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Cardiovascular Responses During Sepsis

Matteo Pecchiari, Konstantinos Pontikis, Emmanouil Alevrakis, Ioannis Vasileiadis, Maria Kompoti, Antonia Koutsoukou

10.1002/cphy.c190044

Source: Volume 11, Issue 2, April 2021

Published online: April 2021

Full Article on Wiley Online Library



Abstract

Sepsis is the life‐threatening organ dysfunction arising from a dysregulated host response to infection. Although the specific mechanisms leading to organ dysfunction are still debated, impaired tissue oxygenation appears to play a major role, and concomitant hemodynamic alterations are invariably present. The hemodynamic phenotype of affected individuals is highly variable for reasons that have been partially elucidated. Indeed, each patient's circulatory condition is shaped by the complex interplay between the medical history, the volemic status, the interval from disease onset, the pathogen, the site of infection, and the attempted resuscitation. Moreover, the same hemodynamic pattern can be generated by different combinations of various pathophysiological processes, so the presence of a given hemodynamic pattern cannot be directly related to a unique cluster of alterations. Research based on endotoxin administration to healthy volunteers and animal models compensate, to an extent, for the scarcity of clinical studies on the evolution of sepsis hemodynamics. Their results, however, cannot be directly extrapolated to the clinical setting, due to fundamental differences between the septic patient, the healthy volunteer, and the experimental model. Numerous microcirculatory derangements might exist in the septic host, even in the presence of a preserved macrocirculation. This dissociation between the macro‐ and the microcirculation might account for the limited success of therapeutic interventions targeting typical hemodynamic parameters, such as arterial and cardiac filling pressures, and cardiac output. Finally, physiological studies point to an early contribution of cardiac dysfunction to the septic phenotype, however, our defective diagnostic tools preclude its clinical recognition. © 2021 American Physiological Society. Compr Physiol 11:1605‐1652, 2021.

