapeutic attempts to reverse or minimize the adverse consequences of shock. Microvascular studies specific to hemorrhagic shock were reviewed and broadly grouped depending on whether data were obtained on animal or human subjects. Dedicated sections were assigned to microcirculatory changes in specific organs, and major categories of pathophysiological alterations and mechanisms such as oxygen distribution, ischemia, inflammation, glycocalyx changes, vasomotion, endothelial dysfunction, and coagulopathy as well as biomarkers and some therapeutic strategies. Innovative experimental methods were also reviewed for quantitative microcirculatory assessment as it pertains to changes during hemorrhagic shock. The text and figures include representative quantitative microvascular data obtained in various organs and tissues such as skin, muscle, lung, liver, brain, heart, kidney, pancreas, intestines, and mesentery from various species including mice, rats, hamsters, sheep, swine, bats, and humans. Based on reviewed findings, a new integrative conceptual model is presented that includes about 100 systemic and local factors linked to microvessels in hemorrhagic shock. The combination of systemic measures with the understanding of these processes at the microvascular level is fundamental to further develop targeted and personalized interventions that will reduce tissue injury, organ dysfunction, and ultimately mortality due to hemorrhagic shock. Published 2018. Compr Physiol 8:61‐101, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Diagram of the system used to evaluate in vivo thrombus formation and platelet adhesion in instrumented rats subjected to HS. A computer‐controlled laser produced endothelial damage in cremaster microvessels. Previously injected fluorescent platelets were imaged using a confocal spinning disc head, laser, and camera. Red blood cell velocity was measured online. Hemorrhage was induced using two synchronized syringe pumps. Systemic parameters were simultaneously recorded while blood samples were collected for immediate analysis. Top left shows fluorescent cold‐stored platelets (arrows) adhering to a thrombus formed in a rat cremaster venule during HS, under flow (left arrow), and an adhering leukocyte (arrowhead); bar is 10 µm. Adapted from (429) with permission.
Figure 2. Figure 2. Average bat wing data for unanesthetized animals (Myotis lucifugus, five per group): Controls (no hemorrhage), severe hemorrhage (40 mL/kg, mean body mass = 7 g), and hemorrhage plus sympathetic denervation 1 week prior to hemorrhage by surgical interruption of the tegmental nerve in the axillary area. The control diameters were 33.8 ± 2.9 µm and 37.0 ± 2.6 µm for innervated and denervated vessels, respectively. Note the disappearance of posthemorrhage vasoconstriction after denervation. Modified from (176) with permission.
Figure 3. Figure 3. On left, typical images of the rabbit ear using a laser Doppler image (LDI) and a charge‐coupled device (CCD) during baseline (pre) and different times posthemorrhagic shock (HS). Mean arterial pressure (MAP) and LDI flux levels according to the flux scale on top right are indicated. The perfusion flux for nine animals is shown on right (mean ± SD). **Values were statistically different from pre‐HS (pre). Adapted from (268) with permission.
Figure 4. Figure 4. Functional capillary density (FCD) in the dorsal skinfold before HS (baseline), during HS, and after autologous whole blood resuscitation for unanesthetized hamsters surviving in good or bad conditions, and not surviving. *Significantly different from baseline; +significantly different between survivors and nonsurvivors; #significantly different between survivors in good and bad condition (P < 0.05). Adapted from (226) with permission.
Figure 5. Figure 5. Intestinal microvasculature after gelatin ink injection (Panel I) and scanning electron microscopy (Panel II) in WT mice at various magnifications. Panel 1. (A) Sham surgery. Complete visualization of crypt vessels, and villi apical and basal portions; (B) HS/R (MAP at 30 to 35 mmHg for 90 min followed by 3 h reperfusion). Only partial visualization of the microvasculature, indicating hypoperfusion; (C) sham surgery. Visualization of arterioles (a), capillaries, and venules (v); [(D)‐(F)] HS/R. (D) Vessels of the distal villi have been destroyed. (E) Arterioles and some capillaries are visualized, but not venules. (F) Only some vessels of basal villous vasculature are visualized. Arrows indicate villous plexus, arrowheads indicate cryptal plexus. Panel II. [(A) and (B)] Normal preparation after sham surgery, showing arterioles, capillaries, and venules; [(C)‐(F)] after HS/R. (C) Vessels of the distal villi (arrowheads) have been destroyed. (D) Arterioles and some capillaries are visible but not venules. (E) Only arterioles are visible. (F) Narrowing of precapillary arterioles and postcapillary venules (white circles). (G) Sham surgery showing lack of narrowing of arterioles and venules. Magnifications: Panel I, [(A) and (B)]: 50×, [(C)‐(F)]: 200×. Panel II. (A): 200×, (B): 450×, (C): 350×, (D): 150×, (E): 180×, (F): 800×, (G): 1000×. Adapted from (519) with permission.
Figure 6. Figure 6. Systemic and local inflammatory responses, and organ damage markers to HS and resuscitation (R). (A) Systemic concentrations of tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, and neutrophil gelatinase‐associated lipocalin (NGAL) protein in plasma of control mice and mice subjected to 90 min of HS and 90 min of HS followed by R (1 and 4 h). (B) Messenger RNA (mRNA) expression of endothelial proinflammatory molecules (cell adhesion molecules and cytokines), vascular integrity‐related molecules [receptor tyrosine kinase (Tie2), cluster of differentiation 31 (CD31), vascular endothelial cadherin (VE‐cad), and angiopoietin (Ang)‐2], and organ damage‐related marker NGAL in kidneys determined by real‐time reverse transcriptase‐polymerase chain reaction. Data are mean ± SD of each group (eight animals per group). * P < 0.05 compared to healthy control; # P < 0.05, 1 h after R versus 90 min HS; and 4 h after R versus 90 min HS. ICAM‐1, intercellular adhesion molecule 1; KLF‐2, Kruppel‐like factor 2; MCP‐1, monocyte chemotactic protein 1; and VCAM‐1, vascular cell adhesion molecule 1. From (250) with permission.
Figure 7. Figure 7. (A) Microvascular PO2 measured in the surfaces of the left ventricle (heart) and the ileum (gut) of swine subjected to HS and resuscitation. Values are mean ± SD. *Statistically different from baseline and †from previous time point (P < 0.05). [(B) and (C)] Correlation analyses of microvascular PO2 in the heart and gut versus cardiac index and mean arterial pressure (MAP), during HS and resuscitation. P < 0.001 for all four correlations. Adapted from (449) with permission.
Figure 8. Figure 8. Example of exposed viscera (A) and laser speckle imaging [(B) and (C)] of microcirculatory blood flow intensities after HS only (group H) in an anesthetized rat. The regions of interest are marked as liver (1), kidney (2), intestinal mucosa (3), serosal muscular layer (4), Peyer's patch (PP, 5), and gracilis muscle (6). (D) Percent changes of blood flow intensity 3 h after HS (T3) compared to baseline (T0) are shown for organs from animals that also received resuscitation (group R, cross bars) or only HS (group H, blank bars). Groups marked 1, 2, and 3 have different percent changes in blood flow (1 < 2 < 3, P < 0.05). Groups marked with ^ represent a significant change between H and R groups. Adapted from (502) with permission.
Figure 9. Figure 9. Progressive hemorrhage in sheep caused significant decrease in cardiac output [panel (A)] and increase in arterial lactate (B). Simultaneous measurements of the microcirculation using sidestream dark‐field (SDF) imaging device [(C)‐(E)] showed significant changes in the semiquantitative flow index from the first step of bleeding. * P < 0.05 versus basal, § P < 0.05 versus CONTROL. From (135) with permission.
Figure 10. Figure 10. Vasomotion and flowmotion after HS in rats. [(A) and (B)] Pancreas: Arteriolar vasomotion was found in 51% of 115 vessels, and intermittent capillary perfusion was observed in all 220 areas, 1 h into HS (40 mmHg). Arrowheads are mean values. From (465) with permission. (C) Mesentery: Diameter recordings during HS (50 mmHg) and postinfusion (control diameter: 29 µm). Vasomotion was found in 24% of 63 arterioles from 16 animals. After hypertonic solution, the number of vessels showing vasomotion increased 80%, and vasomotion amplitude also increased. From (421) with permission. (D) Skeletal muscle (gastrocnemius): Using laser‐Doppler flowmetry (LDF), flowmotion was observed in all 10 animals subjected to progressive hemorrhage. Flowmotion appeared in animals bled 21% of estimated blood volume but disappeared when lower levels of mean arterial pressure (MAP) were reached. Adapted from (171) with permission. [(E) and (F)] Skeletal muscle (diaphragm): Using LDF, flowmotion appeared when animals were kept for 30 min at each indicated MAP. Data in parentheses are numbers of animals (from a total of 24). Adapted from (86) with permission.
Figure 11. Figure 11. Oxygenation and hemodynamic parameters of swine subjected to withdrawal of 40% (A) and 50% (B) of the total blood volume. Microvascular oxygen pressure (µPO2) in the exposed ileum was measured by quenched phosphorescence of Pd‐porphyrin using a fiber phosphorimeter. Data are means ± SD. All shock values were significantly different from preshock values (P < 0.05). MAP, mean arterial blood pressure; a.u., arbitrary units. Adapted from (394) with permission.
Figure 12. Figure 12. Dissociation between systemic arterial pO2 [(paO2, (A)] and microvascular pO2 in hamster skinfold arterioles A1 (B), A2 (C), A3 (D), and A4 (E) during hemorrhagic shock. *Significantly different from control (Con) values. +Significantly different between survivors and nonsurvivors. Adapted from (223) with permission.
Figure 13. Figure 13. Rat mesenteric microvascular pO2 during baseline and during hemorrhagic hypotension (HH, MAP of 50 mmHg for 30 min) expressed as a function of baseline diameter. Systemic pO2 values (Sys.) are also plotted for reference. *All values during HH were statistically different from baseline. Note the appearance of longitudinal pO2 gradients for arterioles and venules during HH. Adapted from (431) with permission.
Figure 14. Figure 14. First evidences of EG degradation during HS obtained using intravital microscopy in anesthetized rats. (A) Special video analysis allows estimating EG thickness from measurement of the gap between RBC image and luminal EC surface (462). Using this technique, a reduction of nearly 50% in EG thickness was measured after HS. From (430) with permission. (B) The EG thickness after HS was 41% of the baseline as measured in 27 vessels from mesentery and cremaster of eight rats using another in vivo methodology. The difference was significant compared to baseline (same group) and to a control group at the same time point (* P < 0.001 on both cases). Data are mean + SEM. Adapted from (418) with permission.
Figure 15. Figure 15. [(A)‐(C)] EG thickness measured from images obtained in cremaster postcapillary venules in vivo. Rats were subjected to HS and resuscitated with lactated Ringer's (LR), Hextend (HEX), fresh frozen plasma (FFP), fresh whole blood (FWB), packed red blood cells (PRBC), or washed PRBC (wPRBC). Some animals were left untreated (Sham) or received hemorrhage only (HEM). Measurements were made before (baseline) and after HS/resuscitation showed EG thickness reduction in HEM, LR, HEX, and wPRBC groups. *Significantly different from baseline; †significantly different from Sham group; #significantly different from FFP group. (D) Electron microscopic images of venules stained with uranyl acetate and lead citrate reveal the EG in different groups of rats after HS and resuscitation with LR or fresh plasma. Black arrows indicate cell membrane and white arrows the EG. Each bar is 1 µm. (E) Image processing also showed EG degradation but important recovery after plasma treatment. Letters indicate statistical difference between groups. (B) Sham versus shock, P < 0.001; sham versus LR, P = 0.001; (C) sham versus plasma, P = 0.01; shock versus plasma, P = 0.001; (B) LR versus plasma, P < 0.001. Data expressed as mean ± SEM. (A) and (B) adapted from (235) with permission; (C): modified from (433) with permission; [(D) and (E)]: modified from (432) with permission.
Figure 16. Figure 16. Representative macroscale view of small intestine, heart [right ventricle (rv)], and lung in sham control (n = 5) and at 2 h after HS in rats without (n = 3) and with a pancreatic enzyme inhibitor (n = 3). Characteristic lesion sites due to escape of RBCs from microvessels are marked by arrows. Adapted from (126) with permission.
Figure 17. Figure 17. Responses of healthy volunteers to progressive LBNP at systemic [(A)‐(F)] and tissue level [(G)‐(I)]. CO, cardiac output; HR, heart rate; MAP, mean arterial blood pressure; DO2, oxygen delivery; O2ER, oxygen extraction ratio; FCD, functional capillary density in sublingual mucosa; SO2, oxygen saturation in the flexor digitorum profundus muscle of the right forearm. Data are means ± SE; n = 20, except for FCD (n = 16), muscle SO2 and pH and (n = 18). * P ≤ 0.013 [(A)‐(C)] and P ≤ 0.047 [(D)‐(I)] compared to baseline. Adapted from (482) with permission.
Figure 18. Figure 18. (A) Microcirculatory flow index (MFI) and (B) proportion of perfused vessels (PPV) of the sublingual mucosa of 18 patients in the first 4 days (D1‐D4) after traumatic HS, obtained using SDF imaging. (C) Receiving operating characteristic (ROC) curves for prediction of Sequential Organ Failure Assessment ≥ 6 at D4 with blood and microvascular variables. Hb, hemoglobin. *Significantly different from control (P < 0.05). Adapted from (410) with permission.
Figure 19. Figure 19. Injury severity score (ISS), circulating catecholamines on admission, and 30‐day mortality in 75 trauma patients, stratified according to high (> median, n = 38) versus low (< median, n = 37) circulating plasma syndecan‐1, a marker for EG degradation. Median values with interquartile ranges are shown. P values represent results for Wilcoxon‐Rank Sum tests. Adapted from (212) with permission.
Figure 20. Figure 20. Integrative diagram of the main factors involving microvessels in HS. Following significant hemorrhage and trauma, microvascular ECs are exposed to lower levels of O2 and hydrostatic blood pressure but increased amounts of catecholamines, and other vasoactive compounds such as vasopressin. Rheological changes include hematocrit and viscosity, especially if resuscitation fluids are used. Platelet‐activating factor (PAF) is also involved, altering vascular reactivity, permeability, and leukocyte‐EC adherence. Leukocytes (WBC), red blood cells (RBC), and platelets (PLT) are affected, changing their interaction with activated ECs. Leukocyte activation is a critical step in formation of reactive O2 species (ROS). Degradation of plasminogen activator inhibitor‐1 (PAI‐1) and higher levels of tissue plasminogen activator (tPA) lead to activated protein C (APC) and is a major driver for coagulopathy, together with thrombomodulin (TM) released by activated EC, PLT dysfunction, microparticle (MP) levels and EG degradation products. Proinflammatory cytokines cause activation of nuclear factor‐κB (NF‐κB) signaling (including IκB kinase, IKK activity), leading to transcription of adhesion molecules (selectins, vascular cell adhesion molecule, VCAM‐1, intercellular adhesion molecule, ICAM‐1), inflammatory cytokines interleukins (IL), and monocyte chemotactic protein, MCP‐1. Angiopoietins (Ang‐1 and ‐2) bind to the tyrosine kinase receptor Tie2, and participate in permeability control. EG degradation and adherens complex disruption contribute to hyperpermeability. Changes in shear rate are sensed by the EC through mechanotransduction and further affect other intracellular processes, decreasing the Kruppel‐like factor (KLF2), disrupting histone deacetylase (HDAC) activity, and reducing production of nitric oxide (NO) by the endothelial NO synthase (eNOS). Vessel hyporeactivity may involve NO, and Rho family proteins RAC1 and RhoA. Neural influences as well as physicochemical changes in blood and tissue alter microvascular resistance, responsiveness, and vasomotion. EC swelling also occurs. Microvascular O2 partial pressure (PO2), O2 saturation (SO2), and functional capillary density (FCD) are critically associated with survival. Blood flow is redistributed among microvessels during HS, also affecting O2 distribution. Microvessels are affected by tissue changes such as lower O2 and pH, higher CO2, and ROS production. Heme oxygenase 1 (HO‐1) expression is induced by oxidative stress. Multiple factors linked to organ damage and EC activation are released into circulation, and function as biomarkers.


Figure 1. Diagram of the system used to evaluate in vivo thrombus formation and platelet adhesion in instrumented rats subjected to HS. A computer‐controlled laser produced endothelial damage in cremaster microvessels. Previously injected fluorescent platelets were imaged using a confocal spinning disc head, laser, and camera. Red blood cell velocity was measured online. Hemorrhage was induced using two synchronized syringe pumps. Systemic parameters were simultaneously recorded while blood samples were collected for immediate analysis. Top left shows fluorescent cold‐stored platelets (arrows) adhering to a thrombus formed in a rat cremaster venule during HS, under flow (left arrow), and an adhering leukocyte (arrowhead); bar is 10 µm. Adapted from (429) with permission.


Figure 2. Average bat wing data for unanesthetized animals (Myotis lucifugus, five per group): Controls (no hemorrhage), severe hemorrhage (40 mL/kg, mean body mass = 7 g), and hemorrhage plus sympathetic denervation 1 week prior to hemorrhage by surgical interruption of the tegmental nerve in the axillary area. The control diameters were 33.8 ± 2.9 µm and 37.0 ± 2.6 µm for innervated and denervated vessels, respectively. Note the disappearance of posthemorrhage vasoconstriction after denervation. Modified from (176) with permission.


Figure 3. On left, typical images of the rabbit ear using a laser Doppler image (LDI) and a charge‐coupled device (CCD) during baseline (pre) and different times posthemorrhagic shock (HS). Mean arterial pressure (MAP) and LDI flux levels according to the flux scale on top right are indicated. The perfusion flux for nine animals is shown on right (mean ± SD). **Values were statistically different from pre‐HS (pre). Adapted from (268) with permission.


Figure 4. Functional capillary density (FCD) in the dorsal skinfold before HS (baseline), during HS, and after autologous whole blood resuscitation for unanesthetized hamsters surviving in good or bad conditions, and not surviving. *Significantly different from baseline; +significantly different between survivors and nonsurvivors; #significantly different between survivors in good and bad condition (P < 0.05). Adapted from (226) with permission.


Figure 5. Intestinal microvasculature after gelatin ink injection (Panel I) and scanning electron microscopy (Panel II) in WT mice at various magnifications. Panel 1. (A) Sham surgery. Complete visualization of crypt vessels, and villi apical and basal portions; (B) HS/R (MAP at 30 to 35 mmHg for 90 min followed by 3 h reperfusion). Only partial visualization of the microvasculature, indicating hypoperfusion; (C) sham surgery. Visualization of arterioles (a), capillaries, and venules (v); [(D)‐(F)] HS/R. (D) Vessels of the distal villi have been destroyed. (E) Arterioles and some capillaries are visualized, but not venules. (F) Only some vessels of basal villous vasculature are visualized. Arrows indicate villous plexus, arrowheads indicate cryptal plexus. Panel II. [(A) and (B)] Normal preparation after sham surgery, showing arterioles, capillaries, and venules; [(C)‐(F)] after HS/R. (C) Vessels of the distal villi (arrowheads) have been destroyed. (D) Arterioles and some capillaries are visible but not venules. (E) Only arterioles are visible. (F) Narrowing of precapillary arterioles and postcapillary venules (white circles). (G) Sham surgery showing lack of narrowing of arterioles and venules. Magnifications: Panel I, [(A) and (B)]: 50×, [(C)‐(F)]: 200×. Panel II. (A): 200×, (B): 450×, (C): 350×, (D): 150×, (E): 180×, (F): 800×, (G): 1000×. Adapted from (519) with permission.


Figure 6. Systemic and local inflammatory responses, and organ damage markers to HS and resuscitation (R). (A) Systemic concentrations of tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, and neutrophil gelatinase‐associated lipocalin (NGAL) protein in plasma of control mice and mice subjected to 90 min of HS and 90 min of HS followed by R (1 and 4 h). (B) Messenger RNA (mRNA) expression of endothelial proinflammatory molecules (cell adhesion molecules and cytokines), vascular integrity‐related molecules [receptor tyrosine kinase (Tie2), cluster of differentiation 31 (CD31), vascular endothelial cadherin (VE‐cad), and angiopoietin (Ang)‐2], and organ damage‐related marker NGAL in kidneys determined by real‐time reverse transcriptase‐polymerase chain reaction. Data are mean ± SD of each group (eight animals per group). * P < 0.05 compared to healthy control; # P < 0.05, 1 h after R versus 90 min HS; and 4 h after R versus 90 min HS. ICAM‐1, intercellular adhesion molecule 1; KLF‐2, Kruppel‐like factor 2; MCP‐1, monocyte chemotactic protein 1; and VCAM‐1, vascular cell adhesion molecule 1. From (250) with permission.


