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Cerebral Blood‐Flow Regulation During Hemorrhage

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ABSTRACT

Massive uncontrolled blood loss can occur under a variety of conditions including trauma, as a complication of childbirth or surgery, ruptured ulcers, clotting disorders, and hemorrhagic fevers. Across the continuum of hemorrhage, loss of blood volume is a significant challenge to the maintenance of cerebral perfusion. During the initial stages of hemorrhage, reflex mechanisms are activated to protect cerebral perfusion, but persistent blood loss will eventually reduce global cerebral blood flow and the delivery of metabolic substrates, leading to generalized cerebral ischemia, hypoxia, and ultimately, neuronal cell death. Cerebral blood flow is controlled by various regulatory mechanisms, including prevailing arterial pressure, intracranial pressure, arterial blood gases, neural activity, and metabolic demand. Hemorrhage represents a unique physiological stress to the brain, as it influences each of these regulatory mechanisms, resulting in complex interplay that ultimately challenges the ability of the brain to maintain adequate perfusion. Early studies of actual hemorrhage in humans employed blood loss protocols up to 1000 mL, but did not include any measurements of cerebral blood flow. As ethical considerations necessarily constrain the use of human volunteers for massive blood loss studies that induce irreversible shock, most of what is known about cerebral blood‐flow responses to hemorrhage has been determined from animal models. Limitations of species differences regarding regulatory mechanisms, anatomy, and the effect of anesthesia, however, must be considered. Advances in monitoring technologies, and a recent renewed interest in understanding cerebral blood‐flow regulation in humans, however, is rapidly accelerating knowledge in this field. © 2015 American Physiological Society. Compr Physiol 5:1585‐1621, 2015.

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Figure 1. Figure 1. Hemodynamic responses to a 1020 mL hemorrhage in a healthy human subject. Right auricular pressure (RAP) and cardiac output (CO) fall progressively, while heart rate (HR) and total peripheral resistance (TPR) increase via a baroreflex‐mediated mechanism. Blood pressure (BP) is maintained until HR and TPR fall precipitously at the onset of syncope (faint). Redrawn from (18) with permission from Elsevier.
Figure 2. Figure 2. Physiological factors affecting cerebral blood flow during hemorrhage. The ultimate response of cerebral blood flow depends upon the strength and magnitude of each stimulus independently, and the combined interrelationship between all factors.
Figure 3. Figure 3.

(A) The major extracranial vessels supplying the Circle of Willis include the left and right internal carotid arteries (ICA), and the left and right vertebral arteries (VA) fusing to form the basilar artery (BA). The ICAs feed the middle cerebral arteries (MCA) and anterior cerebral arteries (ACA), and the BA feeds the posterior cerebral arteries (PCA). Reprinted with permission (58).

(B) The major intracranial vessels form the Circle of Willis. ACA, anterior cerebral artery; AComA, anterior communicating artery; MCA, middle cerebral artery; ICA, internal carotid artery; PCA, posterior cerebral artery; PComA, posterior communicating artery; SCA, superior cerebellar artery; Basilar A, basilar artery. Reprinted with permission (56).