Figure 1. Figure 1. Relation between central venous pressure (CVP) and cardiac index (CI) in 46 medical septic patients drawn according to the data reported by Winslow and colleagues 581. Reused, with permission, from Winslow EJ, et al., (1973) 581.
Figure 2. Figure 2. Venous return curves built using a model with elements in series (A) or in parallel (B). The arrangement of the different elements is indicated by the inserts. For the in‐series model, Ra is arterial resistance, Rv venous resistance, SVR systemic vascular resistance, and RVR resistance to venous return, calculated according to Eq. 5. In (A) the control condition corresponds to VRC1 (Ra, Rv, SVR, and RVR are 16.7, 0.8, 17.5, and 1.1 mmHg min/liter, respectively). Halving of Ra causes SVR and RVR to decrease to 9.2 and 1.0 mmHg min/liter, respectively and rotates clockwise the venous return curve from VRC1 to VRC2. If Ra decreases four times relative to its control value but Rv doubles, SVR becomes 5.8 and RVR 1.7 mmHg min/liter, respectively, and the venous return curve rotates counterclockwise to VRC3. For the in parallel model, Ra is arterial resistance, Rv venous resistance, and C compliance. The subscripts 1 and 2 refer to the non‐compliant and to the compliant compartment, respectively. Fc is the percentage of cardiac output (CO) perfusing the compliant compartment. In (B) VRC1 was built using published data relative to a dog 84. Calculated SVR is 67 mmHg min/liter. If Ra of the non‐compliant compartment is halved and that of the compliant compartment is doubled, so that Fc decreases from 54% to 25%, SVR decreases (57 mmHg min/liter), and the slope of the venous return curve increases (VRC2). If Ra of the non‐compliant compartment is doubled and that of the compliant compartment is halved, so that Fc increases from 54% to 80%, SVR decreases to the same amount as before (57 mmHg min/liter) but the slope of the venous return curve decreases (VRC3).
Figure 3. Figure 3. Equilibrium diagram showing the effects of sepsis‐induced absolute or effective hypovolemia (A), vasodilation of resistive vessels (B), myocardial dysfunction (C), absolute or effective hypovolemia and myocardial dysfunction (D), vasodilation of resistive vessels, and myocardial dysfunction (E) and absolute or effective hypovolemia and vasodilation of resistive vessels (F). Thin lines correspond to the control conditions, thick lines indicate sepsis‐induced alterations of the cardiac and venous return curves. Reflex compensation is not shown.
Figure 4. Figure 4. Relation between the rate or norepinephrine infusion and mean systemic filling pressure (Pmsf), resistance to venous return index (RVRI), and systemic vascular resistance index (SVRI) in stable postoperative cardiac surgery patients (○) and septic shock patients (•). The values corresponding to zero norepinephrine were obtained by extrapolation. Data are from three unrelated studies performed separately on cardiac surgery patients 306,307 and septic shock patients 404. Reused, with permission, from Maas JJ, et al., (2009) 306, Maas JJ, et al., (2013) 307, Persichini R, et al., (2012) 404.
Figure 5. Figure 5. Guyton's equilibrium diagram representing the functional properties of the heart and of the systemic circulation of a healthy human subject before and after the injection of LPS. Before the injection, the intersection of the cardiac function curve (CFCc) and the venous return curve (VRCc) is at point A. After the injection, the equilibrium point moves from point A to point E. An increase of cardiac output (CO) without changes of central venous pressure (CVP) implies unequivocally a counterclockwise rotation of the cardiac function curve (to CFCe) but is compatible with different modifications of the vascular function curve. Either resistance to venous return (RVR) decreases proportionally more than mean systemic filling pressure (Pmsf) (A), or Pmsf increases proportionally more than RVR (B). The measured decrease of systemic vascular resistance (SVR) after bacterial lipopolysaccharide (LPS) administration suggests (but does not prove) that the possibility shown by (A) is more likely.
Figure 6. Figure 6. Glycocheck algorithm on endothelial perfused boundary region (PBR) determination and microvascular perfusion properties. (A) Red blood cells (RBC) are detected through reflection of light‐emitting diodes by hemoglobin. Images captured by the sidestream darkfield camera are sent to the computer for quality checks and assessment. The black contrast is the perfused lumen of the vessels. (B) In each recording, the software automatically places the vascular segments (green), every 10 mm along the vascular segments (black contrast). (C) After the acquisition, for the analysis, the software undergoes several quality checks in the first frame of each recording, to select vascular segments with sufficient quality for further analysis. Invalid vascular segments (yellow) are distinguished from the valid vascular segments (green). During the whole recording session of 40 frames, the percentage of time in which a particular valid vascular segment has RBCs present is used to calculate RBC filling percentage. (D) Depiction of the concept of glycocalyx thickness by lateral RBC movement is shown here. (E) For each vascular segment, the intensity profile is calculated to derive median RBC column width. (F) Then, the distribution of RBC column width is used to calculate the perfused diameter, median RBC column width, and subsequently the PBR. Reused, with permission under the terms of the Creative Commons Attribution License, from Lee DH, et al., (2014) 283.
Figure 7. Figure 7. Pressure volume (P‐V) relations (left) and P‐V‐area (right). Points at top left corners of loops are end‐systolic P‐V points. Line through points is end‐systolic pressure‐volume relation (ESPVR), and its slope and its volume‐axis intercept are Ees and V0, respectively. Effective arterial elastance (Ea) is slope of end‐systolic pressure‐stroke volume relation (ESPSVR). PVA is the area in P‐V diagram that is circumscribed by ESPVR, end‐diastolic P‐V relation curve, and systolic segments of P‐V trajectory (A‐B‐C‐D‐A, right). External work (EW) is the area within P‐V loop trajectory (A‐B‐C‐D‐A), and end‐systolic elastic potential energy (PE) is the area between ESPVR and end‐diastolic P‐V relation curve to left of EW. Reused, with permission © 1996, The American Physiological Society, from Seki K, et al., (1996) 477.
Figure 8. Figure 8. The end‐diastolic pressure‐volume relationship (EDPVR) is nonlinear, having a shallow slope at low left ventricular (LV) volume range and a steeper slope at higher LV volume range. At subphysiological (sub) volumes the EDPVR turns toward negative LV pressures. Reused, with permission © 2005, The American Physiological Society, from Burkhoff D, et al., (2005) 79.
Figure 9. Figure 9. Correlation between mean arterial blood pressure and muscle sympathetic nervous activity (MSNA) (A) or heart rate (B) of the endotoxin (, preinjection; ▪, postinjection) and placebo groups (Δ, preinjection; ∇, postinjection); (§§P < 0.01). Please note that physiologically the stimulus‐response curve of the baroreflex is rather sigmoid, not linear. However, linear regression helps to visualize the apparent differences of vascular baroreflex‐sensitivity (MSNA) and uncoupling of heart rate. The slope, y‐intercept and regression coefficient (R2) of the linear best‐fit lines are (A) , y = −2.0173 × +208.54; R2 = 0.9932; ▪, y = −0.7895 × +80.573; R2 = 0.8427; Δ, y = −1.8098 × +184.73; R2 = 0.9478; ∇, y = −2.1008 × +218.47; R2 = 0.9928. (B) , y = −0.9325 × +144.71; R2 = 0.9756; ▪, y = −0.0817 × +91.208; R2 = 0.0654; Δ, y = −1.1491 × +166.6; R2 = 0.9629; ∇, y = −1.4322 × +193.89; R2 = 0.9628. Reused, with permission, from Sayk F, et al., (2008) 465.
Figure 10. Figure 10. Sympathetic arterial baroreflex system in closed‐loop (A) and open‐loop (B) conditions. Pd indicates external disturbance to arterial pressure (AP). In open‐loop conditions, relationship between baroreceptor pressure (BRP) and sympathetic nerve activity (SNA) and that between SNA and systemic arterial pressure (SAP) can be quantitatively measured. When the two curves characterizing the two relationships are plotted on an equilibrium diagram, intersection of the two curves is supposed to be operating point of AP and SNA under closed‐loop conditions of the feedback system (C). Reused, with permission, from Sato T, et al., (1999) 464.
Figure 11. Figure 11. Open‐loop characteristics of the baroreflex under bacterial lipopolysaccharide (LPS). Open‐loop static characteristics of the total baroreflex arc (A), neural arc (B), peripheral arc (C), CSP to HR relationship (D), CSP to SVR relationship (E), CSP to CO relationship (F), SNA to SVR relationship (G), and SNA to CO relationship (H) obtained at baseline (dotted line with white circles, ○), and 60 min (thin solid line with diamonds, ◊) and 120 min after LPS (thick solid line with black circles, •). Data are expressed as means ± SEM (n = 10). CSP, carotid sinus pressure (mmHg); AP, arterial pressure (mmHg); SNA, sympathetic nerve activity (a.u.); HR, heart rate (bpm); SVR, systemic vascular resistance (mmHg min/mL); CO, cardiac output (mL/min). Reused, with permission under the terms of the Creative Commons Attribution License, from Tohyama T, et al., (2018) 523.
Figure 12. Figure 12. Baroreflex equilibrium diagram under bacterial lipopolysaccharide (LPS). Averaged baroreflex equilibrium diagram at baseline (dotted line with white circle, operating point a), and at 60 min (thin solid line with diamond, operating point b) and 120 min after LPS injection (thick solid line with black circle, operating point c). SNA, sympathetic nerve activity (a.u.); CSP, carotid sinus pressure (mmHg); AP, arterial pressure (mmHg). Reused, with permission under the terms of the Creative Commons Attribution License, from Tohyama T, et al., (2018) 523.