Figure 7. (A) Microvascular PO2 measured in the surfaces of the left ventricle (heart) and the ileum (gut) of swine subjected to HS and resuscitation. Values are mean ± SD. *Statistically different from baseline and †from previous time point (P < 0.05). [(B) and (C)] Correlation analyses of microvascular PO2 in the heart and gut versus cardiac index and mean arterial pressure (MAP), during HS and resuscitation. P < 0.001 for all four correlations. Adapted from (449) with permission.


Figure 8. Example of exposed viscera (A) and laser speckle imaging [(B) and (C)] of microcirculatory blood flow intensities after HS only (group H) in an anesthetized rat. The regions of interest are marked as liver (1), kidney (2), intestinal mucosa (3), serosal muscular layer (4), Peyer's patch (PP, 5), and gracilis muscle (6). (D) Percent changes of blood flow intensity 3 h after HS (T3) compared to baseline (T0) are shown for organs from animals that also received resuscitation (group R, cross bars) or only HS (group H, blank bars). Groups marked 1, 2, and 3 have different percent changes in blood flow (1 < 2 < 3, P < 0.05). Groups marked with ^ represent a significant change between H and R groups. Adapted from (502) with permission.


Figure 9. Progressive hemorrhage in sheep caused significant decrease in cardiac output [panel (A)] and increase in arterial lactate (B). Simultaneous measurements of the microcirculation using sidestream dark‐field (SDF) imaging device [(C)‐(E)] showed significant changes in the semiquantitative flow index from the first step of bleeding. * P < 0.05 versus basal, § P < 0.05 versus CONTROL. From (135) with permission.


Figure 10. Vasomotion and flowmotion after HS in rats. [(A) and (B)] Pancreas: Arteriolar vasomotion was found in 51% of 115 vessels, and intermittent capillary perfusion was observed in all 220 areas, 1 h into HS (40 mmHg). Arrowheads are mean values. From (465) with permission. (C) Mesentery: Diameter recordings during HS (50 mmHg) and postinfusion (control diameter: 29 µm). Vasomotion was found in 24% of 63 arterioles from 16 animals. After hypertonic solution, the number of vessels showing vasomotion increased 80%, and vasomotion amplitude also increased. From (421) with permission. (D) Skeletal muscle (gastrocnemius): Using laser‐Doppler flowmetry (LDF), flowmotion was observed in all 10 animals subjected to progressive hemorrhage. Flowmotion appeared in animals bled 21% of estimated blood volume but disappeared when lower levels of mean arterial pressure (MAP) were reached. Adapted from (171) with permission. [(E) and (F)] Skeletal muscle (diaphragm): Using LDF, flowmotion appeared when animals were kept for 30 min at each indicated MAP. Data in parentheses are numbers of animals (from a total of 24). Adapted from (86) with permission.


Figure 11. Oxygenation and hemodynamic parameters of swine subjected to withdrawal of 40% (A) and 50% (B) of the total blood volume. Microvascular oxygen pressure (µPO2) in the exposed ileum was measured by quenched phosphorescence of Pd‐porphyrin using a fiber phosphorimeter. Data are means ± SD. All shock values were significantly different from preshock values (P < 0.05). MAP, mean arterial blood pressure; a.u., arbitrary units. Adapted from (394) with permission.


Figure 12. Dissociation between systemic arterial pO2 [(paO2, (A)] and microvascular pO2 in hamster skinfold arterioles A1 (B), A2 (C), A3 (D), and A4 (E) during hemorrhagic shock. *Significantly different from control (Con) values. +Significantly different between survivors and nonsurvivors. Adapted from (223) with permission.


Figure 13. Rat mesenteric microvascular pO2 during baseline and during hemorrhagic hypotension (HH, MAP of 50 mmHg for 30 min) expressed as a function of baseline diameter. Systemic pO2 values (Sys.) are also plotted for reference. *All values during HH were statistically different from baseline. Note the appearance of longitudinal pO2 gradients for arterioles and venules during HH. Adapted from (431) with permission.


Figure 14. First evidences of EG degradation during HS obtained using intravital microscopy in anesthetized rats. (A) Special video analysis allows estimating EG thickness from measurement of the gap between RBC image and luminal EC surface (462). Using this technique, a reduction of nearly 50% in EG thickness was measured after HS. From (430) with permission. (B) The EG thickness after HS was 41% of the baseline as measured in 27 vessels from mesentery and cremaster of eight rats using another in vivo methodology. The difference was significant compared to baseline (same group) and to a control group at the same time point (* P < 0.001 on both cases). Data are mean + SEM. Adapted from (418) with permission.


Figure 15. [(A)‐(C)] EG thickness measured from images obtained in cremaster postcapillary venules in vivo. Rats were subjected to HS and resuscitated with lactated Ringer's (LR), Hextend (HEX), fresh frozen plasma (FFP), fresh whole blood (FWB), packed red blood cells (PRBC), or washed PRBC (wPRBC). Some animals were left untreated (Sham) or received hemorrhage only (HEM). Measurements were made before (baseline) and after HS/resuscitation showed EG thickness reduction in HEM, LR, HEX, and wPRBC groups. *Significantly different from baseline; †significantly different from Sham group; #significantly different from FFP group. (D) Electron microscopic images of venules stained with uranyl acetate and lead citrate reveal the EG in different groups of rats after HS and resuscitation with LR or fresh plasma. Black arrows indicate cell membrane and white arrows the EG. Each bar is 1 µm. (E) Image processing also showed EG degradation but important recovery after plasma treatment. Letters indicate statistical difference between groups. (B) Sham versus shock, P < 0.001; sham versus LR, P = 0.001; (C) sham versus plasma, P = 0.01; shock versus plasma, P = 0.001; (B) LR versus plasma, P < 0.001. Data expressed as mean ± SEM. (A) and (B) adapted from (235) with permission; (C): modified from (433) with permission; [(D) and (E)]: modified from (432) with permission.


Figure 16. Representative macroscale view of small intestine, heart [right ventricle (rv)], and lung in sham control (n = 5) and at 2 h after HS in rats without (n = 3) and with a pancreatic enzyme inhibitor (n = 3). Characteristic lesion sites due to escape of RBCs from microvessels are marked by arrows. Adapted from (126) with permission.


Figure 17. Responses of healthy volunteers to progressive LBNP at systemic [(A)‐(F)] and tissue level [(G)‐(I)]. CO, cardiac output; HR, heart rate; MAP, mean arterial blood pressure; DO2, oxygen delivery; O2ER, oxygen extraction ratio; FCD, functional capillary density in sublingual mucosa; SO2, oxygen saturation in the flexor digitorum profundus muscle of the right forearm. Data are means ± SE; n = 20, except for FCD (n = 16), muscle SO2 and pH and (n = 18). * P ≤ 0.013 [(A)‐(C)] and P ≤ 0.047 [(D)‐(I)] compared to baseline. Adapted from (482) with permission.


Figure 18. (A) Microcirculatory flow index (MFI) and (B) proportion of perfused vessels (PPV) of the sublingual mucosa of 18 patients in the first 4 days (D1‐D4) after traumatic HS, obtained using SDF imaging. (C) Receiving operating characteristic (ROC) curves for prediction of Sequential Organ Failure Assessment ≥ 6 at D4 with blood and microvascular variables. Hb, hemoglobin. *Significantly different from control (P < 0.05). Adapted from (410) with permission.


Figure 19. Injury severity score (ISS), circulating catecholamines on admission, and 30‐day mortality in 75 trauma patients, stratified according to high (> median, n = 38) versus low (< median, n = 37) circulating plasma syndecan‐1, a marker for EG degradation. Median values with interquartile ranges are shown. P values represent results for Wilcoxon‐Rank Sum tests. Adapted from (212) with permission.


