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Renal and Cerebral Hypoxia and Inflammation During Cardiopulmonary Bypass

Alemayehu H. Jufar, Yugeesh R. Lankadeva, Clive N. May, Andrew D. Cochrane, Bruno Marino, Rinaldo Bellomo, Roger G. Evans

10.1002/cphy.c210019

Source: Volume 12, Issue 1, January 2022

Published online: December 2021

Full Article on Wiley Online Library



Abstract

Cardiac surgery‐associated acute kidney injury and brain injury remain common despite ongoing efforts to improve both the equipment and procedures deployed during cardiopulmonary bypass (CPB). The pathophysiology of injury of the kidney and brain during CPB is not completely understood. Nevertheless, renal (particularly in the medulla) and cerebral hypoxia and inflammation likely play critical roles. Multiple practical factors, including depth and mode of anesthesia, hemodilution, pump flow, and arterial pressure can influence oxygenation of the brain and kidney during CPB. Critically, these factors may have differential effects on these two vital organs. Systemic inflammatory pathways are activated during CPB through activation of the complement system, coagulation pathways, leukocytes, and the release of inflammatory cytokines. Local inflammation in the brain and kidney may be aggravated by ischemia (and thus hypoxia) and reperfusion (and thus oxidative stress) and activation of resident and infiltrating inflammatory cells. Various strategies, including manipulating perfusion conditions and administration of pharmacotherapies, could potentially be deployed to avoid or attenuate hypoxia and inflammation during CPB. Regarding manipulating perfusion conditions, based on experimental and clinical data, increasing standard pump flow and arterial pressure during CPB appears to offer the best hope to avoid hypoxia and injury, at least in the kidney. Pharmacological approaches, including use of anti‐inflammatory agents such as dexmedetomidine and erythropoietin, have shown promise in preclinical models but have not been adequately tested in human trials. However, evidence for beneficial effects of corticosteroids on renal and neurological outcomes is lacking. © 2021 American Physiological Society. Compr Physiol 11:1‐36, 2021.