Figure 4. Figure 4. Summary of findings from four studies assessing changes in middle cerebral artery diameter (MCA) with perturbations in arterial CO2 using MRI technology. These studies indicate that there may be a threshold level of hypo‐ and hypercapnia that induces changes in MCA diameter (between 7% and 10% from baseline). Reprinted with permission (8).
Figure 5. Figure 5. Duplex‐Doppler ultrasound images in a human subject of the vertebral artery (VA), basilar artery (BA), internal carotid artery (ICA), and external carotid artery (ICA) for assessment of diameter and velocity, and calculation of flow. The middle cerebral artery (MCA) is assessed via transcranial Doppler ultrasound. Reprinted with permission (203).
Figure 6. Figure 6. Near infrared spectroscopy (NIRS)‐derived cerebral oxygen saturation, deoxy‐hemoglobin (dHb), and oxy‐hemoglobin (HbO2) responses to progressive hemorrhage in humans up to 470 mL (approx. 12% blood loss). Adapted from (236) with permission.
Figure 7. Figure 7. Representative hemodynamic responses to progressive central hypovolemia elicited via application of lower body negative pressure (LBNP) to −60 mmHg in a human subject. As stroke volume (SV) falls progressively, heart rate (HR) and total peripheral resistance (not shown) increase via a baroreflex‐mediated mechanism; mean arterial pressure (MAP) is maintained near baseline levels. At presyncope (dashed line), SV and MAP are reduced by 71% and 38% from baseline while mean middle cerebral artery velocity (MCAv) and cerebral oxygen saturation (ScO2) fall by 51% and 12%.
Figure 8. Figure 8. Hemodynamic responses to a 25% hemorrhage and central blood volume‐matched lower body negative pressure (LBNP) levels in baboons. dP/dt, index of cardiac contractility. Data are mean ± SD. Reprinted with permission (102).
Figure 9. Figure 9. Comparison of stroke volume reductions during lower body negative pressure (LBNP) to a chamber pressure of −45 mmHg, and 1000 mL blood loss (BL) in human subjects. Reprinted with permission (114).
Figure 10. Figure 10. Individual plots of mean arterial pressure (MAP) versus mean middle cerebral artery velocity (MCAv) for all 9 subjects for LBNP (blue circles) and blood loss (red circles). Group responses are presented in the lower right panel (N = 9). Reprinted with permission (19).
Figure 11. Figure 11. Representative tracings of end‐tidal CO2 (etCO2), mean arterial pressure (MAP), and mean middle cerebral artery velocity (MCAv) in one high tolerant (HT) subject (A) and one low tolerant (LT) subject (B) during the final 3 min of presyncopal limited lower body negative pressure (LBNP). Note that respiration rate measured from the etCO2 waveform was ∼14.3 breaths/min (0.24 Hz) for the HT subject and ∼13.3 breaths/min (0.22 Hz) for the LT subject. Reprinted with permission (192).
Figure 12. Figure 12. Low‐frequency (LF) oscillations in mean arterial pressure (MAP) and mean middle cerebral artery velocity (MCAv) during progressive lower body negative pressure (LBNP) up to −60 mmHg (A and C), and at presyncope (B and D) in high tolerant (HT) and low tolerant (LT) subjects. * P ≤ 0.001, between HT and LT. Reprinted with permission (192).
Figure 13. Figure 13. The classic cerebral autoregulation curve demonstrating a cerebral blood flow (CBF) plateau across a range of mean arterial pressures. Three hundred seventy‐six individual data points from 11 groups of subjects and 7 different studies are included. Note the limitations of this original representation of the cerebral autoregulatory plateau in the text (see Cerebral Autoregulation section). Redrawn with permission (134).
Figure 14. Figure 14. Cerebral blood velocity (A), and cerebrovascular resistance (CVR) and conductance (CVC) responses (B) in the middle cerebral artery (MCAv) to step‐wise hypotension induced with sodium nitroprusside and hypertension induced by phenylephrine in human subjects. MAP, mean arterial pressure. Reprinted with permission (144).
Figure 15. Figure 15. Arterial pressure‐cerebral blood velocity (flow) relationship at 0.03 Hz oscillatory lower body negative pressure (OLBNP) suggesting a very narrow autoregulatory “plateau” region within 5 mmHg of baseline. Reprinted with permission (91).
Figure 16. Figure 16. The traditional (green) versus contemporary interpretation of cerebral autoregulation (CA) where intact CA may be represented by a pressure passive response of cerebral blood flow (blue) within certain limits of perfusion pressure (a and b), which then increases (red) as CA becomes impaired. The gain of the pressure‐flow relationship may increase outside of these limits.