Figure 20. Integrative diagram of the main factors involving microvessels in HS. Following significant hemorrhage and trauma, microvascular ECs are exposed to lower levels of O2 and hydrostatic blood pressure but increased amounts of catecholamines, and other vasoactive compounds such as vasopressin. Rheological changes include hematocrit and viscosity, especially if resuscitation fluids are used. Platelet‐activating factor (PAF) is also involved, altering vascular reactivity, permeability, and leukocyte‐EC adherence. Leukocytes (WBC), red blood cells (RBC), and platelets (PLT) are affected, changing their interaction with activated ECs. Leukocyte activation is a critical step in formation of reactive O2 species (ROS). Degradation of plasminogen activator inhibitor‐1 (PAI‐1) and higher levels of tissue plasminogen activator (tPA) lead to activated protein C (APC) and is a major driver for coagulopathy, together with thrombomodulin (TM) released by activated EC, PLT dysfunction, microparticle (MP) levels and EG degradation products. Proinflammatory cytokines cause activation of nuclear factor‐κB (NF‐κB) signaling (including IκB kinase, IKK activity), leading to transcription of adhesion molecules (selectins, vascular cell adhesion molecule, VCAM‐1, intercellular adhesion molecule, ICAM‐1), inflammatory cytokines interleukins (IL), and monocyte chemotactic protein, MCP‐1. Angiopoietins (Ang‐1 and ‐2) bind to the tyrosine kinase receptor Tie2, and participate in permeability control. EG degradation and adherens complex disruption contribute to hyperpermeability. Changes in shear rate are sensed by the EC through mechanotransduction and further affect other intracellular processes, decreasing the Kruppel‐like factor (KLF2), disrupting histone deacetylase (HDAC) activity, and reducing production of nitric oxide (NO) by the endothelial NO synthase (eNOS). Vessel hyporeactivity may involve NO, and Rho family proteins RAC1 and RhoA. Neural influences as well as physicochemical changes in blood and tissue alter microvascular resistance, responsiveness, and vasomotion. EC swelling also occurs. Microvascular O2 partial pressure (PO2), O2 saturation (SO2), and functional capillary density (FCD) are critically associated with survival. Blood flow is redistributed among microvessels during HS, also affecting O2 distribution. Microvessels are affected by tissue changes such as lower O2 and pH, higher CO2, and ROS production. Heme oxygenase 1 (HO‐1) expression is induced by oxidative stress. Multiple factors linked to organ damage and EC activation are released into circulation, and function as biomarkers.
References
 1. Aalkjaer C , Boedtkjer D , Matchkov V . Vasomotion—What is currently thought? Acta Physiol (Oxf) 202: 253‐269, 2011.
 2. Aalkjaer C , Nilsson H . Vasomotion: Cellular background for the oscillator and for the synchronization of smooth muscle cells. Br J Pharmacol 144: 605‐616, 2005.
 3. Achakri H , Stergiopulos N , Hoogerwerf N , Hayoz D , Brunner HR , Meister JJ . Intraluminal pressure modulates the magnitude and the frequency of induced vasomotion in rat arteries. J Vasc Res 32: 237‐246, 1995.
 4. Adolphs J , Schmidt DK , Mousa SA , Kamin B , Korsukewitz I , Habazettl H , Schafer M , Welte M . Thoracic epidural anesthesia attenuates hemorrhage‐induced impairment of intestinal perfusion in rats. Anesthesiology 99: 685‐692, 2003.
 5. Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100: 158‐173, 2007.
 6. Aksu U , Bezemer R , Yavuz B , Kandil A , Demirci C , Ince C . Balanced vs unbalanced crystalloid resuscitation in a near‐fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation. Resuscitation 83: 767‐773, 2012.
 7. Altura BM . DPAVP: A vasopressin analog with selective microvascular and RES actions for the treatment of circulatory shock in rats. Eur J Pharmacol 37: 155‐167, 1976.
 8. Altura BM. Microcirculatory approach to the treatment of circulatory shock with a new analog of vasopressin, (2‐phenylalanine, 8‐ornithine)vasopressin. J Pharmacol Exp Ther 198: 187‐196, 1976.
 9. Amundson B , Bagge U . Hemorrhage and skeletal muscle microcirculation. Scand J Plast Reconstr Surg Suppl 19: 16‐17, 1982.
 10. Amundson B , Bagge U , Haljamae H . Control of tissue environment during vital microscopy of the microcirculation in the m. tenuissimus in cat. Acta Physiol Scand 108: 139‐146, 1980.
 11. Amundson B , Jennische E , Haljamae H . Correlative analysis of microcirculatory and cellular metabolic events in skeletal muscle during hemorrhagic shock. Acta Physiol Scand 108: 147‐158, 1980.
 12. Angele MK , Schneider CP , Chaudry IH . Bench‐to‐bedside review: Latest results in hemorrhagic shock. Crit Care 12: 218, 2008.
 13. Audonnet‐Blaise S , Krafft MP , Smani Y , Mertes PM , Marie PY , Labrude P , Longrois D , Menu P . Resuscitation of severe but brief haemorrhagic shock with PFC in rabbits restores skeletal muscle oxygen delivery and does not alter skeletal muscle metabolism. Resuscitation 70: 124‐132, 2006.
 14. Ba ZF , Shimizu T , Szalay L , Bland KI , Chaudry IH . Gender differences in small intestinal perfusion following trauma hemorrhage: The role of endothelin‐1. Am J Physiol Gastrointest Liver Physiol 288: G860‐G865, 2005.
 15. Badonnel MC , DeGirolami U , Joris I , Majno G . The intracerebral microcirculation of the rat in hemorrhagic shock. J Neuropathol Exp Neurol 42: 561‐578, 1983.
 16. Badr KF , Ichikawa I . Prerenal failure: A deleterious shift from renal compensation to decompensation. N Engl J Med 319: 623‐629, 1988.
 17. Baez S , Orkin LR . Microcirculatory effects of anesthesia in shock. Int Anesthesiol Clin 2: 365‐383, 1964.
 18. Baker M , Wayland H . On‐line volume flow rate and velocity profile measurement for blood in microvessels. Microvasc Res 7: 131‐143, 1974.
 19. Balaz D , Komornikova A , Sabaka P , Leichenbergova E , Leichenbergova K , Novy M , Kralikova D , Gaspar L , Dukat A . Changes in vasomotion—Effect of hyperbaric oxygen in patients with diabetes Type 2. Undersea Hyperb Med 43: 123‐134, 2016.
 20. Ban K , Peng Z , Pati S , Witkov RB , Park PW , Kozar RA . Plasma‐mediated gut protection after hemorrhagic shock is lessened in syndecan‐1‐/‐ MICE. Shock 44: 452‐457, 2015.
 21. Baron BJ , Sinert R , Zehtabchi S , Stavile KL , Scalea TM . Diagnostic utility of sublingual PCO2 for detecting hemorrhage in penetrating trauma patients. J Trauma 57: 69‐74, 2004.
 22. Barroso‐Aranda J , Schmid‐Schonbein GW . Transformation of neutrophils as indicator of irreversibility in hemorrhagic shock. Am J Physiol 257: H846‐H852, 1989.
 23. Barroso‐Aranda J , Schmid‐Schonbein GW , Zweifach BW , Engler RL . Granulocytes and no‐reflow phenomenon in irreversible hemorrhagic shock. Circ Res 63: 437‐447, 1988.
 24. Barroso‐Aranda J , Zweifach BW , Mathison JC , Schmid‐Schonbein GW . Neutrophil activation, tumor necrosis factor, and survival after endotoxic and hemorrhagic shock. J Cardiovasc Pharmacol 25(Suppl 2): S23‐S29, 1995.
 25. Bartlett AH , Hayashida K , Park PW . Molecular and cellular mechanisms of syndecans in tissue injury and inflammation. Mol Cells 24: 153‐166, 2007.
 26. Bauer C , Kuntz W , Ohnsmann F , Gasser H , Weber C , Redl H , Marzi I . The attenuation of hepatic microcirculatory alterations by exogenous substitution of nitric oxide by s‐nitroso‐human albumin after hemorrhagic shock in the rat. Shock 21: 165‐169, 2004.
 27. Bauer I , Wanner GA , Rensing H , Alte C , Miescher EA , Wolf B , Pannen BH , Clemens MG , Bauer M . Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress‐exposed rat liver. Hepatology 27: 829‐838, 1998.
 28. Becker BF , Fischer J , Hartmann H , Chen CC , Sommerhoff CP , Tschoep J , Conzen PC , Annecke T . Inosine, not adenosine, initiates endothelial glycocalyx degradation in cardiac ischemia and hypoxia. Nucleosides Nucleotides Nucleic Acids 30: 1161‐1167, 2011.
 29. Becker BF , Jacob M , Leipert S , Salmon AH , Chappell D . Degradation of the endothelial glycocalyx in clinical settings: Searching for the sheddases. Br J Clin Pharmacol 80: 389‐402, 2015.
 30. Behrman SW , Fabian TC , Kudsk KA , Proctor KG . Microcirculatory flow changes after initial resuscitation of hemorrhagic shock with 7.5% hypertonic saline/6% dextran 70. J Trauma 31: 589‐598; discussion 599‐600, 1991.
 31. Beilman GJ , Groehler KE , Lazaron V , Ortner JP . Near‐infrared spectroscopy measurement of regional tissue oxyhemoglobin saturation during hemorrhagic shock. Shock 12: 196‐200, 1999.
 32. Belizaire RM , Prakash PS , Richter JR , Robinson BR , Edwards MJ , Caldwell CC , Lentsch AB , Pritts TA . Microparticles from stored red blood cells activate neutrophils and cause lung injury after hemorrhage and resuscitation. J Am Coll Surg 214: 648‐655; discussion 656‐647, 2012.
 33. Bellamy RF , Pedersen DC , DeGuzman LR . Organ blood flow and the cause of death following massive hemorrhage. Circ Shock 14: 113‐127, 1984.
 34. Bennett HS , Luft JH , Hampton JC . Morphological classifications of vertebrate blood capillaries. Am J Physiol 196: 381‐390, 1959.
 35. Bertuglia S , Colantuoni A . Venular oscillatory flow during hemorrhagic shock and NO inhibition in hamster cheek pouch microcirculation. Microvasc Res 54: 233‐242, 1997.
 36. Bezemer R , Faber DJ , Almac E , Kalkman J , Legrand M , Heger M , Ince C . Evaluation of multi‐exponential curve fitting analysis of oxygen‐quenched phosphorescence decay traces for recovering microvascular oxygen tension histograms. Med Biol Eng Comput 48: 1233‐1242, 2010.
 37. Bezemer R , Legrand M , Klijn E , Heger M , Post IC , van Gulik TM , Payen D , Ince C . Real‐time assessment of renal cortical microvascular perfusion heterogeneities using near‐infrared laser speckle imaging. Opt Express 18: 15054‐15061, 2010.
 38. Bhattacharjee H , Nadipuram A , Kosanke S , Kiani MF , Moore BM, II . Low‐volume binary drug therapy for the treatment of hypovolemia. Shock 35: 590‐596, 2011.
 39. Bicher HI , Bruley D , Knisely MH , Reneau DD . Effect of microcirculation changes on brain tissue oxygenation. J Physiol 217: 689‐707, 1971.
 40. Bjerkvig CK , Strandenes G , Eliassen HS , Spinella PC , Fosse TK , Cap AP , Ward KR . “Blood failure” time to view blood as an organ: How oxygen debt contributes to blood failure and its implications for remote damage control resuscitation. Transfusion 56(Suppl 2): S182‐S189, 2016.
 41. Blahitka J , Rakusan K . Blood flow in rats during hemorrhagic shock: Differences between surviving and dying animals. Circ Shock 4: 79‐93, 1977.
 42. Bohlen HG , Gore RW . Preparation of rat intestinal muscle and mucosa for quantitative microcirculatory studies. Microvasc Res 11: 103‐110, 1976.
 43. Bojic S , Kotur‐Stevuljevic J , Kalezic N , Stevanovic P , Jelic‐Ivanovic Z , Bilanovic D , Memon L , Damnjanovic M , Kalaba Z , Simic‐Ogrizovic S . Diagnostic value of matrix metalloproteinase‐9 and tissue inhibitor of matrix metalloproteinase‐1 in sepsis‐associated acute kidney injury. Tohoku J Exp Med 237: 103‐109, 2015.
 44. Boldt J , Ince C . The impact of fluid therapy on microcirculation and tissue oxygenation in hypovolemic patients: A review. Intensive Care Med 36: 1299‐1308, 2010.
 45. Borgstrom P , Bruttig SP , Lindbom L , Intaglietta M , Arfors KE . Microvascular responses in rabbit skeletal muscle after fixed volume hemorrhage. Am J Physiol 259: H190‐H196, 1990.
 46. Borgstrom P , Schmidt JA , Bruttig SP , Intaglietta M , Arfors KE . Slow‐wave flowmotion in rabbit skeletal muscle after acute fixed‐volume hemorrhage. Circ Shock 36: 57‐61, 1992.
 47. Bougle A , Harrois A , Duranteau J . Resuscitative strategies in traumatic hemorrhagic shock. Ann Intensive Care 3: 1, 2013.
 48. Bouskela E. Vasomotion frequency and amplitude related to intraluminal pressure and temperature in the wing of the intact, unanesthetized bat. Microvasc Res 37: 339‐351, 1989.
 49. Bouskela E , Grampp W , Mellander S . Effects of hypertonic NaCl solution on the hamster cheek pouch microcirculation in normo‐ and hypovolemia. Braz J Med Biol Res 22: 259‐264, 1989.
 50. Bouskela E , Grampp W , Mellander S . Effects of hypertonic NaCl solution on microvascular haemodynamics in normo‐ and hypovolaemia. Acta Physiol Scand 140: 85‐94, 1990.
 51. Bouskela E , Wiederhielm CA . Microvascular myogenic reaction in the wing of the intact unanesthetized bat. Am J Physiol 237: H59‐H65, 1979.
 52. Branemark PI. Rheological aspects of low flow states. In: Microcirculation As Related to Shock. New York: Academic Press, 1968, pp. 161‐180.
 53. Branemark PI. Microvascular function at reduced flow rates. J Tissue Viability 16: 16‐18, 2006.
 54. Bredenberg CE , Nomoto S , Webb WR . Pulmonary and systemic hemodynamics during hemorrhagic shock in baboons. Ann Surg 192: 86‐94, 1980.
 55. Breithaupt‐Faloppa AC , Fantozzi ET , de Assis Ramos MM , Vitoretti LB , Couto GK , Lino‐dos‐Santos‐Franco A , Rossoni LV , Oliveira‐Filho RM , Vargaftig BB , Tavares‐de‐Lima W . Protective effect of estradiol on acute lung inflammation induced by an intestinal ischemic insult is dependent on nitric oxide. Shock 40: 203‐209, 2013.
 56. Breslin JW , Daines DA , Doggett TM , Kurtz KH , Souza‐Smith FM , Zhang XE , Wu MH , Yuan SY . Rnd3 as a novel target to ameliorate microvascular leakage. J Am Heart Assoc 5: e003336, 2016.
 57. Brezis M , Heyman SN , Epstein FH . Determinants of intrarenal oxygenation. II. Hemodynamic effects. Am J Physiol 267: F1063‐F1068, 1994.
 58. Broekhuizen LN , Lemkes BA , Mooij HL , Meuwese MC , Verberne H , Holleman F , Schlingemann RO , Nieuwdorp M , Stroes ES , Vink H . Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia 53: 2646‐2655, 2010.
 59. Brookes ZL , Brown NJ , Reilly CS . Differential effects of intravenous anaesthetic agents on the response of rat mesenteric microcirculation in vivo after haemorrhage. Br J Anaesth 88: 255‐263, 2002.
 60. Bruegger D , Jacob M , Rehm M , Loetsch M , Welsch U , Conzen P , Becker BF . Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts. Am J Physiol Heart Circ Physiol 289: H1993‐H1999, 2005.
 61. Bulger EM , Jurkovich GJ , Nathens AB , Copass MK , Hanson S , Cooper C , Liu PY , Neff M , Awan AB , Warner K , Maier RV . Hypertonic resuscitation of hypovolemic shock after blunt trauma: A randomized controlled trial. Arch Surg 143: 139‐148; discussion 149, 2008.
 62. Bulger EM , May S , Kerby JD , Emerson S , Stiell IG , Schreiber MA , Brasel KJ , Tisherman SA , Coimbra R , Rizoli S , Minei JP , Hata JS , Sopko G , Evans DC , Hoyt DB , investigators ROC. Out‐of‐hospital hypertonic resuscitation after traumatic hypovolemic shock: A randomized, placebo controlled trial. Ann Surg 253: 431‐441, 2011.
 63. Cabrales P. Low dose nitrite enhances perfusion after fluid resuscitation from hemorrhagic shock. Resuscitation 80: 1431‐1436, 2009.
 64. Cabrales P , Intaglietta M , Tsai AG . Increase plasma viscosity sustains microcirculation after resuscitation from hemorrhagic shock and continuous bleeding. Shock 23: 549‐555, 2005.
 65. Cabrales P , Intaglietta M , Tsai AG . Transfusion restores blood viscosity and reinstates microvascular conditions from hemorrhagic shock independent of oxygen carrying capacity. Resuscitation 75: 124‐134, 2007.
 66. Cabrales P , Nacharaju P , Manjula BN , Tsai AG , Acharya SA , Intaglietta M . Early difference in tissue pH and microvascular hemodynamics in hemorrhagic shock resuscitation using polyethylene glycol‐albumin‐ and hydroxyethyl starch‐based plasma expanders. Shock 24: 66‐73, 2005.
 67. Cabrales P , Tsai AG , Intaglietta M . Increased plasma viscosity prolongs microhemodynamic conditions during small volume resuscitation from hemorrhagic shock. Resuscitation 77: 379‐386, 2008.
 68. Cabrales P , Tsai AG , Intaglietta M . Exogenous nitric oxide induces protection during hemorrhagic shock. Resuscitation 80: 707‐712, 2009.
 69. Cabrales P , Tsai AG , Intaglietta M . Hemorrhagic shock resuscitation with carbon monoxide saturated blood. Resuscitation 72: 306‐318, 2007.
 70. Cabrales P , Tsai AG , Intaglietta M . Microvascular pressure and functional capillary density in extreme hemodilution with low‐ and high‐viscosity dextran and a low‐viscosity Hb‐based O2 carrier. Am J Physiol Heart Circ Physiol 287: H363‐H373, 2004.
 71. Cardenas JC , Wade CE , Holcomb JB . Mechanisms of trauma‐induced coagulopathy. Curr Opin Hematol 21: 404‐409, 2014.
 72. Carpentier P , Franco A . La Capillaroscopie Périunguéale. Paris Maisons-Alfort: Laboratoire Lafon, 1981.
 73. Cecconi M , De Backer D , Antonelli M , Beale R , Bakker J , Hofer C , Jaeschke R , Mebazaa A , Pinsky MR , Teboul JL , Vincent JL , Rhodes A . Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 40: 1795‐1815, 2014.
 74. Chambers R , Zweifach B . Topography and function of the mesenteric capillary circulation. Am J Anat 75: 173‐205, 1944.
 75. Chang R , Cardenas JC , Wade CE , Holcomb JB . Advances in the understanding of trauma‐induced coagulopathy. Blood 128: 1043‐1049, 2016.
 76. Chappell D , Brettner F , Doerfler N , Jacob M , Rehm M , Bruegger D , Conzen P , Jacob B , Becker BF . Protection of glycocalyx decreases platelet adhesion after ischaemia/reperfusion: An animal study. Eur J Anaesthesiol 31: 474‐481, 2014.
 77. Chappell D , Dorfler N , Jacob M , Rehm M , Welsch U , Conzen P , Becker BF . Glycocalyx protection reduces leukocyte adhesion after ischemia/reperfusion. Shock 34: 133‐139, 2010.
 78. Chappell D , Heindl B , Jacob M , Annecke T , Chen C , Rehm M , Conzen P , Becker BF . Sevoflurane reduces leukocyte and platelet adhesion after ischemia‐reperfusion by protecting the endothelial glycocalyx. Anesthesiology 115: 483‐491, 2011.
 79. Chappell D , Hofmann‐Kiefer K , Jacob M , Rehm M , Briegel J , Welsch U , Conzen P , Becker BF . TNF‐alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol 104: 78‐89, 2009.
 80. Chappell D , Jacob M , Hofmann‐Kiefer K , Bruegger D , Rehm M , Conzen P , Welsch U , Becker BF . Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology 107: 776‐784, 2007.
 81. Chappell D , Jacob M , Hofmann‐Kiefer K , Rehm M , Welsch U , Conzen P , Becker BF . Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc Res 83: 388‐396, 2009.
 82. Chappell D , Jacob M , Paul O , Rehm M , Welsch U , Stoeckelhuber M , Conzen P , Becker BF . The glycocalyx of the human umbilical vein endothelial cell: An impressive structure ex vivo but not in culture. Circ Res 104: 1313‐1317, 2009.
 83. Chelazzi C , Villa G , Mancinelli P , De Gaudio AR , Adembri C . Glycocalyx and sepsis‐induced alterations in vascular permeability. Crit Care 19: 26, 2015.
 84. Chen B , Mutschler M , Yuan Y , Neugebauer E , Huang Q , Maegele M . Superimposed traumatic brain injury modulates vasomotor responses in third‐order vessels after hemorrhagic shock. Scand J Trauma Resusc Emerg Med 21: 77, 2013.
 85. Chen CW , Hsiue TR , Chang HY . Effects of N(omega)‐nitro‐L‐arginine (L‐NOARG) on blood flow and vasomotion in rat diaphragm microcirculation during hemorrhagic hypotension. Shock 12: 69‐74, 1999.
 86. Chen CW , Lee CH , Hsiue TR , Chang HY . Vasomotion in rat diaphragm microcirculation at rest and during stepwise arterial pressure reduction. Acta Physiol Scand 161: 281‐288, 1997.
 87. Chen H , Inocencio R , Alam HB , Rhee P , Koustova E . Differential expression of extracellular matrix remodeling genes in rat model of hemorrhagic shock and resuscitation. J Surg Res 123: 235‐244, 2005.
 88. Chesebro BB , Rahn P , Carles M , Esmon CT , Xu J , Brohi K , Frith D , Pittet JF , Cohen MJ . Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock 32: 659‐665, 2009.
 89. Cheung AT , Duong PL , Driessen B , Chen PC , Jahr JS , Gunther RA . Systemic function, oxygenation and microvascular correlation during treatment of hemorrhagic shock with blood substitutes. Clin Hemorheol Microcirc 34: 325‐334, 2006.
 90. Chien S. Role of the sympathetic nervous system in hemorrhage. Physiol Rev 47: 214‐288, 1967.
 91. Chignalia AZ , Yetimakman F , Christiaans SC , Unal S , Bayrakci B , Wagener BM , Russell RT , Kerby JD , Pittet JF , Dull RO . The glycocalyx and trauma: A review. Shock 45: 338‐348, 2016.
 92. Childs EW , Tharakan B , Byrge N , Tinsley JH , Hunter FA , Smythe WR . Angiopoietin‐1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock. Am J Physiol Heart Circ Physiol 294: H2285‐H2295, 2008.
 93. Childs EW , Tharakan B , Hunter FA , Isong M , Liggins ND . Mitochondrial complex III is involved in proapoptotic BAK‐induced microvascular endothelial cell hyperpermeability. Shock 29: 636‐641, 2008.
 94. Childs EW , Tharakan B , Hunter FA , Smythe WR . 17beta‐estradiol mediated protection against vascular leak after hemorrhagic shock: Role of estrogen receptors and apoptotic signaling. Shock 34: 229‐235, 2010.
 95. Childs EW , Tharakan B , Hunter FA , Tinsley JH , Cao X . Apoptotic signaling induces hyperpermeability following hemorrhagic shock. Am J Physiol Heart Circ Physiol 292: H3179‐H3189, 2007.
 96. Childs EW , Udobi KF , Hunter FA . Hypothermia reduces microvascular permeability and reactive oxygen species expression after hemorrhagic shock. J Trauma 58: 271‐277, 2005.
 97. Childs EW , Udobi KF , Wood JG , Hunter FA , Smalley DM , Cheung LY . In vivo visualization of reactive oxidants and leukocyte‐endothelial adherence following hemorrhagic shock. Shock 18: 423‐427, 2002.
 98. Choi JY , Lee WH , Yoo TK , Park I , Kim DW . A new severity predicting index for hemorrhagic shock using lactate concentration and peripheral perfusion in a rat model. Shock 38: 635‐641, 2012.