Figure 1. Relation between central venous pressure (CVP) and cardiac index (CI) in 46 medical septic patients drawn according to the data reported by Winslow and colleagues 581. Reused, with permission, from Winslow EJ, et al., (1973) 581.


Figure 2. Venous return curves built using a model with elements in series (A) or in parallel (B). The arrangement of the different elements is indicated by the inserts. For the in‐series model, Ra is arterial resistance, Rv venous resistance, SVR systemic vascular resistance, and RVR resistance to venous return, calculated according to Eq. 5. In (A) the control condition corresponds to VRC1 (Ra, Rv, SVR, and RVR are 16.7, 0.8, 17.5, and 1.1 mmHg min/liter, respectively). Halving of Ra causes SVR and RVR to decrease to 9.2 and 1.0 mmHg min/liter, respectively and rotates clockwise the venous return curve from VRC1 to VRC2. If Ra decreases four times relative to its control value but Rv doubles, SVR becomes 5.8 and RVR 1.7 mmHg min/liter, respectively, and the venous return curve rotates counterclockwise to VRC3. For the in parallel model, Ra is arterial resistance, Rv venous resistance, and C compliance. The subscripts 1 and 2 refer to the non‐compliant and to the compliant compartment, respectively. Fc is the percentage of cardiac output (CO) perfusing the compliant compartment. In (B) VRC1 was built using published data relative to a dog 84. Calculated SVR is 67 mmHg min/liter. If Ra of the non‐compliant compartment is halved and that of the compliant compartment is doubled, so that Fc decreases from 54% to 25%, SVR decreases (57 mmHg min/liter), and the slope of the venous return curve increases (VRC2). If Ra of the non‐compliant compartment is doubled and that of the compliant compartment is halved, so that Fc increases from 54% to 80%, SVR decreases to the same amount as before (57 mmHg min/liter) but the slope of the venous return curve decreases (VRC3).