Figure 17. Figure 17. Cortical blood‐flow (CBF) responses to reductions in mean arterial pressure (MAP) during progressive hemorrhage in cats. CBF becomes pressure passive between 60 and 69 mmHg MAP, but maximal arterial dilation did not occur until 30 and 39 mmHg MAP. Redrawn with permission (146).
Figure 18. Figure 18. Decreasing arterial pressure progressively reduces cerebrovascular reactivity to the partial pressure of arterial carbon dioxide (PaCO2). Reprinted with permission (94); redrawn by Willie et al. (266).
Figure 19. Figure 19. α‐Adrenergic stimulation of perivascular sympathetic nerves, as would occur during hemorrhage, shifts the cerebral autoregulatory curve to the right, resulting in pressure‐passive responses of cerebral blood flow at higher arterial pressures. Redrawn with permission (177).
Figure 20. Figure 20. The cerebral autoregulatory response to hyper‐ and hypocapnia. Hypercapnia increases cerebral blood flow and narrows the effective range of autoregulation, while hypocapnia decreases cerebral blood flow and widens this range. Redrawn with permission (177).
Figure 21. Figure 21. Two potential responses of the cerebral autoregulatory curve with progressive hypotension to presyncope; a rightward shift due to sympathetic activation (A), or a downward shift, likely due to hypocapnia (B). The “threshold of presyncope” represents the level of cerebral blood flow at which presyncope occurs. With progressive hypocapnia, this threshold would be reached even without changes in arterial pressure. CPP, cerebral perfusion pressure (mean arterial minus intracranial pressure). Reprinted with permission (28).
Figure 22. Figure 22. Sympathetic nerve activity (SNA) in the superior cervical ganglion in responses to increasing and decreasing mean arterial pressure (MAP). There is no change in SNA with decreases in MAP to 48% below baseline. Reprinted with permission (36).
Figure 23. Figure 23. Cerebral blood‐flow responses to blood loss are primarily via changes in oxygen delivery (DO2) and arterial carbon dioxide tension (PaCO2), and subsequent chemoreflex‐mediated alterations in ventilation. Increases in PaCO2 elicit cerebral vasodilation and increases in cerebral blood flow, while decreases in PaCO2 cause cerebral vasoconstriction and decreases in cerebral blood flow. Major blood loss (>50%) must occur to elicit any physiologically relevant decrease in arterial oxygen tension (PaO2), and PaO2 must fall to at least 60 mmHg to stimulate an increase in cerebral blood flow. TBV, total blood volume; ECF, extracellular fluid; CSF, cerebrospinal fluid; CBF, cerebral blood flow; H+, hydrogen ions.
Figure 24. Figure 24. Cerebral blood flow (Q) and cerebral blood velocity (CBV) responses to steady state increases and decreases in arterial carbon dioxide (CO2) and oxygen (O2) in the anterior and posterior cerebral circulations. Blood flow was measured in the internal carotid artery (ICA; anterior circulation) and vertebral artery (VA; posterior circulation), and CBV was measured in the middle cerebral artery (MCA; anterior circulation) and posterior cerebral artery (PCA; posterior circulation). * denotes P < 0.05 from baseline (40 mmHg PaCO2 or 100 mmHg PO2); † denotes P < 0.012 between vessel flow (ICA vs. VA) or velocity (MCA vs. PCA) at a given stage. All values are means ± SD. Reprinted with permission (264).
Figure 25. Figure 25. Cerebral blood flow (CBF), cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) responses to progressively decreasing perfusion pressure, as would occur with hemorrhage. A reduction in perfusion pressure elicits vasodilation to maintain CBF up to a threshold (A). Below this threshold, CBF falls, but OEF increases to maintain tissue oxygenation and metabolism (CMRO2). Once oxygen extraction is exhausted (B), CMRO2 decreases, compromising neural function. Redrawn with permission (186).
Figure 26. Figure 26. Cerebral blood flow and oxygenation responses to fluid resuscitation with crystalloid (40 mL/kg) + colloid (20 mL/kg) (FR), hypertonic starch solution (4 mL/kg) plus norepinephrine (NA/HS), or hypertonic starch solution (4 mL/kg) plus arginine vasopressin (AVP/HS) following hemorrhage to MAP of <25 mmHg. BL T: baseline trauma; Th: before start of therapy, and following therapy after 5‐min (Th + 5), 30‐min (Th + 30), and 60‐min (Th + 60); P btO2: brain tissue partial pressure of O2; TOI: tissue oxygenation index; CPP: cerebral perfusion pressure; FV: flow velocity in middle cerebral artery. Values are mean ± SEM. *, denotes P < 0.001 versus BL T for all groups; †, denotes P < 0.001 versus FR; ‡, denotes P < 0.05 versus FR; §, denotes P < 0.01 versus NA/HS. Reprinted with permission (37).