 99. Chong SP , Merkle CW , Leahy C , Radhakrishnan H , Srinivasan VJ . Quantitative microvascular hemoglobin mapping using visible light spectroscopic optical coherence tomography. Biomed Opt Express 6: 1429‐1450, 2015.
 100. Clavijo JA , van Bastelaar J , Pinsky MR , Puyana JC , Mayevsky A . Minimally invasive real time monitoring of mitochondrial NADH and tissue blood flow in the urethral wall during hemorrhage and resuscitation. Med Sci Monit 14: BR175‐BR182, 2008.
 101. Coffey JC , O'Leary DP . The mesentery: Structure, function, and role in disease. Lancet Gastroenterol Hepatol 1: 238‐247, 2016.
 102. Colantuoni A , Bertuglia S , Intaglietta M . Microvessel diameter changes during hemorrhagic shock in unanesthetized hamsters. Microvasc Res 30: 133‐142, 1985.
 103. Colantuoni A , Bertuglia S , Intaglietta M . Microvascular vasomotion: Origin of laser Doppler flux motion. Int J Microcirc Clin Exp 14: 151‐158, 1994.
 104. Convertino VA , Grudic G , Mulligan J , Moulton S . Estimation of individual‐specific progression to impending cardiovascular instability using arterial waveforms. J Appl Physiol (1985) 115: 1196‐1202, 2013.
 105. Cooke WH , Ryan KL , Convertino VA . Lower body negative pressure as a model to study progression to acute hemorrhagic shock in humans. J Appl Physiol (1985) 96: 1249‐1261, 2004.
 106. Cooper ES , Bateman SW , Muir WW . Evaluation of hyperviscous fluid resuscitation in a canine model of hemorrhagic shock: A randomized, controlled study. J Trauma 66: 1365‐1373, 2009.
 107. Coyan GN , Moncure M , Thomas JH , Wood JG . Induced hypothermia during resuscitation from hemorrhagic shock attenuates microvascular inflammation in the rat mesenteric microcirculation. Shock 42: 518‐524, 2014.
 108. Crimi E , Taccone FS , Infante T , Scolletta S , Crudele V , Napoli C . Effects of intracellular acidosis on endothelial function: An overview. J Crit Care 27: 108‐118, 2012.
 109. Crookes BA , Cohn SM , Bloch S , Amortegui J , Manning R , Li P , Proctor MS , Hallal A , Blackbourne LH , Benjamin R , Soffer D , Habib F , Schulman CI , Duncan R , Proctor KG . Can near‐infrared spectroscopy identify the severity of shock in trauma patients? J Trauma 58: 806‐813; discussion 813‐806, 2005.
 110. Cryer HM , Kaebnick H , Harris PD , Flint LM . Effects of tissue acidosis on skeletal muscle microcirculatory responses to hemorrhagic shock in unanesthetized rats. J Surg Res 39: 59‐67, 1985.
 111. Curry FE , Adamson RH . Endothelial glycocalyx: Permeability barrier and mechanosensor. Ann Biomed Eng 40: 828‐839, 2012.
 112. Czabanka M , Peter C , Martin E , Walther A . Microcirculatory endothelial dysfunction during endotoxemia—Insights into pathophysiology, pathologic mechanisms and clinical relevance. Curr Vasc Pharmacol 5: 266‐275, 2007.
 113. Davenport RA , Brohi K . Cause of trauma‐induced coagulopathy. Curr Opin Anaesthesiol 29: 212‐219, 2016.
 114. Davis MJ. Determination of volumetric flow in capillary tubes using an optical Doppler velocimeter. Microvasc Res 34: 223‐230, 1987.
 115. Davis MJ , Gore RW . A new preparation for microcirculatory studies of the hamster cheek pouch. Am J Physiol 248: H143‐H146, 1985.
 116. Davis MJ , Hill MA , Kuo L . In: Local regulation of microvascular perfusion. Comprehensive Physiology. New York: John Wiley & Sons, 2011, pp. 161‐284.
 117. De Backer D , Creteur J , Dubois MJ , Sakr Y , Vincent JL . Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 147: 91‐99, 2004.
 118. De Backer D , Creteur J , Preiser JC , Dubois MJ , Vincent JL . Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166: 98‐104, 2002.
 119. De Backer D , Durand A . Monitoring the microcirculation in critically ill patients. Best Pract Res Clin Anaesthesiol 28: 441‐451, 2014.
 120. De Backer D , Hollenberg S , Boerma C , Goedhart P , Buchele G , Ospina‐Tascon G , Dobbe I , Ince C . How to evaluate the microcirculation: Report of a round table conference. Crit Care 11: R101, 2007.
 121. de Carvalho H , Matos JA , Bouskela E , Svensjo E . Vascular permeability increase and plasma volume loss induced by endotoxin was attenuated by hypertonic saline with or without dextran. Shock 12: 75‐80, 1999.
 122. de Werra I , Jaccard C , Corradin SB , Chiolero R , Yersin B , Gallati H , Assicot M , Bohuon C , Baumgartner JD , Glauser MP , Heumann D . Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors, and procalcitonin concentrations: comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia. Crit Care Med 25: 607‐613, 1997.
 123. Deb S , Martin B , Sun L , Ruff P , Burris D , Rich N , DeBreux S , Austin B , Rhee P . Resuscitation with lactated Ringer's solution in rats with hemorrhagic shock induces immediate apoptosis. J Trauma 46: 582‐588; discussion 588‐589, 1999.
 124. Deitch EA , Condon M , Feketeova E , Machiedo GW , Mason L , Vinluan GM , Alli VA , Neal MD , Tomaio JN , Fishman JE , Duran WN , Spolarics Z . Trauma‐hemorrhagic shock induces a CD36‐dependent RBC endothelial‐adhesive phenotype. Crit Care Med 42: e200‐e210, 2014.
 125. Dekker SE , Sillesen M , Bambakidis T , Jin G , Liu B , Boer C , Johansson PI , Halaweish I , Maxwell J , Alam HB . Normal saline influences coagulation and endothelial function after traumatic brain injury and hemorrhagic shock in pigs. Surgery 156: 556‐563, 2014.
 126. DeLano FA , Hoyt DB , Schmid‐Schonbein GW . Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci Transl Med 5: 169ra111, 2013.
 127. DeLano FA , Schmid‐Schonbein GW . Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock. Shock 41: 55‐61, 2014.
 128. Delano MJ , Rizoli SB , Rhind SG , Cuschieri J , Junger W , Baker AJ , Dubick MA , Hoyt DB , Bulger EM . Prehospital resuscitation of traumatic hemorrhagic shock with hypertonic solutions worsens hypocoagulation and hyperfibrinolysis. Shock 44: 25‐31, 2015.
 129. Demling RH. Lung fluid and protein dynamics during hemorrhagic shock, resuscitation, and recovery. Circ Shock 7: 149‐161, 1980.
 130. Demling RH , Duy N , Manohar M , Proctor R . Comparison between lung fluid filtration rate and measured starling forces after hemorrhagic and endotoxic shock. J Trauma 20: 856‐860, 1980.
 131. Demling RH , Manohar M , Will JA . Response of the pulmonary microcirculation to fluid loading after hemorrhagic shock and resuscitation. Surgery 87: 552‐559, 1980.
 132. Deng X , Cao Y , Huby MP , Duan C , Baer L , Peng Z , Kozar RA , Doursout MF , Holcomb JB , Wade CE , Ko TC . Adiponectin in fresh frozen plasma contributes to restoration of vascular barrier function after hemorrhagic shock. Shock 45: 50‐54, 2016.
 133. Driessen B , Zarucco L , Gunther RA , Burns PM , Lamb SV , Vincent SE , Boston RA , Jahr JS , Cheung AT . Effects of low‐volume hemoglobin glutamer‐200 versus normal saline and arginine vasopressin resuscitation on systemic and skeletal muscle blood flow and oxygenation in a canine hemorrhagic shock model. Crit Care Med 35: 2101‐2109, 2007.
 134. Drucker WR , Howard PL , McCoy S . The influence of diet on response to hemorrhagic shock. Ann Surg 181: 698‐704, 1975.
 135. Dubin A , Pozo MO , Ferrara G , Murias G , Martins E , Canullan C , Canales HS , Kanoore Edul VS , Estenssoro E , Ince C . Systemic and microcirculatory responses to progressive hemorrhage. Intensive Care Med 35: 556‐564, 2009.
 136. Duling BR , Gore RW , Dacey RG, Jr. , Damon DN . Methods for isolation, cannulation, and in vitro study of single microvessels. Am J Physiol 241: H108‐H116, 1981.
 137. Dunphy I , Vinogradov SA , Wilson DF . Oxyphor R2 and G2: Phosphors for measuring oxygen by oxygen‐dependent quenching of phosphorescence. Anal Biochem 310: 191‐198, 2002.
 138. Duret J , Pottecher J , Bouzat P , Brun J , Harrois A , Payen JF , Duranteau J . Skeletal muscle oxygenation in severe trauma patients during haemorrhagic shock resuscitation. Crit Care 19: 141, 2015.
 139. Eastridge BJ , Mabry RL , Seguin P , Cantrell J , Tops T , Uribe P , Mallett O , Zubko T , Oetjen‐Gerdes L , Rasmussen TE , Butler FK , Kotwal RS , Holcomb JB , Wade C , Champion H , Lawnick M , Moores L , Blackbourne LH . Death on the battlefield (2001‐2011): Implications for the future of combat casualty care. J Trauma Acute Care Surg 73: S431‐S437, 2012.
 140. Edul VS , Enrico C , Laviolle B , Vazquez AR , Ince C , Dubin A . Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock. Crit Care Med 40: 1443‐1448, 2012.
 141. Ekelund U , Bjornberg J , Mellander S . Alpha 2‐adrenoceptor activation may trigger the increased production of endothelium‐derived nitric oxide in skeletal muscle during acute haemorrhage. Acta Physiol Scand 164: 285‐292, 1998.
 142. Ekelund U , Mellander S . Endogenous nitric oxide as a physiological regulator of vascular tone in cat skeletal muscle during haemorrhage. Acta Physiol Scand 157: 471‐479, 1996.
 143. Ellis CG , Ellsworth ML , Pittman RN . Determination of red blood cell oxygenation in vivo by dual video densitometric image analysis. Am J Physiol 258: H1216‐H1223, 1990.
 144. Erni D , Banic A , Wheatley AM , Sigurdsson GH . Haemorrhage during anaesthesia and surgery: Continuous measurement of microcirculatory blood flow in the kidney, liver, skin and skeletal muscle. Eur J Anaesthesiol 12: 423‐429, 1995.
 145. Essayagh S , Brisset AC , Terrisse AD , Dupouy D , Tellier L , Navarro C , Arnal JF , Sie P . Microparticles from apoptotic vascular smooth muscle cells induce endothelial dysfunction, a phenomenon prevented by beta3‐integrin antagonists. Thromb Haemost 94: 853‐858, 2005.
 146. Estrada AD , Ponticorvo A , Ford TN , Dunn AK . Microvascular oxygen quantification using two‐photon microscopy. Opt Lett 33: 1038‐1040, 2008.
 147. Faber JE , Harris PD , Wiegman DL . Anesthetic depression of microcirculation, central hemodynamics, and respiration in decerebrate rats. Am J Physiol 243: H837‐H843, 1982.
 148. Fang X , Tang W , Sun S , Huang L , Chang YT , Castillo C , Weil MH . Comparison of buccal microcirculation between septic and hemorrhagic shock. Crit Care Med 34: S447‐S453, 2006.
 149. Fellahi J‐L , Butin G , Fischer M‐O , Zamparini G , Gérard J‐L , Hanouz J‐L . Dynamic evaluation of near‐infrared peripheral oximetry in healthy volunteers: A comparison between INVOS and EQUANOX. J Crit Care 28: 881.e881‐881.e886, 2013.
 150. Filho IT , Nguyen NM , Jivani R , Terner J , Romfh P , Vakhshoori D , Ward KR . Oxygen saturation monitoring using resonance Raman spectroscopy. J Surg Res 201: 425‐431, 2016.
 151. Filmus J , Capurro M , Rast J . Glypicans. Genome Biol 9: 224, 2008.
 152. Flusberg BA , Nimmerjahn A , Cocker ED , Mukamel EA , Barretto RP , Ko TH , Burns LD , Jung JC , Schnitzer MJ . High‐speed, miniaturized fluorescence microscopy in freely moving mice. Nat Methods 5: 935‐938, 2008.
 153. Fruchterman TM , Spain DA , Wilson MA , Harris PD , Garrison RN . Selective microvascular endothelial cell dysfunction in the small intestine following resuscitated hemorrhagic shock. Shock 10: 417‐422, 1998.
 154. Fulop A , Turoczi Z , Garbaisz D , Harsanyi L , Szijarto A . Experimental models of hemorrhagic shock: A review. Eur Surg Res 50: 57‐70, 2013.
 155. Gagnon L , Smith AF , Boas DA , Devor A , Secomb TW , Sakadzic S . Modeling of cerebral oxygen transport based on in vivo microscopic imaging of microvascular network structure, blood flow, and oxygenation. Front Comput Neurosci 10: 82, 2016.
 156. Geppert A , Steiner A , Zorn G , Delle‐Karth G , Koreny M , Haumer M , Siostrzonek P , Huber K , Heinz G . Multiple organ failure in patients with cardiogenic shock is associated with high plasma levels of interleukin‐6. Crit Care Med 30: 1987‐1994, 2002.
 157. Gill R , Tsung A , Billiar T . Linking oxidative stress to inflammation: Toll‐like receptors. Free Radic Biol Med 48: 1121‐1132, 2010.
 158. Goering J , Pope MR , Fleming SD . TLR2 regulates complement‐mediated inflammation induced by blood loss during hemorrhage. Shock 45: 33‐39, 2016.
 159. Golub AS , Popel AS , Zheng L , Pittman RN . Analysis of phosphorescence in heterogeneous systems using distributions of quencher concentration. Biophys J 73: 452‐465, 1997.
 160. Gomez H , Kautza B , Escobar D , Nassour I , Luciano J , Botero AM , Gordon L , Martinez S , Holder A , Ogundele O , Loughran P , Rosengart MR , Pinsky M , Shiva S , Zuckerbraun BS . Inhaled carbon monoxide protects against the development of shock and mitochondrial injury following hemorrhage and resuscitation. PLoS One 10: e0135032, 2015.
 161. Gong W , Marks JA , Sanati P , Sims C , Sarani B , Smith DH , Pascual JL . Hypertonic saline resuscitation of hemorrhagic shock does not decrease in vivo neutrophil interactions with endothelium in the blood‐brain microcirculation. J Trauma 71: 275‐281; discussion 281‐272, 2011.
 162. Gorbunova NA. Various mechanisms of disorders of the regulation of hemostasis in acute hemorrhage. Gematol Transfuziol 36: 3‐7, 1991.
 163. Gotte M. Syndecans in inflammation. FASEB J 17: 575‐591, 2003.
 164. Gouverneur M , Berg B , Nieuwdorp M , Stroes E , Vink H . Vasculoprotective properties of the endothelial glycocalyx: Effects of fluid shear stress. J Intern Med 259: 393‐400, 2006.
 165. Gray SD. Microscopic observation of skeletal muscle vascular responses to vasopressors during severe hemorrhagic hypotension. J Trauma 12: 147‐160, 1972.
 166. Grosslight K , Foster R , Colohan AR , Bedford RF . Isoflurane for neuroanesthesia: Risk factors for increases in intracranial pressure. Anesthesiology 63: 533‐536, 1985.
 167. Gruartmoner G , Mesquida J , Ince C . Fluid therapy and the hypovolemic microcirculation. Curr Opin Crit Care 21: 276‐284, 2015.
 168. Gulati A . Vascular endothelium and hypovolemic shock. Curr Vasc Pharmacol 14: 187‐195, 2016.
 169. Gunnarsson U , Hjelmqvist H , Rundgren M . Centrally mediated influences of hypertonic NaCl and angiotensin II on regional blood flow and hemodynamic responses to hypotensive hemorrhage in conscious sheep. Shock 2: 60‐67, 1994.
 170. Gustafsson U , Sjoberg F , Lewis DH , Thorborg P . Influence of pentobarbital, propofol and ketamine on skeletal muscle capillary perfusion during hemorrhage: A comparative study in the rabbit. Int J Microcirc Clin Exp 15: 163‐169, 1995.
 171. Gustafsson U , Wardell K , Nilsson GE , Lewis DH . Vasomotion in rat skeletal muscle induced by hemorrhage as recorded by laser‐Doppler flowmetry. Microvasc Res 42: 224‐228, 1991.
 172. Gutierrez G , Reines HD , Wulf‐Gutierrez ME . Clinical review: Hemorrhagic shock. Crit Care 8: 373‐381, 2004.
 173. Hahnenkamp K , Theilmeier G , Van Aken HK , Hoenemann CW . The effects of local anesthetics on perioperative coagulation, inflammation, and microcirculation. Anesth Analg 94: 1441‐1447, 2002.
 174. Haldenby KA , Chappell DC , Winlove CP , Parker KH , Firth JA . Focal and regional variations in the composition of the glycocalyx of large vessel endothelium. J Vasc Res 31: 2‐9, 1994.
 175. Haljamae H. Microcirculation and hemorrhagic shock. Am J Emerg Med 2: 100‐107, 1984.
 176. Harris PD , Greenwald EK , Nicoll PA . Neural mechanisms in small vessel response to hemorrhage in the unanesthetized bat. Am J Physiol 218: 560‐565, 1970.
 177. Harrois A , Baudry N , Huet O , Kato H , Lohez M , Ziol M , Duranteau J , Vicaut E . Synergistic deleterious effect of hypoxemia and hypovolemia on microcirculation in intestinal villi* . Crit Care Med 41: e376‐e384, 2013.
 178. Haugaa H , Gomez H , Maberry DR , Holder A , Ogundele O , Quintero AM , Escobar D , Tonnessen TI , Airgood H , Dezfulian C , Kenny E , Shiva S , Zuckerbraun B , Pinsky MR . Effects of inhalation of low‐dose nitrite or carbon monoxide on post‐reperfusion mitochondrial function and tissue injury in hemorrhagic shock swine. Crit Care 19: 184, 2015.
 179. Haywood‐Watson RJ , Holcomb JB , Gonzalez EA , Peng Z , Pati S , Park PW , Wang W , Zaske AM , Menge T , Kozar RA . Modulation of syndecan‐1 shedding after hemorrhagic shock and resuscitation. PLoS One 6: e23530, 2011.
 180. Helling TS. The liver and hemorrhagic shock. J Am Coll Surg 201: 774‐783, 2005.
 181. Henry CB , Duling BR . TNF‐alpha increases entry of macromolecules into luminal endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol 279: H2815‐H2823, 2000.
 182. Hershey SG , Zweifach BW . Peripheral vascular homeostasis in relation to anesthetic agents. Anesthesiology 11: 145‐154, 1950.
 183. Hierholzer C , Harbrecht BG , Billiar TR , Tweardy DJ . Hypoxia‐inducible factor‐1 activation and cyclo‐oxygenase‐2 induction are early reperfusion‐independent inflammatory events in hemorrhagic shock. Arch Orthop Trauma Surg 121: 219‐222, 2001.
 184. Hildebrand F , Hubbard WJ , Choudhry MA , Thobe BM , Pape HC , Chaudry IH . Are the protective effects of 17beta‐estradiol on splenic macrophages and splenocytes after trauma‐hemorrhage mediated via estrogen‐receptor (ER)‐alpha or ER‐beta? J Leukoc Biol 79: 1173‐1180, 2006.
 185. Hillen GP , Gaisford WD , Jensen CG . Pulmonary changes in treated and untreated hemorrhagic shock. I. Early functional and ultrastructural alterations after moderate shock. Am J Surg 122: 639‐649, 1971.
 186. Hinojosa‐Laborde C , Shade RE , Muniz GW , Bauer C , Goei KA , Pidcoke HF , Chung KK , Cap AP , Convertino VA . Validation of lower body negative pressure as an experimental model of hemorrhage. J Appl Physiol (1985) 116: 406‐415, 2014.
 187. Hiratsuka M , Katayama T , Uematsu K , Kiyomura M , Ito M . In vivo visualization of nitric oxide and interactions among platelets, leukocytes, and endothelium following hemorrhagic shock and reperfusion. Inflamm Res 58: 463‐471, 2009.
 188. Hofmann‐Kiefer KF , Kemming GI , Chappell D , Flondor M , Kisch‐Wedel H , Hauser A , Pallivathukal S , Conzen P , Rehm M . Serum heparan sulfate levels are elevated in endotoxemia. Eur J Med Res 14: 526‐531, 2009.
 189. Holcomb JB. A novel and potentially unifying mechanism for shock induced early coagulopathy. Ann Surg 254: 201‐202, 2011.
 190. Holcomb JB , del Junco DJ , Fox EE , Wade CE , Cohen MJ , Schreiber MA , Alarcon LH , Bai Y , Brasel KJ , Bulger EM , Cotton BA , Matijevic N , Muskat P , Myers JG , Phelan HA , White CE , Zhang J , Rahbar MH , Group PS . The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: Comparative effectiveness of a time‐varying treatment with competing risks. JAMA Surg 148: 127‐136, 2013.
 191. Horstick G , Lauterbach M , Kempf T , Bhakdi S , Heimann A , Horstick M , Meyer J , Kempski O . Early albumin infusion improves global and local hemodynamics and reduces inflammatory response in hemorrhagic shock. Crit Care Med 30: 851‐855, 2002.
 192. Hu Y , Yang G , Xiao X , Liu L , Li T . Bkca opener, NS1619 pretreatment protects against shock‐induced vascular hyporeactivity through PDZ‐Rho GEF‐RhoA‐Rho kinase pathway in rats. J Trauma Acute Care Surg 76: 394‐401, 2014.
 193. Hubbard W , Keith J , Berman J , Miller M , Scott C , Peck C , Chaudry IH . 17 alpha‐ethynylestradiol‐3‐sulfate treatment of severe blood loss in rats. J Surg Res 193: 355‐360, 2015.
 194. Huguet C , Nordlinger B , Bloch P , Conard J . Tolerance of the human liver to prolonged normothermic ischemia. A biological study of 20 patients submitted to extensive hepatectomy. Arch Surg 113: 1448‐1451, 1978.
 195. Hungerer S , Nolte D , Botzlar A , Messmer K . Effects of diaspirin crosslinked hemoglobin (DCLHb) on microcirculation and local tissue pO2 of striated skin muscle following resuscitation from hemorrhagic shock. Artif Cells Blood Substit Immobil Biotechnol 34: 455‐471, 2006.
 196. Hutchins PM , Goldstone J , Wells R . Effects of hemorrhagic shock on the microvasculature of skeletal muscle. Microvasc Res 5: 131‐140, 1973.
 197. Hyttel‐Sorensen S , Hessel TW , Greisen G . Peripheral tissue oximetry: Comparing three commercial near‐infrared spectroscopy oximeters on the forearm. J Clin Monit Comput 28: 149‐155, 2014.
 198. Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 19 Suppl 3: S8, 2015.
 199. Ince C , Mik EG . Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol (1985) 120: 226‐235, 2016.
 200. Inoue K , Takahashi T , Uehara K , Shimuzu H , Ido K , Morimatsu H , Omori E , Katayama H , Akagi R , Morita K . Protective role of heme oxygenase 1 in the intestinal tissue injury in hemorrhagic shock in rats. Shock 29: 252‐261, 2008.
 201. Intaglietta M. The measurement of pressure and flow in the microcirculation: Application to physiological and clinical problems. Med Prog Technol 4: 55‐60, 1976.
 202. Intaglietta M. Arteriolar vasomotion: Implications for tissue ischemia. Blood Vessels 28(Suppl 1): 1‐7, 1991.
 203. Intaglietta M , Tompkins WR . System for the measurement of velocity of microscopic particles in liquids. IEEE Trans Biomed Eng 18: 376‐379, 1971.
 204. Intaglietta M , Tompkins WR . On‐line measurement of microvascular dimensions by television microscopy. J Appl Physiol 32: 546‐551, 1972.
 205. Israel A. The IKK complex, a central regulator of NF‐kappaB activation. Cold Spring Harb Perspect Biol 2: a000158, 2010.
 206. Ivanov KP , Mel'nikova NN . Leukocytes as a cause of microcirculatory dysfunction. Bull Exp Biol Med 141: 666‐668, 2006.
 207. Japee SA , Ellis CG , Pittman RN . Flow visualization tools for image analysis of capillary networks. Microcirculation 11: 39‐54, 2004.
 208. Japee SA , Pittman RN , Ellis CG . A new video image analysis system to study red blood cell dynamics and oxygenation in capillary networks. Microcirculation 12: 489‐506, 2005.
 209. Jia JM , Chowdary PD , Gao X , Ci B , Li W , Mulgaonkar A , Plautz EJ , Hassan G , Kumar A , Stowe AM , Yang SH , Zhou W , Sun X , Cui B , Ge WP . Control of cerebral ischemia with magnetic nanoparticles. Nat Methods 14(2): 160‐166, 2017.