Figure 3. Equilibrium diagram showing the effects of sepsis‐induced absolute or effective hypovolemia (A), vasodilation of resistive vessels (B), myocardial dysfunction (C), absolute or effective hypovolemia and myocardial dysfunction (D), vasodilation of resistive vessels, and myocardial dysfunction (E) and absolute or effective hypovolemia and vasodilation of resistive vessels (F). Thin lines correspond to the control conditions, thick lines indicate sepsis‐induced alterations of the cardiac and venous return curves. Reflex compensation is not shown.


Figure 4. Relation between the rate or norepinephrine infusion and mean systemic filling pressure (Pmsf), resistance to venous return index (RVRI), and systemic vascular resistance index (SVRI) in stable postoperative cardiac surgery patients (○) and septic shock patients (•). The values corresponding to zero norepinephrine were obtained by extrapolation. Data are from three unrelated studies performed separately on cardiac surgery patients 306,307 and septic shock patients 404. Reused, with permission, from Maas JJ, et al., (2009) 306, Maas JJ, et al., (2013) 307, Persichini R, et al., (2012) 404.


Figure 5. Guyton's equilibrium diagram representing the functional properties of the heart and of the systemic circulation of a healthy human subject before and after the injection of LPS. Before the injection, the intersection of the cardiac function curve (CFCc) and the venous return curve (VRCc) is at point A. After the injection, the equilibrium point moves from point A to point E. An increase of cardiac output (CO) without changes of central venous pressure (CVP) implies unequivocally a counterclockwise rotation of the cardiac function curve (to CFCe) but is compatible with different modifications of the vascular function curve. Either resistance to venous return (RVR) decreases proportionally more than mean systemic filling pressure (Pmsf) (A), or Pmsf increases proportionally more than RVR (B). The measured decrease of systemic vascular resistance (SVR) after bacterial lipopolysaccharide (LPS) administration suggests (but does not prove) that the possibility shown by (A) is more likely.


Figure 6. Glycocheck algorithm on endothelial perfused boundary region (PBR) determination and microvascular perfusion properties. (A) Red blood cells (RBC) are detected through reflection of light‐emitting diodes by hemoglobin. Images captured by the sidestream darkfield camera are sent to the computer for quality checks and assessment. The black contrast is the perfused lumen of the vessels. (B) In each recording, the software automatically places the vascular segments (green), every 10 mm along the vascular segments (black contrast). (C) After the acquisition, for the analysis, the software undergoes several quality checks in the first frame of each recording, to select vascular segments with sufficient quality for further analysis. Invalid vascular segments (yellow) are distinguished from the valid vascular segments (green). During the whole recording session of 40 frames, the percentage of time in which a particular valid vascular segment has RBCs present is used to calculate RBC filling percentage. (D) Depiction of the concept of glycocalyx thickness by lateral RBC movement is shown here. (E) For each vascular segment, the intensity profile is calculated to derive median RBC column width. (F) Then, the distribution of RBC column width is used to calculate the perfused diameter, median RBC column width, and subsequently the PBR. Reused, with permission under the terms of the Creative Commons Attribution License, from Lee DH, et al., (2014) 283.


Figure 7. Pressure volume (P‐V) relations (left) and P‐V‐area (right). Points at top left corners of loops are end‐systolic P‐V points. Line through points is end‐systolic pressure‐volume relation (ESPVR), and its slope and its volume‐axis intercept are Ees and V0, respectively. Effective arterial elastance (Ea) is slope of end‐systolic pressure‐stroke volume relation (ESPSVR). PVA is the area in P‐V diagram that is circumscribed by ESPVR, end‐diastolic P‐V relation curve, and systolic segments of P‐V trajectory (A‐B‐C‐D‐A, right). External work (EW) is the area within P‐V loop trajectory (A‐B‐C‐D‐A), and end‐systolic elastic potential energy (PE) is the area between ESPVR and end‐diastolic P‐V relation curve to left of EW. Reused, with permission © 1996, The American Physiological Society, from Seki K, et al., (1996) 477.