Figure 1. Hemodynamic responses to a 1020 mL hemorrhage in a healthy human subject. Right auricular pressure (RAP) and cardiac output (CO) fall progressively, while heart rate (HR) and total peripheral resistance (TPR) increase via a baroreflex‐mediated mechanism. Blood pressure (BP) is maintained until HR and TPR fall precipitously at the onset of syncope (faint). Redrawn from (18) with permission from Elsevier.


Figure 2. Physiological factors affecting cerebral blood flow during hemorrhage. The ultimate response of cerebral blood flow depends upon the strength and magnitude of each stimulus independently, and the combined interrelationship between all factors.


Figure 3.

(A) The major extracranial vessels supplying the Circle of Willis include the left and right internal carotid arteries (ICA), and the left and right vertebral arteries (VA) fusing to form the basilar artery (BA). The ICAs feed the middle cerebral arteries (MCA) and anterior cerebral arteries (ACA), and the BA feeds the posterior cerebral arteries (PCA). Reprinted with permission (58).

(B) The major intracranial vessels form the Circle of Willis. ACA, anterior cerebral artery; AComA, anterior communicating artery; MCA, middle cerebral artery; ICA, internal carotid artery; PCA, posterior cerebral artery; PComA, posterior communicating artery; SCA, superior cerebellar artery; Basilar A, basilar artery. Reprinted with permission (56).



Figure 4. Summary of findings from four studies assessing changes in middle cerebral artery diameter (MCA) with perturbations in arterial CO2 using MRI technology. These studies indicate that there may be a threshold level of hypo‐ and hypercapnia that induces changes in MCA diameter (between 7% and 10% from baseline). Reprinted with permission (8).


Figure 5. Duplex‐Doppler ultrasound images in a human subject of the vertebral artery (VA), basilar artery (BA), internal carotid artery (ICA), and external carotid artery (ICA) for assessment of diameter and velocity, and calculation of flow. The middle cerebral artery (MCA) is assessed via transcranial Doppler ultrasound. Reprinted with permission (203).


Figure 6. Near infrared spectroscopy (NIRS)‐derived cerebral oxygen saturation, deoxy‐hemoglobin (dHb), and oxy‐hemoglobin (HbO2) responses to progressive hemorrhage in humans up to 470 mL (approx. 12% blood loss). Adapted from (236) with permission.


Figure 7. Representative hemodynamic responses to progressive central hypovolemia elicited via application of lower body negative pressure (LBNP) to −60 mmHg in a human subject. As stroke volume (SV) falls progressively, heart rate (HR) and total peripheral resistance (not shown) increase via a baroreflex‐mediated mechanism; mean arterial pressure (MAP) is maintained near baseline levels. At presyncope (dashed line), SV and MAP are reduced by 71% and 38% from baseline while mean middle cerebral artery velocity (MCAv) and cerebral oxygen saturation (ScO2) fall by 51% and 12%.