 210. Jiang H , Hu R , Sun L , Chai D , Cao Z , Li Q . Critical role of toll‐like receptor 4 in hypoxia‐inducible factor 1alpha activation during trauma/hemorrhagic shocky induced acute lung injury after lymph infusion in mice. Shock 42: 271‐278, 2014.
 211. Jin X , Weil MH , Sun S , Tang W , Bisera J , Mason EJ . Decreases in organ blood flows associated with increases in sublingual PCO2 during hemorrhagic shock. J Appl Physiol (1985) 85: 2360‐2364, 1998.
 212. Johansson PI , Stensballe J , Rasmussen LS , Ostrowski SR . A high admission syndecan‐1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg 254: 194‐200, 2011.
 213. Johnson BD , van Helmond N , Curry TB , van Buskirk CM , Convertino VA , Joyner MJ . Reductions in central venous pressure by lower body negative pressure or blood loss elicit similar hemodynamic responses. J Appl Physiol (1985) 117: 131‐141, 2014.
 214. Johnson PC. Photometric scanning techniques for measurement of blood vessel dimensions. Microvasc Res 5: 292‐298, 1973.
 215. Jones TW. Discovery that the veins of the bat's wing are endowed with rhythmical contractility and that onward flow of blood is accelerated by each contraction. Philos Trans Roy Soc Lond 142: 131‐136, 1852.
 216. Junger WG , Rhind SG , Rizoli SB , Cuschieri J , Shiu MY , Baker AJ , Li L , Shek PN , Hoyt DB , Bulger EM . Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline‐without dextran‐inhibits neutrophil and endothelial cell activation. Shock 38: 341‐350, 2012.
 217. Kalogeris T , Baines CP , Krenz M , Korthuis RJ . Ischemia/Reperfusion. Compr Physiol 7: 113‐170, 2016.
 218. Kamoun WS , Chae SS , Lacorre DA , Tyrrell JA , Mitre M , Gillissen MA , Fukumura D , Jain RK , Munn LL . Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks. Nat Methods 7: 655‐660, 2010.
 219. Kara A , Akin S , Ince C . Monitoring microcirculation in critical illness. Curr Opin Crit Care 22: 444‐452, 2016.
 220. Karin M. How NF‐kappaB is activated: The role of the IkappaB kinase (IKK) complex. Oncogene 18: 6867‐6874, 1999.
 221. Kauvar DS , Lefering R , Wade CE . Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 60: S3‐S11, 2006.
 222. Kerger H , Saltzman DJ , Gonzales A , Tsai AG , van Ackern K , Winslow RM , Intaglietta M . Microvascular oxygen delivery and interstitial oxygenation during sodium pentobarbital anesthesia. Anesthesiology 86: 372‐386, 1997.
 223. Kerger H , Saltzman DJ , Menger MD , Messmer K , Intaglietta M . Systemic and subcutaneous microvascular PO2 dissociation during 4‐h hemorrhagic shock in conscious hamsters. Am J Physiol 270: H827‐H836, 1996.
 224. Kerger H , Torres Filho IP , Rivas M , Winslow RM , Intaglietta M . Systemic and subcutaneous microvascular oxygen tension in conscious Syrian golden hamsters. Am J Physiol 268: H802‐H810, 1995.
 225. Kerger H , Tsai AG , Saltzman DJ , Winslow RM , Intaglietta M . Fluid resuscitation with O2 vs. non‐O2 carriers after 2 h of hemorrhagic shock in conscious hamsters. Am J Physiol 272: H525‐H537, 1997.
 226. Kerger H , Waschke KF , Ackern KV , Tsai AG , Intaglietta M . Systemic and microcirculatory effects of autologous whole blood resuscitation in severe hemorrhagic shock. Am J Physiol 276: H2035‐H2043, 1999.
 227. Kheirbek T , Kochanek AR , Alam HB . Hypothermia in bleeding trauma: A friend or a foe? Scand J Trauma Resusc Emerg Med 17: 65, 2009.
 228. Kitajima T , Tani K , Yamaguchi T , Kubota Y , Okuhira M , Mizuno T , Inoue K . Role of endogenous endothelin in gastric mucosal injury induced by hemorrhagic shock in rats. Digestion 56: 111‐116, 1995.
 229. Koo A , Liang IY . Blood flow in hepatic sinusoids in experimental hemorrhagic shock in the rat. Microvasc Res 13: 315‐325, 1977.
 230. Korzonek‐Szlacheta I , Gwozdz B . Effects of endothelin‐1 on prevention of microvascular endothelium injuries in hemorrhagic shock in rats. Pharmacol Rep 59: 98‐106, 2007.
 231. Kottke MA , Walters TJ . Where's the leak in vascular barriers? A review. Shock 46: 20‐36, 2016.
 232. Koury J , Deitch EA , Homma H , Abungu B , Gangurde P , Condon MR , Lu Q , Xu DZ , Feinman R . Persistent HIF‐1alpha activation in gut ischemia/reperfusion injury: Potential role of bacteria and lipopolysaccharide. Shock 22: 270‐277, 2004.
 233. Kovach AG. Cerebral circulation in hypoxia and ischemia. Prog Clin Biol Res 264: 147‐158, 1988.
 234. Kovach AG , Dora E . Intracellular oxygen tension and energy metabolism in the cat brain cortex during haemorrhagic shock. Acta Physiol Acad Sci Hung 54: 333‐346, 1979.
 235. Kozar RA , Peng Z , Zhang R , Holcomb JB , Pati S , Park P , Ko TC , Paredes A . Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg 112: 1289‐1295, 2011.
 236. Koziol JM , Rush BF, Jr. , Smith SM , Machiedo GW . Occurrence of bacteremia during and after hemorrhagic shock. J Trauma 28: 10‐16, 1988.
 237. Krejci V , Hiltebrand L , Banic A , Erni D , Wheatley AM , Sigurdsson GH . Continuous measurements of microcirculatory blood flow in gastrointestinal organs during acute haemorrhage. Br J Anaesth 84: 468‐475, 2000.
 238. Krizbai IA , Lenzser G , Szatmari E , Farkas AE , Wilhelm I , Fekete Z , Erdos B , Bauer H , Bauer HC , Sandor P , Komjati K . Blood‐brain barrier changes during compensated and decompensated hemorrhagic shock. Shock 24: 428‐433, 2005.
 239. Kubulus D , Mathes A , Pradarutti S , Raddatz A , Heiser J , Pavlidis D , Wolf B , Bauer I , Rensing H . Hemin arginate‐induced heme oxygenase 1 expression improves liver microcirculation and mediates an anti‐inflammatory cytokine response after hemorrhagic shock. Shock 29: 583‐590, 2008.
 240. Kubulus D , Mathes A , Reus E , Pradarutti S , Pavlidis D , Thierbach JT , Heiser J , Wolf B , Bauer I , Rensing H . Endothelin‐1 contributes to hemoglobin glutamer‐200‐mediated hepatocellular dysfunction after hemorrhagic shock. Shock 32: 179‐189, 2009.
 241. Kutcher ME , Redick BJ , McCreery RC , Crane IM , Greenberg MD , Cachola LM , Nelson MF , Cohen MJ . Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 73: 13‐19, 2012.
 242. Lapi D , Marchiafava PL , Colantuoni A . Pial microvascular responses to transient bilateral common carotid artery occlusion: effects of hypertonic glycerol. J Vasc Res 45: 89‐102, 2008.
 243. Lazarus HM , Warnick CT , Hutto W . Influence of a protein‐free diet on survival and DNA following hemorrhagic shock and ischemia. Circ Shock 13: 171‐181, 1984.
 244. Le Dorze M , Legrand M , Payen D , Ince C . The role of the microcirculation in acute kidney injury. Curr Opin Crit Care 15: 503‐508, 2009.
 245. Lee RE , Zweifach BW . Vasodepressor responses to morphine following hemorrhagic hypotension. Am J Physiol 157: 259‐264, 1949.
 246. Lefrancais E , Ortiz‐Munoz G , Caudrillier A , Mallavia B , Liu F , Sayah DM , Thornton EE , Headley MB , David T , Coughlin SR , Krummel MF , Leavitt AD , Passegue E , Looney MR . The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 544: 105‐109, 2017.
 247. Legrand M , Mik EG , Balestra GM , Lutter R , Pirracchio R , Payen D , Ince C . Fluid resuscitation does not improve renal oxygenation during hemorrhagic shock in rats. Anesthesiology 112: 119‐127, 2010.
 248. Leong B , Reynolds PS , Tiba MH , Holbert WH , Draucker GT , Medina JA , Barbee RW , White NJ , Ward KR . Effects of a combination hemoglobin based oxygen carrier‐hypertonic saline solution on oxygen transport in the treatment of traumatic shock. Resuscitation 82: 937‐943, 2011.
 249. Levick JR , Michel CC . Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res 87: 198‐210, 2010.
 250. Li R , Aslan A , Yan R , Jongman RM , Moser J , Zwiers PJ , Moorlag HE , Zijlstra JG , Molema G , van Meurs M . Histone deacetylase inhibition and IkappaB kinase/nuclear factor‐kappaB blockade ameliorate microvascular proinflammatory responses associated with hemorrhagic shock/resuscitation in mice. Crit Care Med 43: e567‐e580, 2015.
 251. Li T , Yang G , Xu J , Zhu Y , Liu L . Regulatory effect of Rac1 on vascular reactivity after hemorrhagic shock in rats. J Cardiovasc Pharmacol 57: 656‐665, 2011.
 252. Li Y , Xiang M , Yuan Y , Xiao G , Zhang J , Jiang Y , Vodovotz Y , Billiar TR , Wilson MA , Fan J . Hemorrhagic shock augments lung endothelial cell activation: Role of temporal alterations of TLR4 and TLR2. Am J Physiol Regul Integr Comp Physiol 297: R1670‐R1680, 2009.
 253. Lima R , Villela NR , Bouskela E . Microcirculatory effects of selective receptor blockade during hemorrhagic shock treatment with vasopressin: Experimental study in the hamster dorsal chamber. Shock 38: 493‐498, 2012.
 254. Lindbom L , Arfors KE . Mechanisms and site of control for variation in the number of perfused capillaries in skeletal muscle. Int J Microcirc Clin Exp 4: 19‐30, 1985.
 255. Lipowsky HH , Gao L , Lescanic A . Shedding of the endothelial glycocalyx in arterioles, capillaries, and venules and its effect on capillary hemodynamics during inflammation. Am J Physiol Heart Circ Physiol 301: H2235‐H2245, 2011.
 256. Liu H , Xiao X , Sun C , Sun D , Li Y , Yang M . Systemic inflammation and multiple organ injury in traumatic hemorrhagic shock. Front Biosci (Landmark Ed) 20: 927‐933, 2015.
 257. Liu J , Zhao K . The ATP‐sensitive K(+) channel and membrane potential in the pathogenesis of vascular hyporeactivity in severe hemorrhagic shock. Chin J Traumatol 3: 39‐44, 2000.
 258. Liu LM , Dubick MA . Hemorrhagic shock‐induced vascular hyporeactivity in the rat: Relationship to gene expression of nitric oxide synthase, endothelin‐1, and select cytokines in corresponding organs. J Surg Res 125: 128‐136, 2005.
 259. Lomas‐Neira JL , Heffernan DS , Ayala A , Monaghan SF . Blockade of endothelial growth factor, angiopoietin‐2, reduces indices of Ards and mortality in mice resulting from the dual‐insults of hemorrhagic shock and sepsis. Shock 45: 157‐165, 2016.
 260. Lomas‐Niera JL , Perl M , Chung CS , Ayala A . Shock and hemorrhage: An overview of animal models. Shock 24(Suppl 1): 33‐39, 2005.
 261. Longnecker DE , Harris PD . Microcirculatory actions of general anesthetics. Fed Proc 39: 1580‐1583, 1980.
 262. Longnecker DE , Ross DC , Silver IA . Anesthetic influence on arteriolar diameters and tissue oxygen tension in hemorrhaged rats. Anesthesiology 57: 177‐182, 1982.
 263. Looney MR , Bhattacharya J . Live imaging of the lung. Annu Rev Physiol 76: 431‐445, 2014.
 264. Lu H , Zheng J , Zhao P , Zhang G , Wu T . Buccal partial pressure of carbon dioxide outweighs traditional vital signs in predicting the severity of hemorrhagic shock in a rat model. J Surg Res 187: 262‐269, 2014.
 265. Lu X , Kang X , Zhan L , Lv C , Fan Z , Wang Y , Ali R , Lv C , Li S , Mu J . Dai Huang Fu Zi Tang could ameliorate intestinal injury in a rat model of hemorrhagic shock by regulating intestinal blood flow and intestinal expression of p‐VASP and ZO‐1. BMC Complement Altern Med 14: 80, 2014.
 266. Lubbers DW , Baumgartl H . Heterogeneities and profiles of oxygen pressure in brain and kidney as examples of the pO2 distribution in the living tissue. Kidney Int 51: 372‐380, 1997.
 267. Luft JH. Fine structures of capillary and endocapillary layer as revealed by ruthenium red. Fed Proc 25: 1773‐1783, 1966.
 268. Luo Z , Wang P , Zhang A , Zuo G , Zheng Y , Huang Y . Evaluation of the microcirculation in a rabbit hemorrhagic shock model using laser Doppler imaging. PLoS One 10: e0116076, 2015.
 269. Maier M , Strobele H , Voges J , Bauer C , Marzi I . Attenuation of leukocyte adhesion by recombinant TNF‐binding protein after hemorrhagic shock in the rat. Shock 19: 457‐461, 2003.
 270. Maier S , Holz‐Holzl C , Pajk W , Ulmer H , Hengl C , Dunser M , Haas T , Velik‐Salchner C , Fries D , Greiner A , Hasibeder W , Knotzer H . Microcirculatory parameters after isotonic and hypertonic colloidal fluid resuscitation in acute hemorrhagic shock. J Trauma 66: 337‐345, 2009.
 271. Majde JA. Animal models for hemorrhage and resuscitation research. J Trauma 54: S100‐S105, 2003.
 272. Manley GT , Pitts LH , Morabito D , Doyle CA , Gibson J , Gimbel M , Hopf HW , Knudson MM . Brain tissue oxygenation during hemorrhagic shock, resuscitation, and alterations in ventilation. J Trauma 46: 261‐267, 1999.
 273. Marki A , Esko JD , Pries AR , Ley K . Role of the endothelial surface layer in neutrophil recruitment. J Leukoc Biol 98: 503‐515, 2015.
 274. Martini J , Cabrales P , Fries D , Intaglietta M , Tsai AG . Effects of fibrinogen concentrate after shock/resuscitation: a comparison between in vivo microvascular clot formation and thromboelastometry*. Crit Care Med 41: e301‐e308, 2013.
 275. Martini J , Cabrales P , K A , Acharya SA , Intaglietta M , Tsai AG . Survival time in severe hemorrhagic shock after perioperative hemodilution is longer with PEG‐conjugated human serum albumin than with HES 130/0.4: A microvascular perspective. Crit Care 12: R54, 2008.
 276. Massey MJ , Shapiro NI . A guide to human in vivo microcirculatory flow image analysis. Crit Care 20: 35, 2016.
 277. Matheson PJ , Garrison RN . Intravital intestinal videomicroscopy: Techniques and experiences. Microsurgery 25: 247‐257, 2005.
 278. Matsuki T , Duling BR . TNF‐alpha modulates arteriolar reactivity secondary to a change in intimal permeability. Microcirculation 7: 411‐418, 2000.
 279. Mazzoni MC , Borgstrom P , Intaglietta M , Arfors KE . Lumenal narrowing and endothelial cell swelling in skeletal muscle capillaries during hemorrhagic shock. Circ Shock 29: 27‐39, 1989.
 280. Mazzoni MC , Borgstrom P , Warnke KC , Skalak TC , Intaglietta M , Arfors KE . Mechanisms and implications of capillary endothelial swelling and luminal narrowing in low‐flow ischemias. Int J Microcirc Clin Exp 15: 265‐270, 1995.
 281. Mazzoni MC , Cragoe EJ, Jr. , Arfors KE . Systemic blood acidosis in low‐flow ischemia induces capillary luminal narrowing. Int J Microcirc Clin Exp 14: 144‐150, 1994.
 282. Mazzoni MC , Intaglietta M , Cragoe EJ, Jr. , Arfors KE . Amiloride‐sensitive Na+ pathways in capillary endothelial cell swelling during hemorrhagic shock. J Appl Physiol (1985) 73: 1467‐1473, 1992.
 283. Mazzoni MC , Warnke KC , Arfors KE , Skalak TC . Capillary hemodynamics in hemorrhagic shock and reperfusion: In vivo and model analysis. Am J Physiol 267: H1928‐H1935, 1994.
 284. Mehta D , Malik AB . Signaling mechanisms regulating endothelial permeability. Physiol Rev 86: 279‐367, 2006.
 285. Mellander S , Bjornberg J , Maspers M , Myrhage R . Method for continuous recording of hydrostatic exchange vessel pressure in cat skeletal muscle. Acta Physiol Scand 129: 325‐335, 1987.
 286. Mellander S , Lewis DH . Effect of hemorrhagic shock on the reactivity of resistance and capacitance vessels and on capillary filtration transfer in cat skeletal muscle. Circ Res 13: 105‐118, 1963.
 287. Metzger H , Heuber‐Metzger S . The hypoxic response to hypovolemia. Adv Exp Med Biol 180: 599‐607, 1984.
 288. Meyer JU , Borgstrom P , Lindbom L , Intaglietta M . Vasomotion patterns in skeletal muscle arterioles during changes in arterial pressure. Microvasc Res 35: 193‐203, 1988.
 289. Mik EG , van Leeuwen TG , Raat NJ , Ince C . Quantitative determination of localized tissue oxygen concentration in vivo by two‐photon excitation phosphorescence lifetime measurements. J Appl Physiol (1985) 97: 1962‐1969, 2004.
 290. Miyabe M , Yanagi K , Ohshima N , Sato S , Fukuda T , Toyooka H . Sodium nitroprusside decreases leukocyte adhesion and emigration after hemorrhagic shock. Anesth Analg 94: 296‐301, table of contents, 2002.
 291. Moochhala S , Wu J , Lu J . Hemorrhagic shock: An overview of animal models. Front Biosci (Landmark Ed) 14: 4631‐4639, 2009.
 292. Motaharinia J , Etezadi F , Moghaddas A , Mojtahedzadeh M . Immunomodulatory effect of hypertonic saline in hemorrhagic shock. Daru 23: 47, 2015.
 293. Moy AJ , White SM , Indrawan ES , Lotfi J , Nudelman MJ , Costantini SJ , Agarwal N , Jia W , Kelly KM , Sorg BS , Choi B . Wide‐field functional imaging of blood flow and hemoglobin oxygen saturation in the rodent dorsal window chamber. Microvasc Res 82: 199‐209, 2011.
 294. Muir WW , Del Rio CL , Ueyama Y , Youngblood BL , George RS , Rausch CW , Lau BS , Hamlin RL . Dose‐dependent hemodynamic, biochemical, and tissue oxygen effects of OC99 following severe oxygen debt produced by hemorrhagic shock in dogs. Crit Care Res Pract 2014: 864237, 2014.
 295. Mulivor AW , Lipowsky HH . Role of glycocalyx in leukocyte‐endothelial cell adhesion. Am J Physiol Heart Circ Physiol 283: H1282‐H1291, 2002.
 296. Mulivor AW , Lipowsky HH . Inflammation‐ and ischemia‐induced shedding of venular glycocalyx. Am J Physiol Heart Circ Physiol 286: H1672‐H1680, 2004.
 297. Myburgh JA , Mythen MG . Resuscitation fluids. N Engl J Med 369: 2462‐2463, 2013.
 298. Myers BD , Moran SM . Hemodynamically mediated acute renal failure. N Engl J Med 314: 97‐105, 1986.
 299. Nagakawa B , Goldberg L , McCartney J , Matsumoto T . The effect of dopamine on renal microcirculation in hemorrhagic shock in dogs. Surg Gynecol Obstet 142: 871‐874, 1976.
 300. Nassour I , Kautza B , Rubin M , Escobar D , Luciano J , Loughran P , Gomez H , Scott J , Gallo D , Brumfield J , Otterbein LE , Zuckerbraun BS . Carbon monoxide protects against hemorrhagic shock and resuscitation‐induced microcirculatory injury and tissue injury. Shock 43: 166‐171, 2015.
 301. Naumann DN , Beaven A , Dretzke J , Hutchings S , Midwinter MJ . Searching for the optimal fluid to restore microcirculatory flow dynamics after haemorrhagic shock: A systematic review of preclinical studies. Shock 46: 609‐622, 2016.
 302. Naumann DN , Dretzke J , Hutchings S , Midwinter MJ . Protocol for a systematic review of the impact of resuscitation fluids on the microcirculation after haemorrhagic shock in animal models. Syst Rev 4: 135, 2015.
 303. Nerlich M , Gunther R , Demling RH . Resuscitation from hemorrhagic shock with hypertonic saline or lactated Ringer's (effect on the pulmonary and systemic microcirculations). Circ Shock 10: 179‐188, 1983.
 304. Nicoll PA , Webb RL . Blood circulation in the subcutaneous tissue of the living bat's wing. Ann N Y Acad Sci 46: 697‐711, 1946.
 305. Nilsson H , Aalkjaer C . Vasomotion: Mechanisms and physiological importance. Mol Interv 3: 79‐89, 51, 2003.
 306. Nystrom SH. Studies of the effect of experimental hypocupremia on the rabbit circulatory system, with special reference to the vessels of the neck and the base of the brain. Acta Neuropathol 10: 209‐217, 1968.
 307. Ortiz D , Barros M , Yan S , Cabrales P . Resuscitation from hemorrhagic shock using polymerized hemoglobin compared to blood. Am J Emerg Med 32: 248‐255, 2014.
 308. Ostrowski SR , Henriksen HH , Stensballe J , Gybel‐Brask M , Cardenas JC , Baer LA , Cotton BA , Holcomb JB , Wade CE , Johansson PI . Sympathoadrenal activation and endotheliopathy are drivers of hypocoagulability and hyperfibrinolysis in trauma: A prospective observational study of 404 severely injured patients. J Trauma Acute Care Surg 82: 293‐301, 2017.
 309. Ostrowski SR , Johansson PI . Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg 73: 60‐66, 2012.
 310. Oude Vrielink HH , Slaaf DW , Tangelder GJ , Reneman RS . Changes in vasomotion pattern and local arteriolar resistance during stepwise pressure reduction. Pflugers Arch 414: 571‐578, 1989.
 311. Oude Vrielink HH , Slaaf DW , Tangelder GJ , Weijmer‐Van Velzen S , Reneman RS . Analysis of vasomotion waveform changes during pressure reduction and adenosine application. Am J Physiol 258: H29‐H37, 1990.
 312. Paes‐da‐Silva F , Gonzalez AP , Tibirica E . Effects of fluid resuscitation on mesenteric microvascular blood flow and lymphatic activity after severe hemorrhagic shock in rats. Shock 19: 55‐60, 2003.
 313. Page AV , Liles WC . Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence 4: 507‐516, 2013.
 314. Pajk W , Schwarz B , Knotzer H , Friesenecker B , Mayr A , Dunser M , Hasibeder W . Jejunal tissue oxygenation and microvascular flow motion during hemorrhage and resuscitation. Am J Physiol Heart Circ Physiol 283: H2511‐H2517, 2002.
 315. Palagyi P , Kaszaki J , Rostas A , Erces D , Nemeth M , Boros M , Molnar Z . Monitoring microcirculatory blood flow with a new sublingual tonometer in a porcine model of hemorrhagic shock. Biomed Res Int 2015: 847152, 2015.
 316. Pannen BH , Kohler N , Hole B , Bauer M , Clemens MG , Geiger KK . Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats. J Clin Invest 102: 1220‐1228, 1998.
 317. Pascual JL , Ferri LE , Seely AJ , Campisi G , Chaudhury P , Giannias B , Evans DC , Razek T , Michel RP , Christou NV . Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil rolling and adherence to endothelium and reduces in vivo vascular leakage. Ann Surg 236: 634‐642, 2002.
 318. Pascual JL , Khwaja KA , Chaudhury P , Christou NV . Hypertonic saline and the microcirculation. J Trauma 54: S133‐S140, 2003.
 319. Pati S , Gerber MH , Menge TD , Wataha KA , Zhao Y , Baumgartner JA , Zhao J , Letourneau PA , Huby MP , Baer LA , Salsbury JR , Kozar RA , Wade CE , Walker PA , Dash PK , Cox CS, Jr. , Doursout MF , Holcomb JB . Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock. PLoS One 6: e25171, 2011.
 320. Pati S , Matijevic N , Doursout MF , Ko T , Cao Y , Deng X , Kozar RA , Hartwell E , Conyers J , Holcomb JB . Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw. J Trauma 69(Suppl 1): S55‐S63, 2010.
 321. Paxian M , Bauer I , Rensing H , Jaeschke H , Mautes AE , Kolb SA , Wolf B , Stockhausen A , Jeblick S , Bauer M . Recovery of hepatocellular ATP and “pericentral apoptosis” after hemorrhage and resuscitation. FASEB J 17: 993‐1002, 2003.
