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Hemorrhagic Shock and the Microvasculature

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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.

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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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 (). Using this technique, a reduction of nearly 50% in EG thickness was measured after HS. From () 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 () 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 () with permission; (C): modified from () with permission; [(D) and (E)]: modified from () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 () 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 (). Using this technique, a reduction of nearly 50% in EG thickness was measured after HS. From () 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 () 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 () with permission; (C): modified from () with permission; [(D) and (E)]: modified from () 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 () 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 () 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 () 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 () 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.
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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.

 


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How to Cite

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