Figure 8. Hemodynamic responses to a 25% hemorrhage and central blood volume‐matched lower body negative pressure (LBNP) levels in baboons. dP/dt, index of cardiac contractility. Data are mean ± SD. Reprinted with permission (102).


Figure 9. Comparison of stroke volume reductions during lower body negative pressure (LBNP) to a chamber pressure of −45 mmHg, and 1000 mL blood loss (BL) in human subjects. Reprinted with permission (114).


Figure 10. Individual plots of mean arterial pressure (MAP) versus mean middle cerebral artery velocity (MCAv) for all 9 subjects for LBNP (blue circles) and blood loss (red circles). Group responses are presented in the lower right panel (N = 9). Reprinted with permission (19).


Figure 11. Representative tracings of end‐tidal CO2 (etCO2), mean arterial pressure (MAP), and mean middle cerebral artery velocity (MCAv) in one high tolerant (HT) subject (A) and one low tolerant (LT) subject (B) during the final 3 min of presyncopal limited lower body negative pressure (LBNP). Note that respiration rate measured from the etCO2 waveform was ∼14.3 breaths/min (0.24 Hz) for the HT subject and ∼13.3 breaths/min (0.22 Hz) for the LT subject. Reprinted with permission (192).


Figure 12. Low‐frequency (LF) oscillations in mean arterial pressure (MAP) and mean middle cerebral artery velocity (MCAv) during progressive lower body negative pressure (LBNP) up to −60 mmHg (A and C), and at presyncope (B and D) in high tolerant (HT) and low tolerant (LT) subjects. * P ≤ 0.001, between HT and LT. Reprinted with permission (192).


Figure 13. The classic cerebral autoregulation curve demonstrating a cerebral blood flow (CBF) plateau across a range of mean arterial pressures. Three hundred seventy‐six individual data points from 11 groups of subjects and 7 different studies are included. Note the limitations of this original representation of the cerebral autoregulatory plateau in the text (see Cerebral Autoregulation section). Redrawn with permission (134).


Figure 14. Cerebral blood velocity (A), and cerebrovascular resistance (CVR) and conductance (CVC) responses (B) in the middle cerebral artery (MCAv) to step‐wise hypotension induced with sodium nitroprusside and hypertension induced by phenylephrine in human subjects. MAP, mean arterial pressure. Reprinted with permission (144).


Figure 15. Arterial pressure‐cerebral blood velocity (flow) relationship at 0.03 Hz oscillatory lower body negative pressure (OLBNP) suggesting a very narrow autoregulatory “plateau” region within 5 mmHg of baseline. Reprinted with permission (91).


Figure 16. The traditional (green) versus contemporary interpretation of cerebral autoregulation (CA) where intact CA may be represented by a pressure passive response of cerebral blood flow (blue) within certain limits of perfusion pressure (a and b), which then increases (red) as CA becomes impaired. The gain of the pressure‐flow relationship may increase outside of these limits.


Figure 17. Cortical blood‐flow (CBF) responses to reductions in mean arterial pressure (MAP) during progressive hemorrhage in cats. CBF becomes pressure passive between 60 and 69 mmHg MAP, but maximal arterial dilation did not occur until 30 and 39 mmHg MAP. Redrawn with permission (146).


Figure 18. Decreasing arterial pressure progressively reduces cerebrovascular reactivity to the partial pressure of arterial carbon dioxide (PaCO2). Reprinted with permission (94); redrawn by Willie et al. (266).


Figure 19. α‐Adrenergic stimulation of perivascular sympathetic nerves, as would occur during hemorrhage, shifts the cerebral autoregulatory curve to the right, resulting in pressure‐passive responses of cerebral blood flow at higher arterial pressures. Redrawn with permission (177).


Figure 20. The cerebral autoregulatory response to hyper‐ and hypocapnia. Hypercapnia increases cerebral blood flow and narrows the effective range of autoregulation, while hypocapnia decreases cerebral blood flow and widens this range. Redrawn with permission (177).