 322. Paxian M , Keller SA , Cross B , Huynh TT , Clemens MG . High‐resolution visualization of oxygen distribution in the liver in vivo. Am J Physiol Gastrointest Liver Physiol 286: G37‐44, 2004.
 323. Paxian M , Keller SA , Huynh TT , Clemens MG . Perflubron emulsion improves hepatic microvascular integrity and mitochondrial redox state after hemorrhagic shock. Shock 20: 449‐457, 2003.
 324. Paxian M , Rensing H , Geckeis K , Bauer I , Kubulus D , Spahn DR , Bauer M . Perflubron emulsion in prolonged hemorrhagic shock: Influence on hepatocellular energy metabolism and oxygen‐dependent gene expression. Anesthesiology 98: 1391‐1399, 2003.
 325. Paxian M , Rensing H , Rickauer A , Schonhofen S , Schmeck J , Pannen BH , Bauer I , Bauer M . Kupffer cells and neutrophils as paracrine regulators of the heme oxygenase‐1 gene in hepatocytes after hemorrhagic shock. Shock 15: 438‐445, 2001.
 326. Peiniger S , Paffrath T , Mutschler M , Brockamp T , Borgmann M , Spinella PC , Bouillon B , Maegele M , TraumaRegister DGU . The trauma patient in hemorrhagic shock: How is the C‐priority addressed between emergency and ICU admission? Scand J Trauma Resusc Emerg Med 20: 78, 2012.
 327. Peitzman AB , Billiar TR , Harbrecht BG , Kelly E , Udekwu AO , Simmons RL . Hemorrhagic shock. Curr Probl Surg 32: 925‐1002, 1995.
 328. Peng Z , Pati S , Potter D , Brown R , Holcomb JB , Grill R , Wataha K , Park PW , Xue H , Kozar RA . Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1. Shock 40: 195‐202, 2013.
 329. Pennings FA , Bouma GJ , Ince C . Direct observation of the human cerebral microcirculation during aneurysm surgery reveals increased arteriolar contractility. Stroke 35: 1284‐1288, 2004.
 330. Perez‐Barcena J , Romay E , Llompart‐Pou JA , Ibanez J , Brell M , Llinas P , Gonzalez E , Merenda A , Ince C , Bullock R . Direct observation during surgery shows preservation of cerebral microcirculation in patients with traumatic brain injury. J Neurol Sci 353: 38‐43, 2015.
 331. Peruski AM , Cooper ES . Assessment of microcirculatory changes by use of sidestream dark field microscopy during hemorrhagic shock in dogs. Am J Vet Res 72: 438‐445, 2011.
 332. Peruski AM , Cooper ES , Butler AL . Microcirculatory effects of a hyperviscous hemoglobin‐based solution administered intravenously in dogs with experimentally induced hemorrhagic shock. Am J Vet Res 75: 77‐84, 2014.
 333. Pinsky MR , Vincent JL , Deviere J , Alegre M , Kahn RJ , Dupont E . Serum cytokine levels in human septic shock. Relation to multiple‐system organ failure and mortality. Chest 103: 565‐575, 1993.
 334. Pittman RN. Oxygen gradients in the microcirculation. Acta Physiol (Oxf) 202: 311‐322, 2011.
 335. Popel AS , Johnson PC . Microcirculation and Hemorheology. Annu Rev Fluid Mech 37: 43‐69, 2005.
 336. Potter DR , Baimukanova G , Keating SM , Deng X , Chu JA , Gibb SL , Peng Z , Muench MO , Fomin ME , Spinella PC , Kozar R , Pati S . Fresh frozen plasma and spray‐dried plasma mitigate pulmonary vascular permeability and inflammation in hemorrhagic shock. J Trauma Acute Care Surg 78: S7‐S17, 2015.
 337. Potter DR , Damiano ER . The hydrodynamically relevant endothelial cell glycocalyx observed in vivo is absent in vitro. Circ Res 102: 770‐776, 2008.
 338. Pries AR , Kuebler WM . Normal endothelium. Handb Exp Pharmacol 176/1: 1‐40, 2006.
 339. Pries AR , Secomb TW , Gaehtgens P . The endothelial surface layer. Pflugers Arch 440: 653‐666, 2000.
 340. Pries AR , Secomb TW , Gaehtgens P . Structure and hemodynamics of microvascular networks: Heterogeneity and correlations. Am J Physiol 269: H1713‐H1722, 1995.
 341. Prince JM , Levy RM , Yang R , Mollen KP , Fink MP , Vodovotz Y , Billiar TR . Toll‐like receptor‐4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock. J Am Coll Surg 202: 407‐417, 2006.
 342. Proctor HJ , Wood JJ , Palladino W , Woodley C . Effects of hypoxia and hypotension on oxygen delivery in the brain. J Trauma 19: 682‐685, 1979.
 343. Pruefer D , Makowski J , Dahm M , Guth S , Oelert H , Darius H , Buerke M . Aprotinin inhibits leukocyte‐endothelial cell interactions after hemorrhage and reperfusion. Ann Thorac Surg 75: 210‐215; discussion 215‐216, 2003.
 344. Puyana JC , Soller BR , Zhang S , Heard SO . Continuous measurement of gut pH with near‐infrared spectroscopy during hemorrhagic shock. J Trauma 46: 9‐15, 1999.
 345. Rahbar E , Cardenas JC , Baimukanova G , Usadi B , Bruhn R , Pati S , Ostrowski SR , Johansson PI , Holcomb JB , Wade CE . Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med 13: 117, 2015.
 346. Rajnik M , Salkowski CA , Thomas KE , Li YY , Rollwagen FM , Vogel SN . Induction of early inflammatory gene expression in a murine model of nonresuscitated, fixed‐volume hemorrhage. Shock 17: 322‐328, 2002.
 347. Rana MW , Singh G , Wang P , Ayala A , Zhou M , Chaudry IH . Protective effects of preheparinization on the microvasculature during and after hemorrhagic shock. J Trauma 32: 420‐426, 1992.
 348. Rehm M , Bruegger D , Christ F , Conzen P , Thiel M , Jacob M , Chappell D , Stoeckelhuber M , Welsch U , Reichart B , Peter K , Becker BF . Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116: 1896‐1906, 2007.
 349. Reitsma S , Oude Egbrink MG , Heijnen VV , Megens RT , Engels W , Vink H , Slaaf DW , van Zandvoort MA . Endothelial glycocalyx thickness and platelet‐vessel wall interactions during atherogenesis. Thromb Haemost 106: 939‐946, 2011.
 350. Reitsma S , Slaaf DW , Vink H , van Zandvoort MA , oude Egbrink MG . The endothelial glycocalyx: Composition, functions, and visualization. Pflugers Arch 454: 345‐359, 2007.
 351. Rhee CJ , Kibler KK , Easley RB , Andropoulos DB , Czosnyka M , Smielewski P , Brady KM . Renovascular reactivity measured by near‐infrared spectroscopy. J Appl Physiol (1985) 113: 307‐314, 2012.
 352. Rickards CA . Cerebral blood‐flow regulation during hemorrhage. Compr Physiol 5: 1585‐1621, 2015.
 353. Rickards CA , Johnson BD , Harvey RE , Convertino VA , Joyner MJ , Barnes JN . Cerebral blood velocity regulation during progressive blood loss compared with lower body negative pressure in humans. J Appl Physiol (1985) 119: 677‐685, 2015.
 354. Rixen D , Raum M , Holzgraefe B , Sauerland S , Nagelschmidt M , Neugebauer EA , Shock, Trauma Study G . A pig hemorrhagic shock model: Oxygen debt and metabolic acidemia as indicators of severity. Shock 16: 239‐244, 2001.
 355. Rixen D , Siegel JH . Bench‐to‐bedside review: Oxygen debt and its metabolic correlates as quantifiers of the severity of hemorrhagic and post‐traumatic shock. Crit Care 9: 441‐453, 2005.
 356. Roesner JP , Vagts DA , Iber T , Eipel C , Vollmar B , Noldge‐Schomburg GF . Protective effects of PARP inhibition on liver microcirculation and function after haemorrhagic shock and resuscitation in male rats. Intensive Care Med 32: 1649‐1657, 2006.
 357. Romanus M , Bagge U , Seifert F , Branemark PI . Intravital microscopy of the microcirculation in man during and after experimentally controlled ischemia. Scand J Plast Reconstr Surg 12: 181‐187, 1978.
 358. Rossaint R , Bouillon B , Cerny V , Coats TJ , Duranteau J , Fernandez‐Mondejar E , Hunt BJ , Komadina R , Nardi G , Neugebauer E , Ozier Y , Riddez L , Schultz A , Stahel PF , Vincent JL , Spahn DR , Task Force for Advanced Bleeding Care in T. Management of bleeding following major trauma: An updated European guideline. Crit Care 14: R52, 2010.
 359. Rowland MR , Ragina NP , Sarkar J , Uyehara CF , Senagore AJ . Is arginine/asymetric dimethylarginine ratio depletion an indicator of insufficient resuscitation in a porcine model of hemorrhage‐reperfusion? Surgery 156: 861‐868, 2014.
 360. Rumsey WL , Vanderkooi JM , Wilson DF . Imaging of phosphorescence: A novel method for measuring oxygen distribution in perfused tissue. Science 241: 1649‐1651, 1988.
 361. Rush BF, Jr. , Redan JA , Flanagan JJ, Jr. , Heneghan JB , Hsieh J , Murphy TF , Smith S , Machiedo GW . Does the bacteremia observed in hemorrhagic shock have clinical significance? A study in germ‐free animals. Ann Surg 210: 342‐345; discussion 346‐347, 1989.
 362. Russell DH , Barreto JC , Klemm K , Miller TA . Hemorrhagic shock increases gut macromolecular permeability in the rat. Shock 4: 50‐55, 1995.
 363. Sailhamer EA , Li Y , Smith EJ , Liu B , Shuja F , Soupir CP , DeMoya MA , Velmahos GC , Alam HB . Hypoxic “second hit” in leukocytes from trauma patients: Modulation of the immune response by histone deacetylase inhibition. Cytokine 49: 303‐311, 2010.
 364. Sakadzic S , Roussakis E , Yaseen MA , Mandeville ET , Srinivasan VJ , Arai K , Ruvinskaya S , Devor A , Lo EH , Vinogradov SA , Boas DA . Two‐photon high‐resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue. Nat Methods 7: 755‐759, 2010.
 365. Sakai H , Hara H , Tsai AG , Tsuchida E , Johnson PC , Intaglietta M . Changes in resistance vessels during hemorrhagic shock and resuscitation in conscious hamster model. Am J Physiol 276: H563‐H571, 1999.
 366. Sakai H , Horinouchi H , Tsuchida E , Kobayashi K . Hemoglobin vesicles and red blood cells as carriers of carbon monoxide prior to oxygen for resuscitation after hemorrhagic shock in a rat model. Shock 31: 507‐514, 2009.
 367. Salazar Vazquez BY , Martini J , Chavez Negrete A , Cabrales P , Tsai AG , Intaglietta M . Microvascular benefits of increasing plasma viscosity and maintaining blood viscosity: Counterintuitive experimental findings. Biorheology 46: 167‐179, 2009.
 368. Salazar Vazquez BY , Wettstein R , Cabrales P , Tsai AG , Intaglietta M . Microvascular experimental evidence on the relative significance of restoring oxygen carrying capacity vs. blood viscosity in shock resuscitation. Biochim Biophys Acta 1784: 1421‐1427, 2008.
 369. Samarska IV , van Meurs M , Buikema H , Houwertjes MC , Wulfert FM , Molema G , Epema AH , Henning RH . Adjunct nitrous oxide normalizes vascular reactivity changes after hemorrhagic shock in mice under isoflurane anesthesia. Anesthesiology 111: 600‐608, 2009.
 370. Sarelius IH , Glading AJ . Control of vascular permeability by adhesion molecules. Tissue Barriers 3: e985954, 2015.
 371. Sawant DA , Tharakan B , Hunter FA , Childs EW . The role of intrinsic apoptotic signaling in hemorrhagic shock‐induced microvascular endothelial cell barrier dysfunction. J Cardiovasc Transl Res 7: 711‐718, 2014.
 372. Sawant DA , Tharakan B , Hunter FA , Smythe WR , Childs EW . Role of beta‐catenin in regulating microvascular endothelial cell hyperpermeability. J Trauma 70: 481‐487; discussion 487‐488, 2011.
 373. Sawant DA , Wilson RL , Tharakan B , Stagg HW , Hunter FA , Childs EW . Tumor necrosis factor‐alpha‐induced microvascular endothelial cell hyperpermeability: Role of intrinsic apoptotic signaling. J Physiol Biochem 70: 971‐980, 2014.
 374. Scalia R , Armstead VE , Minchenko AG , Lefer AM . Essential role of P‐selectin in the initiation of the inflammatory response induced by hemorrhage and reinfusion. J Exp Med 189: 931‐938, 1999.
 375. Scalia SV , Taheri PA , Force S , Ozmen V , Lui D , Fish J , Hansen D , Chambers R , Flint L , Steinberg S . Mesenteric microcirculatory changes in nonlethal hemorrhagic shock: The role of resuscitation with balanced electrolyte or hypertonic saline/dextran. J Trauma 33: 321‐325, 1992.
 376. Schmid‐Schonbein GW , Engler RL . Perspectives of leukocyte activation in the microcirculation. Biorheology 27: 859‐869, 1990.
 377. Schmid‐Schonbein GW , Hugli TE . A new hypothesis for microvascular inflammation in shock and multiorgan failure: Self‐digestion by pancreatic enzymes. Microcirculation 12: 71‐82, 2005.
 378. Schmid‐Schonbein GW , Kistler EB , Hugli TE . Mechanisms for cell activation and its consequences for biorheology and microcirculation: Multi‐organ failure in shock. Biorheology 38: 185‐201, 2001.
 379. Schmid‐Schonbein GW , Penn A , Kistler E . The autodigestion hypothesis in shock and multi‐organ failure: Degrading protease activity. Bol Soc Port Hemorreol Microcirc 26: 6‐15, 2011.
 380. Schumacher J , Binkowski K , Dendorfer A , Klotz KF . Organ‐specific extravasation of albumin‐bound Evans blue during nonresuscitated hemorrhagic shock in rats. Shock 20: 565‐568, 2003.
 381. Schumacher J , Puchakayala MR , Binkowski K , Eichler W , Dendorfer A , Klotz KF . Effects of candesartan and enalaprilat on the organ‐specific microvascular permeability during haemorrhagic shock in rats. Br J Anaesth 96: 437‐443, 2006.
 382. Schwartz M. Rho signalling at a glance. J Cell Sci 117: 5457‐5458, 2004.
 383. Schywalsky M , Metzger HP . Redistribution of local hepatic blood flow during acute bleeding and prolonged hemorrhagic hypotension studied using fluorochromed plasma proteins and surface PO2 measurements. Adv Exp Med Biol 277: 697‐703, 1990.
 384. Segal SS. Regulation of blood flow in the microcirculation. Microcirculation 12: 33‐45, 2005.
 385. Seyde WC , Longnecker DE . Anesthetic influences on regional hemodynamics in normal and hemorrhaged rats. Anesthesiology 61: 686‐698, 1984.
 386. Shen Q , Holloway N , Thimmesch A , Wood JG , Clancy RL , Pierce JD . Ubiquinol decreases hemorrhagic shock/resuscitation‐induced microvascular inflammation in rat mesenteric microcirculation. Physiol Rep 2(11): e12199-1‐e12199-8, 2017.
 387. Shinohara H , Tanaka A , Kitai T , Yanabu N , Inomoto T , Satoh S , Hatano E , Yamaoka Y , Hirao K . Direct measurement of hepatic indocyanine green clearance with near‐infrared spectroscopy: Separate evaluation of uptake and removal. Hepatology 23: 137‐144, 1996.
 388. Shires GT , Browder LK , Steljes TP , Williams SJ , Browder TD , Barber AE . The effect of shock resuscitation fluids on apoptosis. Am J Surg 189: 85‐91, 2005.
 389. Shorr E , Zweifach BW , Furchgott RF . Hepato‐renal factors in circulatory hemeostasis; the influence of humoral factors of hepato‐renal origin on the vascular reactions to hemorrhage. Ann N Y Acad Sci 49: 571‐592, 1948.
 390. Sielenkamper AW , Eicker K , Van Aken H . Thoracic epidural anesthesia increases mucosal perfusion in ileum of rats. Anesthesiology 93: 844‐851, 2000.
 391. Sillesen M , Johansson PI , Rasmussen LS , Jin G , Jepsen CH , Imam A , Hwabejire JO , Deperalta D , Duggan M , DeMoya M , Velmahos GC , Alam HB . Fresh frozen plasma resuscitation attenuates platelet dysfunction compared with normal saline in a large animal model of multisystem trauma. J Trauma Acute Care Surg 76: 998‐1007, 2014.
 392. Sillesen M , Rasmussen LS , Jin G , Jepsen CH , Imam A , Hwabejire JO , Halaweish I , DeMoya M , Velmahos G , Johansson PI , Alam HB . Assessment of coagulopathy, endothelial injury, and inflammation after traumatic brain injury and hemorrhage in a porcine model. J Trauma Acute Care Surg 76: 12‐19; discussion 19‐20, 2014.
 393. Simoes C , Svensjo E , Bouskela E . Effects of cromakalim and glibenclamide on arteriolar and venular diameters and macromolecular leakage in the microcirculation during ischemia/reperfusion. J Cardiovasc Pharmacol 39: 340‐346, 2002.
 394. Sinaasappel M , van Iterson M , Ince C . Microvascular oxygen pressure in the pig intestine during haemorrhagic shock and resuscitation. J Physiol 514(Pt 1): 245‐253, 1999.
 395. Slaaf DW , Tangelder GJ , Reneman RS , Jager K , Bollinger A . A versatile incident illuminator for intravital microscopy. Int J Microcirc Clin Exp 6: 391‐397, 1987.
 396. Slaaf DW , Vrielink HH , Tangelder GJ , Reneman RS . Effective diameter as a determinant of local vascular resistance in presence of vasomotion. Am J Physiol 255: H1240‐H1243, 1988.
 397. Smith M , Abraham E . Conjunctival oxygen tension monitoring during hemorrhage. J Trauma 26: 217‐224, 1986.
 398. Soller BR , Zou F , Ryan KL , Rickards CA , Ward K , Convertino VA . Lightweight noninvasive trauma monitor for early indication of central hypovolemia and tissue acidosis: a review. J Trauma Acute Care Surg 73: S106‐S111, 2012.
 399. Song D , Murphy S , Olano M , Wilson DF , Pastuszko A . Effect of hemorrhagic hypotension on hydroxyl radicals in cat brain. Adv Exp Med Biol 454: 173‐180, 1998.
 400. Sordi R , Chiazza F , Johnson FL , Patel NS , Brohi K , Collino M , Thiemermann C . Inhibition of IkappaB kinase attenuates the organ injury and dysfunction associated with hemorrhagic shock. Molecular medicine 21: 563‐575, 2015.
 401. Sordia T , Tatarishvili J , Varazashvili M , McHedlishvili G . Hemorheological disorders in the microcirculation following hemorrhage. Clin Hemorheol Microcirc 30: 461‐462, 2004.
 402. Stern S , Rice J , Philbin N , McGwin G , Arnaud F , Johnson T , Flournoy WS , Ahlers S , Pearce LB , McCarron R , Freilich D . Resuscitation with the hemoglobin‐based oxygen carrier, HBOC‐201, in a swine model of severe uncontrolled hemorrhage and traumatic brain injury. Shock 31: 64‐79, 2009.
 403. Stevens PM , Lamb LE . Effects of lower body negative pressure on the cardiovascular system. Am J Cardiol 16: 506‐515, 1965.
 404. Stringham JR , Moore EE , Gamboni F , Harr JN , Fragoso M , Chin TL , Carr CE , Silliman CC , Banerjee A . Mesenteric lymph diversion abrogates 5‐lipoxygenase activation in the kidney following trauma and hemorrhagic shock. J Trauma Acute Care Surg 76: 1214‐1221, 2014.
 405. Styp‐Rekowska B , Disassa NM , Reglin B , Ulm L , Kuppe H , Secomb TW , Pries AR . An imaging spectroscopy approach for measurement of oxygen saturation and hematocrit during intravital microscopy. Microcirculation 14: 207‐221, 2007.
 406. Sun N , Luo W , Li LZ , Luo Q . Monitoring hemodynamic and metabolic alterations during severe hemorrhagic shock in rat brains. Acad Radiol 21: 175‐184, 2014.
 407. Szabo A , Suki B , Csonka E , Eszlari E , Kucsa K , Vajda K , Kaszaki J , Boros M . Flow motion in the intestinal villi during hemorrhagic shock: A new method to characterize the microcirculatory changes. Shock 21: 320‐328, 2004.
 408. Szabo C , Thiemermann C . Invited opinion: Role of nitric oxide in hemorrhagic, traumatic, and anaphylactic shock and thermal injury. Shock 2: 145‐155, 1994.
 409. Szopinski J , Kusza K , Semionow M . Microcirculatory responses to hypovolemic shock. J Trauma 71: 1779‐1788, 2011.
 410. Tachon G , Harrois A , Tanaka S , Kato H , Huet O , Pottecher J , Vicaut E , Duranteau J . Microcirculatory alterations in traumatic hemorrhagic shock. Crit Care Med 42: 1433‐1441, 2014.
 411. Takasu A , Carrillo P , Stezoski SW , Safar P , Tisherman SA . Mild or moderate hypothermia but not increased oxygen breathing prolongs survival during lethal uncontrolled hemorrhagic shock in rats, with monitoring of visceral dysoxia. Crit Care Med 27: 1557‐1564, 1999.
 412. Tanaka S , Escudier E , Hamada S , Harrois A , Leblanc PE , Vicaut E , Duranteau J . Effect of RBC transfusion on sublingual microcirculation in hemorrhagic shock patients: A pilot study. Crit Care Med 45(2): e154‐e160, 2017.
 413. Tarbell JM , Ebong EE . The endothelial glycocalyx: A mechano‐sensor and ‐transducer. Sci Signal 1: pt8, 2008.
 414. Tarbell JM , Pahakis MY . Mechanotransduction and the glycocalyx. J Intern Med 259: 339‐350, 2006.
 415. Tharakan B , Hellman J , Sawant DA , Tinsley JH , Parrish AR , Hunter FA , Smythe WR , Childs EW . beta‐Catenin dynamics in the regulation of microvascular endothelial cell hyperpermeability. Shock 37: 306‐311, 2012.
 416. Thiemermann C , Szabo C , Mitchell JA , Vane JR . Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci U S A 90: 267‐271, 1993.
 417. Tiba MH , Draucker GT , Barbee RW , Terner J , Filho IT , Romfh P , Vakhshoori D , Ward KR . Tissue oxygenation monitoring using resonance Raman spectroscopy during hemorrhage. J Trauma Acute Care Surg 76: 402‐408, 2014.
 418. Torres Filho I , Torres LN , Sondeen JL , Polykratis IA , Dubick MA . In vivo evaluation of venular glycocalyx during hemorrhagic shock in rats using intravital microscopy. Microvasc Res 85: 128‐133, 2013.
 419. Torres Filho IP , Boegehold MA , Bouskela E , House SD , Johnson PC . Microcirculatory responses in cat sartorius muscle to hemorrhagic hypotension. Am J Physiol 257: H1647‐H1655, 1989.
 420. Torres Filho IP , Contaifer Junior D , Garcia S , Neves LdS . Vasomotion in rat mesentery during hemorrhagic hypotension. Life Sci 68: 1057‐1065, 2001.
 421. Torres Filho IP , Contaifer Junior D , Garcia S , Torres LN . Effects of hypertonic saline solution on mesenteric microcirculation. Shock 15: 353‐359, 2001.
 422. Torres Filho IP , Cyrino FZ , Popel AS , Bouskela E , Johnson PC . Morphometric analysis of the anastomosing arteriolar network in cat sartorius muscle. Int J Microcirc Clin Exp 14: 3‐13, 1994.
 423. Torres Filho IP , Intaglietta M . Microvessel PO2 measurements by phosphorescence decay method. Am J Physiol 265: H1434‐H1438, 1993.
 424. Torres Filho IP , Kerger H , Intaglietta M . pO2 measurements in arteriolar networks. Microvasc Res 51: 202‐212, 1996.
 425. Torres Filho IP , Leunig M , Yuan F , Intaglietta M , Jain RK . Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice. Proc Natl Acad Sci U S A 91: 2081‐2085, 1994.
 426. Torres Filho IP , Terner J , Pittman RN , Proffitt E , Ward KR . Measurement of hemoglobin oxygen saturation using Raman microspectroscopy and 532‐nm excitation. J Appl Physiol (1985) 104: 1809‐1817, 2008.
 427. Torres Filho IP , Terner J , Pittman RN , Somera LG, 3rd , Ward KR . Hemoglobin oxygen saturation measurements using resonance Raman intravital microscopy. Am J Physiol Heart Circ Physiol 289: H488‐H495, 2005.