Figure 8. The end‐diastolic pressure‐volume relationship (EDPVR) is nonlinear, having a shallow slope at low left ventricular (LV) volume range and a steeper slope at higher LV volume range. At subphysiological (sub) volumes the EDPVR turns toward negative LV pressures. Reused, with permission © 2005, The American Physiological Society, from Burkhoff D, et al., (2005) 79.


Figure 9. Correlation between mean arterial blood pressure and muscle sympathetic nervous activity (MSNA) (A) or heart rate (B) of the endotoxin (, preinjection; ▪, postinjection) and placebo groups (Δ, preinjection; ∇, postinjection); (§§P < 0.01). Please note that physiologically the stimulus‐response curve of the baroreflex is rather sigmoid, not linear. However, linear regression helps to visualize the apparent differences of vascular baroreflex‐sensitivity (MSNA) and uncoupling of heart rate. The slope, y‐intercept and regression coefficient (R2) of the linear best‐fit lines are (A) , y = −2.0173 × +208.54; R2 = 0.9932; ▪, y = −0.7895 × +80.573; R2 = 0.8427; Δ, y = −1.8098 × +184.73; R2 = 0.9478; ∇, y = −2.1008 × +218.47; R2 = 0.9928. (B) , y = −0.9325 × +144.71; R2 = 0.9756; ▪, y = −0.0817 × +91.208; R2 = 0.0654; Δ, y = −1.1491 × +166.6; R2 = 0.9629; ∇, y = −1.4322 × +193.89; R2 = 0.9628. Reused, with permission, from Sayk F, et al., (2008) 465.


Figure 10. Sympathetic arterial baroreflex system in closed‐loop (A) and open‐loop (B) conditions. Pd indicates external disturbance to arterial pressure (AP). In open‐loop conditions, relationship between baroreceptor pressure (BRP) and sympathetic nerve activity (SNA) and that between SNA and systemic arterial pressure (SAP) can be quantitatively measured. When the two curves characterizing the two relationships are plotted on an equilibrium diagram, intersection of the two curves is supposed to be operating point of AP and SNA under closed‐loop conditions of the feedback system (C). Reused, with permission, from Sato T, et al., (1999) 464.


Figure 11. Open‐loop characteristics of the baroreflex under bacterial lipopolysaccharide (LPS). Open‐loop static characteristics of the total baroreflex arc (A), neural arc (B), peripheral arc (C), CSP to HR relationship (D), CSP to SVR relationship (E), CSP to CO relationship (F), SNA to SVR relationship (G), and SNA to CO relationship (H) obtained at baseline (dotted line with white circles, ○), and 60 min (thin solid line with diamonds, ◊) and 120 min after LPS (thick solid line with black circles, •). Data are expressed as means ± SEM (n = 10). CSP, carotid sinus pressure (mmHg); AP, arterial pressure (mmHg); SNA, sympathetic nerve activity (a.u.); HR, heart rate (bpm); SVR, systemic vascular resistance (mmHg min/mL); CO, cardiac output (mL/min). Reused, with permission under the terms of the Creative Commons Attribution License, from Tohyama T, et al., (2018) 523.


Figure 12. Baroreflex equilibrium diagram under bacterial lipopolysaccharide (LPS). Averaged baroreflex equilibrium diagram at baseline (dotted line with white circle, operating point a), and at 60 min (thin solid line with diamond, operating point b) and 120 min after LPS injection (thick solid line with black circle, operating point c). SNA, sympathetic nerve activity (a.u.); CSP, carotid sinus pressure (mmHg); AP, arterial pressure (mmHg). Reused, with permission under the terms of the Creative Commons Attribution License, from Tohyama T, et al., (2018) 523.
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Article Title: Cardiovascular Responses During Sepsis
 

How to Cite

Matteo Pecchiari, Konstantinos Pontikis, Emmanouil Alevrakis, Ioannis Vasileiadis, Maria Kompoti, Antonia Koutsoukou. Cardiovascular Responses During Sepsis. Compr Physiol 2021, 11: 1605-1652. doi: 10.1002/cphy.c190044