Figure 21. Two potential responses of the cerebral autoregulatory curve with progressive hypotension to presyncope; a rightward shift due to sympathetic activation (A), or a downward shift, likely due to hypocapnia (B). The “threshold of presyncope” represents the level of cerebral blood flow at which presyncope occurs. With progressive hypocapnia, this threshold would be reached even without changes in arterial pressure. CPP, cerebral perfusion pressure (mean arterial minus intracranial pressure). Reprinted with permission (28).


Figure 22. Sympathetic nerve activity (SNA) in the superior cervical ganglion in responses to increasing and decreasing mean arterial pressure (MAP). There is no change in SNA with decreases in MAP to 48% below baseline. Reprinted with permission (36).


Figure 23. Cerebral blood‐flow responses to blood loss are primarily via changes in oxygen delivery (DO2) and arterial carbon dioxide tension (PaCO2), and subsequent chemoreflex‐mediated alterations in ventilation. Increases in PaCO2 elicit cerebral vasodilation and increases in cerebral blood flow, while decreases in PaCO2 cause cerebral vasoconstriction and decreases in cerebral blood flow. Major blood loss (>50%) must occur to elicit any physiologically relevant decrease in arterial oxygen tension (PaO2), and PaO2 must fall to at least 60 mmHg to stimulate an increase in cerebral blood flow. TBV, total blood volume; ECF, extracellular fluid; CSF, cerebrospinal fluid; CBF, cerebral blood flow; H+, hydrogen ions.


Figure 24. Cerebral blood flow (Q) and cerebral blood velocity (CBV) responses to steady state increases and decreases in arterial carbon dioxide (CO2) and oxygen (O2) in the anterior and posterior cerebral circulations. Blood flow was measured in the internal carotid artery (ICA; anterior circulation) and vertebral artery (VA; posterior circulation), and CBV was measured in the middle cerebral artery (MCA; anterior circulation) and posterior cerebral artery (PCA; posterior circulation). * denotes P < 0.05 from baseline (40 mmHg PaCO2 or 100 mmHg PO2); † denotes P < 0.012 between vessel flow (ICA vs. VA) or velocity (MCA vs. PCA) at a given stage. All values are means ± SD. Reprinted with permission (264).


Figure 25. Cerebral blood flow (CBF), cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) responses to progressively decreasing perfusion pressure, as would occur with hemorrhage. A reduction in perfusion pressure elicits vasodilation to maintain CBF up to a threshold (A). Below this threshold, CBF falls, but OEF increases to maintain tissue oxygenation and metabolism (CMRO2). Once oxygen extraction is exhausted (B), CMRO2 decreases, compromising neural function. Redrawn with permission (186).


Figure 26. Cerebral blood flow and oxygenation responses to fluid resuscitation with crystalloid (40 mL/kg) + colloid (20 mL/kg) (FR), hypertonic starch solution (4 mL/kg) plus norepinephrine (NA/HS), or hypertonic starch solution (4 mL/kg) plus arginine vasopressin (AVP/HS) following hemorrhage to MAP of <25 mmHg. BL T: baseline trauma; Th: before start of therapy, and following therapy after 5‐min (Th + 5), 30‐min (Th + 30), and 60‐min (Th + 60); P btO2: brain tissue partial pressure of O2; TOI: tissue oxygenation index; CPP: cerebral perfusion pressure; FV: flow velocity in middle cerebral artery. Values are mean ± SEM. *, denotes P < 0.001 versus BL T for all groups; †, denotes P < 0.001 versus FR; ‡, denotes P < 0.05 versus FR; §, denotes P < 0.01 versus NA/HS. Reprinted with permission (37).
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Caroline A. Rickards. Cerebral Blood‐Flow Regulation During Hemorrhage. Compr Physiol 2015, 5: 1585-1621. doi: 10.1002/cphy.c140058