 428. Torres Filho IP , Torres LN , Salgado C , Dubick MA . Plasma syndecan‐1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids. Am J Physiol Heart Circ Physiol 310: H1468‐H1478, 2016.
 429. Torres Filho IP , Torres LN , Valdez C , Salgado C , Cap AP , Dubick MA . Refrigerated platelets stored in whole blood up to 5 days adhere to thrombi formed during hemorrhagic hypotension in rats. J Thromb Haemost 15: 163‐175, 2017.
 430. Torres Filho IP , Vink, H , Torres, LN , Pittman, RN . Reduction in endothelial glycocalyx thickness after hemorrhage. FASEB J 23: 950, 2009.
 431. Torres LN , Pittman RN , Torres Filho IP . Microvascular blood flow and oxygenation during hemorrhagic hypotension. Microvasc Res 75: 217‐226, 2008.
 432. Torres LN , Sondeen JL , Dubick MA , Filho IT . Systemic and microvascular effects of resuscitation with blood products after severe hemorrhage in rats. J Trauma Acute Care Surg 77: 716‐723, 2014.
 433. Torres LN , Sondeen JL , Ji L , Dubick MA , Torres Filho I . Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function after hemorrhagic shock in rats. J Trauma Acute Care Surg 75: 759‐766, 2013.
 434. Tsai AG , Cabrales P , Intaglietta M . Microvascular perfusion upon exchange transfusion with stored red blood cells in normovolemic anemic conditions. Transfusion 44: 1626‐1634, 2004.
 435. Tsai AG , Cabrales P , Intaglietta M . Oxygen‐carrying blood substitutes: A microvascular perspective. Expert Opin Biol Ther 4: 1147‐1157, 2004.
 436. Tsai AG , Hofmann A , Cabrales P , Intaglietta M . Perfusion vs. oxygen delivery in transfusion with “fresh” and “old” red blood cells: The experimental evidence. Transfus Apher Sci 43: 69‐78, 2010.
 437. Tsai AG , Intaglietta M . Evidence of flowmotion induced changes in local tissue oxygenation. Int J Microcirc Clin Exp 12: 75‐88, 1993.
 438. Tsai AG , Intaglietta M . High viscosity plasma expanders: Volume restitution fluids for lowering the transfusion trigger. Biorheology 38: 229‐237, 2001.
 439. Tsukada K , Sekizuka E , Oshio C , Tsujioka K , Minamitani H . Red blood cell velocity and oxygen tension measurement in cerebral microvessels by double‐wavelength photoexcitation. J Appl Physiol (1985) 96: 1561‐1568, 2004.
 440. Turek Z , Sykora R , Matejovic M , Cerny V . Anesthesia and the microcirculation. Semin Cardiothorac Vasc Anesth 13: 249‐258, 2009.
 441. Uhl E , Lehmberg J , Steiger HJ , Messmer K . Intraoperative detection of early microvasospasm in patients with subarachnoid hemorrhage by using orthogonal polarization spectral imaging. Neurosurgery 52: 1307‐1315; disacussion 1315‐1307, 2003.
 442. Vajda K , Szabo A , Boros M . Heterogeneous microcirculation in the rat small intestine during hemorrhagic shock: Quantification of the effects of hypertonic‐hyperoncotic resuscitation. Eur Surg Res 36: 338‐344, 2004.
 443. Vajda K , Szabo A , Kucsa K , Suki B , Boros M . Microcirculatory heterogeneity in the rat small intestine during compromised flow conditions. Microcirculation 11: 307‐315, 2004.
 444. Vallet B. Intravascular volume expansion: Which surrogate markers could help the clinician to assess improved tissue perfusion? Anesth Analg 112: 258‐259, 2011.
 445. van Bommel J , de Korte D , Lind A , Siegemund M , Trouwborst A , Verhoeven AJ , Ince C , Henny CP . The effect of the transfusion of stored RBCs on intestinal microvascular oxygenation in the rat. Transfusion 41: 1515‐1523, 2001.
 446. van Bommel J , Maas MA , Sinaasappel M , Ince C . Intestinal microvascular pO2 measurement with Pd‐porphyrin phosphorescence in the mechanically ventilated mouse. Adv Exp Med Biol 454: 189‐193, 1998.
 447. van der Kleij AJ , de Koning J , Beerthuizen G , Goris RJ , Kreuzer F , Kimmich HP . Early detection of hemorrhagic hypovolemia by muscle oxygen pressure assessment: preliminary report. Surgery 93: 518‐524, 1983.
 448. van Golen RF , van Gulik TM , Heger M . Mechanistic overview of reactive species‐induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury. Free Radic Biol Med 52: 1382‐1402, 2012.
 449. van Iterson M , Bezemer R , Heger M , Siegemund M , Ince C . Microcirculation follows macrocirculation in heart and gut in the acute phase of hemorrhagic shock and isovolemic autologous whole blood resuscitation in pigs. Transfusion 52: 1552‐1559, 2012.
 450. van Iterson M , Siegemund M , Burhop K , Ince C . Hemoglobin‐based oxygen carrier provides heterogeneous microvascular oxygenation in heart and gut after hemorrhage in pigs. J Trauma 55: 1111‐1124, 2003.
 451. van Iterson M , Sinaasappel M , Burhop K , Trouwborst A , Ince C . Low‐volume resuscitation with a hemoglobin‐based oxygen carrier after hemorrhage improves gut microvascular oxygenation in swine. J Lab Clin Med 132: 421‐431, 1998.
 452. van Meurs M , Kurniati NF , Wulfert FM , Asgeirsdottir SA , de Graaf IA , Satchell SC , Mathieson PW , Jongman RM , Kumpers P , Zijlstra JG , Heeringa P , Molema G . Shock‐induced stress induces loss of microvascular endothelial Tie2 in the kidney which is not associated with reduced glomerular barrier function. Am J Physiol Renal Physiol 297: F272‐F281, 2009.
 453. van Meurs M , Wulfert FM , Jongman RM , Schipper M , Houwertjes MC , Vaneker M , Scheffer GJ , Teppema LJ , Aarts LP , Heeringa P , Zijlstra JG , Molema G . Hemorrhagic shock‐induced endothelial cell activation in a spontaneous breathing and a mechanical ventilation hemorrhagic shock model is induced by a proinflammatory response and not by hypoxia. Anesthesiology 115: 474‐482, 2011.
 454. van Meurs M , Wulfert FM , Knol AJ , De Haes A , Houwertjes M , Aarts LP , Molema G . Early organ‐specific endothelial activation during hemorrhagic shock and resuscitation. Shock 29: 291‐299, 2008.
 455. Vanderkooi JM , Maniara G , Green TJ , Wilson DF . An optical method for measurement of dioxygen concentration based upon quenching of phosphorescence. J Biol Chem 262: 5476‐5482, 1987.
 456. Vazquez BY , Hightower CM , Martini J , Messmer C , Frienesenecker B , Corbels P , Tsai AG , Intaglietta M . Vasoactive hemoglobin solution improves survival in hemodilution followed by hemorrhagic shock. Crit Care Med 39: 1461‐1466, 2011.
 457. Vedder NB , Winn RK , Rice CL , Chi EY , Arfors KE , Harlan JM . A monoclonal antibody to the adherence‐promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. J Clin Invest 81: 939‐944, 1988.
 458. Villela NR , Salazar Vazquez BY , Intaglietta M . Microcirculatory effects of intravenous fluids in critical illness: Plasma expansion beyond crystalloids and colloids. Curr Opin Anaesthesiol 22: 163‐167, 2009.
 459. Villela NR , Tsai AG , Cabrales P , Intaglietta M . Improved resuscitation from hemorrhagic shock with Ringer's lactate with increased viscosity in the hamster window chamber model. J Trauma 71: 418‐424, 2011.
 460. Vincent JL , De Backer D . Circulatory shock. N Engl J Med 369: 1726‐1734, 2013.
 461. Vink H , Duling BR . Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ Res 79: 581‐589, 1996.
 462. Vlahu CA , Lemkes BA , Struijk DG , Koopman MG , Krediet RT , Vink H . Damage of the endothelial glycocalyx in dialysis patients. J Am Soc Nephrol 23: 1900‐1908, 2012.
 463. Vollmar B , Burkhardt M , Minor T , Klauke H , Menger MD . High‐resolution microscopic determination of hepatic NADH fluorescence for in vivo monitoring of tissue oxygenation during hemorrhagic shock and resuscitation. Microvasc Res 54: 164‐173, 1997.
 464. Vollmar B , Burkhardt M , Minor T , Klauke H , Menger MD . A correlation of intravital microscopically assessed NADH fluorescence, tissue oxygenation, and organ function during shock and resuscitation of the rat liver. Adv Exp Med Biol 454: 95‐101, 1998.
 465. Vollmar B , Preissler G , Menger MD . Hemorrhagic hypotension induces arteriolar vasomotion and intermittent capillary perfusion in rat pancreas. Am J Physiol 267: H1936‐H1940, 1994.
 466. Vollmar MD , Preissler G , Menger MD . Small‐volume resuscitation restores hemorrhage‐induced microcirculatory disorders in rat pancreas. Crit Care Med 24: 445‐450, 1996.
 467. Vollmer C , Schwartges I , Swertz M , Beck C , Bauer I , Picker O . Hypothermia improves oral and gastric mucosal microvascular oxygenation during hemorrhagic shock in dogs. Oxid Med Cell Longev 2013: 589606, 2013.
 468. Wan Z , Sun S , Ristagno G , Weil MH , Tang W . The cerebral microcirculation is protected during experimental hemorrhagic shock. Crit Care Med 38: 928‐932, 2010.
 469. Wandall‐Frostholm C , Dalsgaard T , Bajoriunas V , Olivan‐Viguera A , Sadda V , Beck L , Mogensen S , Stankevicius E , Simonsen U , Kohler R . Genetic deficit of KCa 3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation. Br J Pharmacol 172(18): 4493‐4505, 2015.
 470. Wang B , Chen G , Zhang J , Xue J , Cao Y , Wu Y . Increased neutrophil gelatinase‐associated lipocalin is associated with mortality and multiple organ dysfunction syndrome in severe sepsis and septic shock. Shock 44: 234‐238, 2015.
 471. Wang P , Ba ZF , Burkhardt J , Chaudry IH . Measurement of hepatic blood flow after severe hemorrhage: Lack of restoration despite adequate resuscitation. Am J Physiol 262: G92‐G98, 1992.
 472. Wang P , Ba ZF , Chaudry IH . Endothelial cell dysfunction occurs after hemorrhage in nonheparinized but not in preheparinized models. J Surg Res 54: 499‐506, 1993.
 473. Wang P , Ba ZF , Chaudry IH . Endothelial cell dysfunction occurs very early following trauma‐hemorrhage and persists despite fluid resuscitation. Am J Physiol 265: H973‐H979, 1993.
 474. Wang P , Ba ZF , Dean RE , Chaudry IH . ATP‐MgCl2 restores the depressed hepatocellular function and hepatic blood flow following hemorrhage and resuscitation. J Surg Res 50: 368‐374, 1991.
 475. Wang P , Hauptman JG , Chaudry IH . Hemorrhage produces depression in microvascular blood flow which persists despite fluid resuscitation. Circ Shock 32: 307‐318, 1990.
 476. Wang P , Singh G , Rana MW , Ba ZF , Chaudry IH . Preheparinization improves organ function after hemorrhage and resuscitation. Am J Physiol 259: R645‐R650, 1990.
 477. Wang P , Zhou M , Rana MW , Singh G , Ba ZF , Ayala A , Chaudry IH . ATP‐MgCl2 restores renal microcirculation following trauma and severe hemorrhage. Can J Physiol Pharmacol 70: 349‐357, 1992.
 478. Wang X , Song R , Bian HN , Brunk UT , Zhao M , Zhao KS . Polydatin, a natural polyphenol, protects arterial smooth muscle cells against mitochondrial dysfunction and lysosomal destabilization following hemorrhagic shock. Am J Physiol Regul Integr Comp Physiol 302: R805‐R814, 2012.
 479. Wanner GA , Keel M , Steckholzer U , Beier W , Stocker R , Ertel W . Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Crit Care Med 28: 950‐957, 2000.
 480. Ward BJ , Donnelly JL . Hypoxia induced disruption of the cardiac endothelial glycocalyx: Implications for capillary permeability. Cardiovasc Res 27: 384‐389, 1993.
 481. Ward KR , Ivatury RR , Barbee RW , Terner J , Pittman R , Filho IP , Spiess B . Near infrared spectroscopy for evaluation of the trauma patient: A technology review. Resuscitation 68: 27‐44, 2006.
 482. Ward KR , Tiba MH , Ryan KL , Filho IP , Rickards CA , Witten T , Soller BR , Ludwig DA , Convertino VA . Oxygen transport characterization of a human model of progressive hemorrhage. Resuscitation 81: 987‐993, 2010.
 483. Ward KR , Torres Filho I , Barbee RW , Torres L , Tiba MH , Reynolds PS , Pittman RN , Ivatury RR , Terner J . Resonance Raman spectroscopy: A new technology for tissue oxygenation monitoring. Crit Care Med 34: 792‐799, 2006.
 484. Waschke KF , Riedel M , Albrecht DM , van Ackern K , Kuschinsky W . Regional heterogeneity of cerebral blood flow response to graded volume‐controlled hemorrhage. Intensive Care Med 22: 1026‐1033, 1996.
 485. Waschke KF , Riedel M , Lenz C , Albrecht DM , van Ackern K , Kuschinsky W . Regional heterogeneity of cerebral blood flow response to graded pressure‐controlled hemorrhage. J Trauma 56: 591‐603, 2004.
 486. Wayland H , Johnson PC . Erythrocyte velocity measurement in microvessels by a two‐slit photometric method. J Appl Physiol 22: 333‐337, 1967.
 487. Weil MH , Henning RJ . New concepts in the diagnosis and fluid treatment of circulatory shock. Thirteenth annual Becton, Dickinson and Company Oscar Schwidetsky Memorial Lecture. Anesth Analg 58: 124‐132, 1979.
 488. Weinbaum S , Tarbell JM , Damiano ER . The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9: 121‐167, 2007.
 489. Wennerberg K , Der CJ . Rho‐family GTPases: it's not only Rac and Rho (and I like it). J Cell Sci 117: 1301‐1312, 2004.
 490. Wettstein R , Tsai AG , Erni D , Lukyanov AN , Torchilin VP , Intaglietta M . Improving microcirculation is more effective than substitution of red blood cells to correct metabolic disorder in experimental hemorrhagic shock. Shock 21: 235‐240, 2004.
 491. Wettstein R , Tsai AG , Erni D , Winslow RM , Intaglietta M . Resuscitation with polyethylene glycol‐modified human hemoglobin improves microcirculatory blood flow and tissue oxygenation after hemorrhagic shock in awake hamsters. Crit Care Med 31: 1824‐1830, 2003.
 492. Whalen WJ , Riley J , Nair P . A microelectrode for measuring intracellular PO2 . J Appl Physiol 23: 798‐801, 1967.
 493. White NJ , Contaifer D, Jr. , Martin EJ , Newton JC , Mohammed BM , Bostic JL , Brophy GM , Spiess BD , Pusateri AE , Ward KR , Brophy DF . Early hemostatic responses to trauma identified with hierarchical clustering analysis. J Thromb Haemost 13: 978‐988, 2015.
 494. Whitehouse T , Stotz M , Taylor V , Stidwill R , Singer M . Tissue oxygen and hemodynamics in renal medulla, cortex, and corticomedullary junction during hemorrhage‐reperfusion. Am J Physiol Renal Physiol 291: F647‐F653, 2006.
 495. Wichmann MW , Ayala A , Chaudry IH . Severe depression of host immune functions following closed‐bone fracture, soft‐tissue trauma, and hemorrhagic shock. Crit Care Med 26: 1372‐1378, 1998.
 496. Wiederhielm CA , Bouskela E , Heald R , Black L . A method for varying arterial and venous pressures in intact, unanesthetized mammals. Microvasc Res 18: 124‐128, 1979.
 497. Wiederhielm CA , Woodbury JW , Kirk S , Rushmer RF . Pulsatile pressures in the microcirculation of Frog's mesentery. Am J Physiol 207: 173‐176, 1964.
 498. Wilson DF , Harrison DK . Simultaneous monitoring of brain and skin oxygenation during haemorrhagic shock in piglets. Adv Exp Med Biol 789: 51‐57, 2013.
 499. Winslow RM. MP4, a new nonvasoactive polyethylene glycol‐hemoglobin conjugate. Artif Organs 28: 800‐806, 2004.
 500. Wu CH , Johnson PC . A microcomputer‐based system for mapping microvascular networks. Int J Microcirc Clin Exp 8: 303‐311, 1989.
 501. Wu CY , Chan KC , Cheng YJ , Yeh YC , Chien CT , Research NCoMM. Effects of different types of fluid resuscitation for hemorrhagic shock on splanchnic organ microcirculation and renal reactive oxygen species formation. Crit Care 19: 434, 2015.
 502. Wu CY , Yeh YC , Chien CT , Chao A , Sun WZ , Cheng YJ , Research NCoMM. Laser speckle contrast imaging for assessing microcirculatory changes in multiple splanchnic organs and the gracilis muscle during hemorrhagic shock and fluid resuscitation. Microvasc Res 101: 55‐61, 2015.
 503. Xiang M , Shi X , Li Y , Xu J , Yin L , Xiao G , Scott MJ , Billiar TR , Wilson MA , Fan J . Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells. J Immunol 187: 4809‐4817, 2011.
 504. Xu J , Lan D , Li T , Yang G , Liu L . Angiopoietins regulate vascular reactivity after haemorrhagic shock in rats through the Tie2‐nitric oxide pathway. Cardiovasc Res 96: 308‐319, 2012.
 505. Xu J , Li T , Yang GM , Liu LM . Protein kinase C isoforms responsible for the regulation of vascular calcium sensitivity and their relationship to integrin‐linked kinase pathway after hemorrhagic shock. J Trauma 69: 1274‐1281, 2010.
 506. Xu J , Ma L , Sun S , Lu X , Wu X , Li Z , Tang W . Fluid resuscitation guided by sublingual partial pressure of carbon dioxide during hemorrhagic shock in a porcine model. Shock 39: 361‐365, 2013.
 507. Yada‐Langui MM , Anjos‐Valotta EA , Sannomiya P , Rocha e Silva M , Coimbra R . Resuscitation affects microcirculatory polymorphonuclear leukocyte behavior after hemorrhagic shock: Role of hypertonic saline and pentoxifylline. Exp Biol Med (Maywood) 229: 684‐693, 2004.
 508. Yamashita M , Oyama T , Kudo T . Effect of the inhibitor of angiotensin I converting enzyme on endocrine function and renal perfusion in haemorrhagic shock. Can Anaesth Soc J 24: 695‐701, 1977.
 509. Yang G , Li T , Xu J , Peng X , Liu L . Mitogen‐activated protein kinases regulate vascular reactivity after hemorrhagic shock through myosin light chain phosphorylation pathway. J Trauma Acute Care Surg 74: 1033‐1043, 2013.
 510. Yang Y , Schmidt EP . The endothelial glycocalyx: an important regulator of the pulmonary vascular barrier. Tissue Barriers 1: e-23494-1‐e-23494-6, 2013.
 511. Yu HP , Shimizu T , Hsieh YC , Suzuki T , Choudhry MA , Schwacha MG , Chaudry IH . Tissue‐specific expression of estrogen receptors and their role in the regulation of neutrophil infiltration in various organs following trauma‐hemorrhage. J Leukoc Biol 79: 963‐970, 2006.
 512. Zaets SB , Xu DZ , Lu Q , Feketova E , Berezina TL , Malinina IV , Deitch EA , Olsen EH . Recombinant factor XIII mitigates hemorrhagic shock‐induced organ dysfunction. J Surg Res 166: e135‐e142, 2011.
 513. Zakaria el R , Ehringer WD , Tsakadze N , Li N , Garrison RN . Direct energy delivery improves tissue perfusion after resuscitated shock. Surgery 138: 195‐203, 2005.
 514. Zakaria el R , Garrison RN , Kawabe T , Harris PD . Direct peritoneal resuscitation from hemorrhagic shock: Effect of time delay in therapy initiation. J Trauma 58: 499‐506; discussion 506‐498, 2005.
 515. Zakaria el R , Li N , Garrison RN . Mechanisms of direct peritoneal resuscitation‐mediated splanchnic hyperperfusion following hemorrhagic shock. Shock 27: 436‐442, 2007.
 516. Zakaria el R , Li N , Matheson PJ , Garrison RN . Cellular edema regulates tissue capillary perfusion after hemorrhage resuscitation. Surgery 142: 487‐496; discussion 496 e481‐482, 2007.
 517. Zakaria el R , Tsakadze NL , Garrison RN . Hypertonic saline resuscitation improves intestinal microcirculation in a rat model of hemorrhagic shock. Surgery 140: 579‐587; discussion 587‐578, 2006.
 518. Zhang G , Xu S , Qian Y , He P . Sphingosine‐1‐phosphate prevents permeability increases via activation of endothelial sphingosine‐1‐phosphate receptor 1 in rat venules. Am J Physiol Heart Circ Physiol 299: H1494‐H1504, 2010.
 519. Zhang HY , Radulescu A , Chen Y , Besner GE . HB‐EGF improves intestinal microcirculation after hemorrhagic shock. J Surg Res 171: 218‐225, 2011.
 520. Zhao KS , Huang X , Liu J , Huang Q , Jin C , Jiang Y , Jin J , Zhao G . New approach to treatment of shock‐‐‐restitution of vasoreactivity. Shock 18: 189‐192, 2002.
 521. Zhao KS , Junker D , Delano FA , Zweifach BW . Microvascular adjustments during irreversible hemorrhagic shock in rat skeletal muscle. Microvasc Res 30: 143‐153, 1985.
 522. Zhao KS , Liu J , Yang GY , Jin C , Huang Q , Huang X . Peroxynitrite leads to arteriolar smooth muscle cell membrane hyperpolarization and low vasoreactivity in severe shock. Clin Hemorheol Microcirc 23: 259‐267, 2000.
 523. Zhao KS , Zhu ZG , Woo GY , Haun XL . Effect of naloxone on microcirculatory behavior during irreversible hemorrhagic shock. Microvasc Res 34: 84‐95, 1987.
 524. Zhu Y , Liu L , Peng X , Ding X , Yang G , Li T . Role of adenosine A2A receptor in organ‐specific vascular reactivity following hemorrhagic shock in rats. J Surg Res 184: 951‐958, 2013.
 525. Zuurbier CJ , Demirci C , Koeman A , Vink H , Ince C . Short‐term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells. J Appl Physiol (1985) 99: 1471‐1476, 2005.
 526. Zweifach B , Hershey S , Rovenstine E , Lee R , Chambers R . Anesthetic agents as factors in circulatory reactions induced by hemorrhage. Surgery 18: 48‐65, 1945.
 527. Zweifach B , Lowenstein B , Chambers R . Responses of blood capillaries to acute hemorrhage in the rat. Am J Physiol 142: 80‐93, 1944.
 528. Zweifach BW. Functional deterioration of terminal vascular bed in irreversible hemorrhagic shock. Ann N Y Acad Sci 55: 370‐380, 1952.
 529. Zweifach BW. Mechanisms of blood flow and fluid exchange in microvessels: Hemorrhagic hypotension model. Anesthesiology 41: 157‐168, 1974.
 530. Zweifach BW. Microcirculatory homeostasis 1930‐1990: Insight into microcirculatory readjustments provided by studies on the peripheral circulatory insufficiency of the shock syndrome. Microcirculation 2: 245‐251, 1995.
 531. Zweifach BW , Benacerraf B , Thomas L . The relationship between the vascular manifestations of shock produced by endotoxin, trauma, and hemorrhage. II. The possible role of the reticulo‐endothelial system in resistance to each type of shock. J Exp Med 106: 403‐414, 1957.
 532. Zweifach BW , Chambers R , Lee RE , Hyman C . Reactions of peripheral blood vessels in experimental hemorrhage. Ann N Y Acad Sci 49: 553‐570, 1948.
 533. Zweifach BW , Hershey SG . Predisposing action of anesthetic agents on the vascular responses in hemorrhagic shock. Surg Gynecol Obstet 89: 469‐477, 1949.
 534. Zweifach BW , Lee RE , Hyman C , Chambers R . Omental circulation in morphinized dogs subjected to graded hemorrhage. Ann Surg 120: 232‐250, 1944.
 535. Zweifach BW , Thomas L . The relationship between the vascular manifestations of shock produced by endotoxin, trauma, and hemorrhage. I. Certain similarities between the reactions in normal and endotoxin‐tolerant rats. J Exp Med 106: 385‐401, 1957.