Figure 1. Figure 1. Cardiopulmonary bypass circuit. Venous blood is drained from the right atrium to the venous reservoir of the heart‐lung machine. Blood is then pumped by the bypass circuit into the oxygenator and then into the arterial system. Also illustrated are monitors for flow, pressure, blood gases (including venous oxygen saturation), and detection of air bubbles, along with cardiotomy suction, the heat exchanger, the arterial line filter, cardioplegia delivery, and gas and water delivery systems for the oxygenator and heat‐exchangers. Arrows show direction of flow of fluid or gas. Redrawn, with permission, from Machin D and Allsager C, 2006 245.
Figure 2. Figure 2. Cardiopulmonary bypass (CPB) activates the complement system. The alternative complement pathway is activated when blood is exposed to the nonphysiological surface of the CPB circuit. The classic complement pathway is activated by the protamine/heparin‐antibody complex which occurs after weaning from CPB following administration of protamine to reverse anticoagulation induced by heparin. Both pathways lead to the formation of the membrane attack complex. The complement fragments C3a and C5a (anaphylatoxins) enhance the systemic inflammatory response to CPB by activating mast cells and white blood cells to release inflammatory chemical mediators. Orange arrows indicate processes that activate the alternative complement pathway. Blue arrows indicate processes that activate the classic complement pathway.
Figure 3. Figure 3. Cardiopulmonary bypass (CPB) activates blood clotting pathways. The intrinsic clotting pathway is activated when clotting factor (CF) XII is exposed to the nonphysiological surface of the CPB circuit. Activation of the extrinsic clotting pathway occurs after tissue thromboplastin (CFIII) is released from injured blood vessels. Both pathways activate CF X which subsequently leads to the formation of a clot. Activated CF XII also enhances the systemic inflammatory response by cleaving kininogen into bradykinin. Orange arrows indicate processes that activate the individual clotting pathways. Blue arrows indicate common pathways activated by both the intrinsic and extrinsic clotting pathways.
Figure 4. Figure 4. Renal hemodynamics and tissue oxygenation during transition to experimental cardiopulmonary bypass in sheep. Data were compiled from four separate experimental studies 91,218,219,222. Measurements were made over 20 to 30 min experimental periods. Observations were initially made in conscious sheep in their home‐cages (Conscious). Sheep were then anesthetized with either isoflurane (n = 30) or propofol and fentanyl (n = 5) and measurements were generated under stable anesthesia. Cardiopulmonary bypass (CPB) was then initiated at a pump flow of 80 mL/kg/min, target arterial pressure of 70 mmHg, and target body temperature of 36 °C. Variables were again measured after a 30 min stabilization period on CPB (On CPB). Columns and error bars show mean and 95% confidence intervals for n = 35 for mean arterial pressure. However, due to equipment failure, n = 34 for renal blood flow and cortical perfusion, and n = 33 for medullary perfusion, cortical PO2, and medullary PO2. ***P ≤ 0.001 compared with “Conscious”. †††P ≤ 0.001 compared with “Anesthetized”, by Student's paired t‐test with a Dunn‐Sidak correction to control risk of type 1 error (three comparisons). Based on data, with permission, from Evans RG, et al., 2020 91; Lankadeva YR, et al., 2019 218; Lankadeva YR, et al., 2021 219; Lankadeva YR, et al., 2020 222.
Figure 5. Figure 5. Urinary oxygen tension in the urinary bladder of two patients undergoing cardiac surgery and cardiopulmonary bypass. In Patient (A), urinary oxygen tension decreased after CPB commenced and then gradually increased after weaning from CPB. In Patient (B), urinary oxygen tension gradually decreased after weaning from bypass. Based on data, with permission, from Kainuma M, et al., 1996 189 and Reproduced, with permission, from Evans RG, et al., 2016 94.
Figure 6. Figure 6. Renal and systemic oxygenation during transition to experimental cardiopulmonary bypass in sheep. Data are from the studies depicted in Figure 4. Columns and error bars show mean and 95% confidence intervals for n = 35 for systemic oxygen extraction. However, due to equipment failure n = 34 for renal oxygen delivery (DO2), n = 25 for renal oxygen consumption (Vo2), and n = 23 for renal oxygen extraction. *P ≤ 0.05, ***P ≤ 0.001 compared with “Conscious”. †P ≤ 0.05, ††P ≤ 0.01, †††P ≤ 0.001 compared with “Anesthetized”, by Student's paired t‐test with a Dunn‐Sidak correction to control risk of type 1 error (three comparisons).
Figure 7. Figure 7. The effects of cardiopulmonary bypass (CPB) on systemic oxygen delivery index (DO2I) and renal oxygen delivery (RDO2) (A), and renal oxygen extraction (B) in humans. Data are presented as mean ± standard deviation. In (A), despite maintained DO2I, the RDO2 during CPB is significantly less than the value before CPB. This led to impairment of the balance between renal oxygen supply and demand, as evidenced by significantly increased renal oxygen extraction during CPB (B). As discussed in the text, it appears that CPB leads to redistribution of blood flow away from the kidney and thus leads to decreased RDO2 although the DO2 is maintained. CPB 30′, 30 min after the start of CPB, CPB 60′, 60 min after the start of CPB. ***P < 0.001 and *P < 0.05 are for comparisons with pre‐CPB values. Redrawn, with permission, from Lannemyr L, et al., 2017 225.