 

Teaching Material

I. Torres Filho. Hemorrhagic Shock and the Microvasculature. Compr Physiol. 8: 2018, 61-101.

Didactic Synopsis

Major Teaching Points:

  • Microcirculatory blood flow is greatly reduced in skin, muscle and intestine during HS, but flow distribution shows spatial and temporal heterogeneity, affecting oxygenation, and outcome.
  • Vascular hyporeactivity may be partially responsible for the decompensation associated with HS.
  • Vasomotion/flowmotion may appear following HS although its full significance is unknown.
  • Hyperventilation and local ischemia may lead to normal systemic oxygenation concomitant with tissue/microvascular hypoxia. Noninvasive measurements of oxygen saturation may provide noninvasive tools for managing HS patients.
  • The potent inflammatory response associated with HS includes upregulation of interleukins/cytokines, microvascular endothelium and neutrophil activation, ROS generation, and increased permeability that is also caused by glycocalyx degradation, and adherens junction complex disruption.
  • HS/trauma disrupts the balance between microvasculature and multiple blood components, sometimes leading to coagulopathy.
  • Biomarkers of microvascular events and tissue injury can be used to help HS diagnosis and prognosis.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: An integrated system can be used to evaluate in vivo thrombus formation and platelet (PLT) adhesion in rats during HS. A computer-controlled laser produces endothelial damage in cremaster microvessels. Previously injected fluorescent PLTs are imaged with a confocal spinning disc, laser, and camera. Red blood cell velocity is measured online with a velocimeter, hemorrhage is induced using synchronized pumps, systemic parameters are recorded and blood samples are collected for immediate analysis. On the top left, image shows fluorescent cold-stored PLTs (arrows) adhering to a thrombus formed in a venule during HS, under flow (left arrow), and an adhering leukocyte (arrowhead).

Figure 2. Teaching point: Experimental data demonstrates the importance of neural control on microvessels during hemorrhage. Some unanesthetized bats were used as controls (no hemorrhage), others were subjected to severe hemorrhage (40 mL/kg, mean body mass = 7 g), or and hemorrhage plus sympathetic denervation one week prior to hemorrhage. The posthemorrhage vasoconstriction disappears of after denervation.

Figure 3. Teaching points: Demonstration of microcirculatory blood flow after HS and utilization of new noninvasive technologies for microcirculatory blood flow measurement. Left: Images of the rabbit ear using a Laser Doppler image (LDI) and a charge-coupled device (CCD) during baseline (Pre) and at different times post-HS. The perfusion flux is also shown.

Figure 4. Teaching point: The functional capillary density (FCD) is considered an important microcirculatory parameter because of its correlation with survival to HS. This work presents the FCD in the dorsal skinfold before HS (baseline), during HS, and after autologous whole blood resuscitation for unanesthetized hamsters surviving in good or bad conditions, and not surviving. Higher survival is observed in animals showing higher FCD, with or without resuscitation.

Figure 5. Teaching point: HS elicits profound morphological changes in the intestinal microcirculation. Here, the intestinal microvasculature can be seen after gelatin ink injection (Panel I) and scanning electron microscopy (Panel II) in WT mice at various magnifications. In animals subjected to sham surgery, there is complete visualization of crypt vessels, and villi apical and basal portions as well as visualization of arterioles, capillaries, and venules. However, in animals subjected to HS/R, only partial visualization of arterioles and some capillaries is achieved, with narrowing of precapillary arterioles and postcapillary venules, indicating hypoperfusion, and in some cases vessels of the distal villi is destroyed.

Figure 6. Teaching point: A complex inflammatory response follows HS. This Figure illustrates some systemic and local inflammatory markers, and organ damage indicators of HS and resuscitation. Higher systemic levels of TNF-α, IL-6, and NGAL protein can be detected in plasma of mice subjected to 90 min of HS and 90 min of HS followed by resuscitation. The mRNA expression of endothelial proinflammatory molecules (cell adhesion molecules and cytokines), vascular integrity–related molecules (e.g., CD31, VE-cad), and organ damage–related marker NGAL in kidneys is also increased.

Figure 7. Teaching points: Vulnerability to hemorrhage and correlation between microvascular and systemic variables. Direct microvascular PO2 measurements show that the heart is less vulnerable to hemorrhage than the gut but at bleeding levels of 45% substantial decreases in PO2 are detected. The microvascular PO2 measured in the surfaces of the left ventricle (heart) and the ileum (gut) of swine subjected to HS and resuscitation correlates with cardiac index and mean arterial pressure (MAP), during HS and resuscitation.

Figure 8. Teaching point: The microvascular flow distribution during HS is highly heterogeneous. A recently described noninvasive technique of laser speckle imaging can be used to demonstrate that microcirculatory blood flow intensities after HS vary widely among liver, kidney, intestinal mucosa, serosal muscular layer, Peyer's patch, and gracilis muscle.

Figure 9. Teaching points: correlation between microvascular and systemic variables/hypovolemia level. Progressive hemorrhage in sheep causes significant decrease in cardiac output and increase in arterial lactate. In different tissues, measurements of the microvascular flow correlate with the degree of hypovolemia from the first step of bleeding, showing that a microvascular index can be used to identify hypovolemia.

Figure 10. Teaching points: Vasomotion and flowmotion can be modulated by arterial blood pressure level, HS and resuscitation. Vasomotion has been observed and measured in various organs such as pancreas, mesentery, and skeletal muscle. It can also appear after HS, be enhanced by certain therapeutic procedures and disappear at low levels of MAP. Vasomotion induces intermittent perfusion and blood flow oscillations (flowmotion) that can be detected using LDF in animals and humans.

Figure 11. Teaching point: Oxygenation of the gut can become lower than the mesenteric venous PO2 during HS. Precise noninvasive µPO2 measurements in the exposed ileum by PQM reveals that the intense microvascular vasoconstriction during prolonged severe HS results in intestinal µPO2 values significantly lower than mesenteric PO2.

Figure 12. Teaching points: During HS, hyperventilation leads to progressively higher levels of systemic PO2, whereas ischemia of skin microvessels produces very low levels of arteriolar PO2. During prolonged HS, microvascular PO2 can reach very low levels while systemic levels remain high. This dissociation between systemic arterial pO2 and microvascular pO2 is demonstrated in the hamster during hemorrhagic shock.

Figure 13. Teaching points: As blood flows in microvessels, oxygen is exchanged to the tissues, causing the intravascular pO2 to decrease as a function of vessel size. This longitudinal pO2 gradient can increase during HS as the blood flow decreases. In the rat mesentery, longitudinal PO2 gradients for arterioles and venules is demonstrated during HH.

Figure 14. Teaching point: First quantitative evidence of EG degradation during HS obtained using intravital microscopy in anesthetized rats. Analysis of video sequences obtained in vivo was used to estimate EG thickness before and posthemorrhage. Control animals did not show any changes in EG thickness of mesentery and cremaster vessels. However, in hemorrhaged animals the EG thickness after HS was 41% of the baseline.

Figure 15. Teaching points: EG degradation can be evaluated using different techniques and can be modulated by HS and fluid resuscitation. Microvascular EG thickness can be measured from images obtained using electron microscopy and intravital microscopy. Following HS, EG degradation can be measured using both techniques in different organs. Resuscitation with different solutions reveal that EG thickness can be remain at the same level as during HS using crystalloids (such as lactated Ringer's) or be restored to baseline conditions using fluids such as fresh frozen plasma.

Figure 16. Teaching point: Treatment with protease inhibitors decreases microvascular damage after HS. Representative macroscale images show that untreated animals present characteristic lesion sites due to escape of RBCs from microvessels in the small intestine, right ventricle and lung. Rats treated with a pancreatic enzyme inhibitor do not show the lesions.

Figure 17. Teaching point: HS in humans can be simulated using the lower body negative pressure (LBNP) method. In the laboratory, application of negative pressure to the lower extremities allows controlled decreases in venous return, resulting in proportional responses in cardiac output (CO), heart rate (HR), mean arterial blood pressure (MAP), oxygen delivery (DO2), oxygen extraction ratio (O2ER), functional capillary density in sublingual mucosa (FCD), and oxygen saturation in the forearm muscle (SO2).

Figure 18. Teaching points: Microcirculation is impaired in patients with traumatic HS, remains impaired up to 72 h despite restoration of macrovascular hemodynamics, and correlates with organ failure. Microcirculatory flow index (MFI) and proportion of perfused vessels (PPV) of the sublingual mucosa were studied in the first 4 days (D1-D4) after traumatic HS. Systemic parameters included lactate and hemoglobin (Hb).

Figure 19. Teaching points: Endothelial glycocalyx degradation occurs in severely injured HS patients, and correlates with mortality. Data from trauma patients, if stratified according to high versus low circulating plasma syndecan-1 (a marker for glycocalyx degradation), show correlation with catecholamines and mortality.

Figure 20. Teaching points: An integrative diagram depicts the main factors involving microvessels in HS. A microvessel is continuously influenced by multiple factors coming from the blood, nervous system, and the tissues. Following hemorrhage/trauma, microvascular ECs are exposed to changing levels of physical (e.g., blood pressure) and chemical factors (e.g., PO2, catecholamines). Leukocytes (WBC), red blood cells (RBC), and platelets (PLT) are functionally altered and their relationship with the ECs is also affected. Proinflammatory cytokines activate NF-κB signaling, leading to transcription of adhesion molecules (VCAM-1, ICAM-1), interleukins (IL), and MCP-1. Other intracellular processes are impacted (e.g., HDAC activity, eNOS). EG degradation and adherens complex disruption contribute to hyperpermeability. Coagulopathy may occur, involving multiple components (e.g., PAI-1 degradation, APC, TM, and PLT dysfunction). Neural influences as well as physicochemical changes in blood and tissue alter microvascular resistance, responsiveness, and vasomotion. Vessel hyporeactivity may involve NO, and proteins RAC1 and RhoA. Microvascular PO2, SO2, and FCD are critically associated with survival. Blood flow is redistributed among microvessels that are also affected by tissue changes (e.g., pH and ROS). Multiple factors linked to endothelial activation and organ damage are released into circulation, and function as biomarkers.

 


Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Hemorrhagic Shock and the Microvasculature
 

How to Cite

Ivo Torres Filho. Hemorrhagic Shock and the Microvasculature. Compr Physiol 2017, 8: 61-101. doi: 10.1002/cphy.c170006