Figure 8. Figure 8. Renal function and efficiency of oxygen utilization for sodium reabsorption during transition to experimental cardiopulmonary bypass in sheep. Data are from the studies depicted in Figure 4. Columns and error bars show mean and 95% confidence intervals for n = 35 for creatinine clearance and sodium reabsorption (TNa+). However, due to equipment failure n = 25 for the ratio of sodium reabsorption to renal oxygen consumption (TNa+/Vo2). *P ≤ 0.05, **P ≤ 0.01 compared with “Conscious” by Student's paired t‐test with a Dunn‐Sidak correction to control risk of type 1 error (three comparisons).
Figure 9. Figure 9. Effects of altered perfusion conditions on renal hemodynamics and tissue perfusion during experimental cardiopulmonary bypass in sheep. Pump flow was decreased from 80 to 60 mL/kg/min (Pump Flow Down) or increased from 80 to 100 mL/kg/min (Pump Flow Up) while arterial pressure was maintained at a target of 70 mmHg through titration of the vasopressor metaraminol (n = 9–12) 218. Arterial pressure was increased either by infusion of the vasopressor metaraminol at a dose of 0.2 mg/min while maintaining pump flow constant (Pressor, n = 9–11) 218 or by increasing pump flow from 80 to 104 mL/kg/min and then only giving metaraminol if target arterial pressure was not met (Flow, n = 7–8) 219. The effects of partially pulsatile flow (Pulse, n = 7–8) 219 and increasing blood hemoglobin concentration from approximately 7 to 9 g/dL ([Hb], n = 9–10) are also shown. Data are mean ± 95% confidence intervals. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 by single‐sample t‐test.
Figure 10. Figure 10. Effects of altered perfusion conditions on renal and systemic oxygenation during experimental cardiopulmonary bypass in sheep. The various interventions, data presentation, and statistical symbols are as for Figure 9. DO2, oxygen delivery; Vo2, oxygen consumption. The number of observations for each dataset varies from 5 to 12.
Figure 11. Figure 11. Effects of altered perfusion conditions on renal function and efficiency of oxygen utilization for sodium reabsorption during experimental cardiopulmonary bypass in sheep. The various interventions, data presentation, and statistical symbols are as for Figure 9. TNa+, sodium reabsorption; Vo2, oxygen consumption. The number of observations for each dataset varies from 5 to 12.
Figure 12. Figure 12. Renal oxygen extraction (%) before and during cardiopulmonary bypass (CPB) at pump flows of 2.4, 2.7, and 3.0 liter/min/m2. Renal oxygen extraction was significantly increased during transition to CPB at a pump flow of 2.4 liter/min/m2. However, progressively increasing pump flow to 2.7 and then to 3.0 liter/min/m2 was found to significantly decrease renal oxygen extraction. Data are expressed as mean ± standard deviation. The P values are post hoc t tests of the difference versus a pump flow of 2.4 liter/min/m2. Redrawn, with permission, from Lannemyr L, et al., 2019 224.
Figure 13. Figure 13. The influence of goal‐directed perfusion during cardiopulmonary bypass on the incidence of postoperative acute kidney injury (AKI). Goal‐directed perfusion, aiming to maintain systemic oxygen delivery ≥280 mL/min/m2 during cardiopulmonary bypass, was associated with significantly lesser incidence of postoperative AKI (15.4%) compared with the usual care group (24.7%) who were perfused at a pump flow of 2.4 liter/min/m2. Redrawn, with permission, from Ranucci M, et al., 2018 312.
Figure 14. Figure 14. The impact of cardiopulmonary bypass (CPB) on the kidney and brain. CPB leads to development of hypoxia in the renal medulla and cerebral cortex. It also induces systemic and local inflammatory responses. Renal and cerebral tissue hypoxia and inflammation contribute to the development of cardiac surgery‐associated acute kidney injury (AKI) and brain injury. Increasing either pump flow or mean arterial pressure (MAP) or both during CPB mitigate (‐) the risk of renal medullary hypoxia during CPB and therefore have the potential to reduce the risk of cardiac surgery‐associated AKI. Transfusion of blood and maintaining MAP at higher level during CPB increases cerebral oxygen delivery or cerebral blood flow and hence could potentially mitigate (‐) cerebral hypoxia during CPB and the risk of postoperative brain injury. Anti‐inflammatory agents including corticosteroids, dexmedetomidine, erythropoietin, melatonin, and statins attenuate (‐) the inflammatory response to CPB. However, as discussed in the text, there is limited evidence that these pharmacological therapies improve postoperative kidney and brain functions. Blue lines indicate pathways leading to tissue hypoxia, inflammation, and injury. Red lines indicate potential mitigating strategies and therapies.


Figure 1. Cardiopulmonary bypass circuit. Venous blood is drained from the right atrium to the venous reservoir of the heart‐lung machine. Blood is then pumped by the bypass circuit into the oxygenator and then into the arterial system. Also illustrated are monitors for flow, pressure, blood gases (including venous oxygen saturation), and detection of air bubbles, along with cardiotomy suction, the heat exchanger, the arterial line filter, cardioplegia delivery, and gas and water delivery systems for the oxygenator and heat‐exchangers. Arrows show direction of flow of fluid or gas. Redrawn, with permission, from Machin D and Allsager C, 2006 245.


Figure 2. Cardiopulmonary bypass (CPB) activates the complement system. The alternative complement pathway is activated when blood is exposed to the nonphysiological surface of the CPB circuit. The classic complement pathway is activated by the protamine/heparin‐antibody complex which occurs after weaning from CPB following administration of protamine to reverse anticoagulation induced by heparin. Both pathways lead to the formation of the membrane attack complex. The complement fragments C3a and C5a (anaphylatoxins) enhance the systemic inflammatory response to CPB by activating mast cells and white blood cells to release inflammatory chemical mediators. Orange arrows indicate processes that activate the alternative complement pathway. Blue arrows indicate processes that activate the classic complement pathway.


Figure 3. Cardiopulmonary bypass (CPB) activates blood clotting pathways. The intrinsic clotting pathway is activated when clotting factor (CF) XII is exposed to the nonphysiological surface of the CPB circuit. Activation of the extrinsic clotting pathway occurs after tissue thromboplastin (CFIII) is released from injured blood vessels. Both pathways activate CF X which subsequently leads to the formation of a clot. Activated CF XII also enhances the systemic inflammatory response by cleaving kininogen into bradykinin. Orange arrows indicate processes that activate the individual clotting pathways. Blue arrows indicate common pathways activated by both the intrinsic and extrinsic clotting pathways.


Figure 4. Renal hemodynamics and tissue oxygenation during transition to experimental cardiopulmonary bypass in sheep. Data were compiled from four separate experimental studies 91,218,219,222. Measurements were made over 20 to 30 min experimental periods. Observations were initially made in conscious sheep in their home‐cages (Conscious). Sheep were then anesthetized with either isoflurane (n = 30) or propofol and fentanyl (n = 5) and measurements were generated under stable anesthesia. Cardiopulmonary bypass (CPB) was then initiated at a pump flow of 80 mL/kg/min, target arterial pressure of 70 mmHg, and target body temperature of 36 °C. Variables were again measured after a 30 min stabilization period on CPB (On CPB). Columns and error bars show mean and 95% confidence intervals for n = 35 for mean arterial pressure. However, due to equipment failure, n = 34 for renal blood flow and cortical perfusion, and n = 33 for medullary perfusion, cortical PO2, and medullary PO2. ***P ≤ 0.001 compared with “Conscious”. †††P ≤ 0.001 compared with “Anesthetized”, by Student's paired t‐test with a Dunn‐Sidak correction to control risk of type 1 error (three comparisons). Based on data, with permission, from Evans RG, et al., 2020 91; Lankadeva YR, et al., 2019 218; Lankadeva YR, et al., 2021 219; Lankadeva YR, et al., 2020 222.


Figure 5. Urinary oxygen tension in the urinary bladder of two patients undergoing cardiac surgery and cardiopulmonary bypass. In Patient (A), urinary oxygen tension decreased after CPB commenced and then gradually increased after weaning from CPB. In Patient (B), urinary oxygen tension gradually decreased after weaning from bypass. Based on data, with permission, from Kainuma M, et al., 1996 189 and Reproduced, with permission, from Evans RG, et al., 2016 94.


Figure 6. Renal and systemic oxygenation during transition to experimental cardiopulmonary bypass in sheep. Data are from the studies depicted in Figure 4. Columns and error bars show mean and 95% confidence intervals for n = 35 for systemic oxygen extraction. However, due to equipment failure n = 34 for renal oxygen delivery (DO2), n = 25 for renal oxygen consumption (Vo2), and n = 23 for renal oxygen extraction. *P ≤ 0.05, ***P ≤ 0.001 compared with “Conscious”. †P ≤ 0.05, ††P ≤ 0.01, †††P ≤ 0.001 compared with “Anesthetized”, by Student's paired t‐test with a Dunn‐Sidak correction to control risk of type 1 error (three comparisons).


Figure 7. The effects of cardiopulmonary bypass (CPB) on systemic oxygen delivery index (DO2I) and renal oxygen delivery (RDO2) (A), and renal oxygen extraction (B) in humans. Data are presented as mean ± standard deviation. In (A), despite maintained DO2I, the RDO2 during CPB is significantly less than the value before CPB. This led to impairment of the balance between renal oxygen supply and demand, as evidenced by significantly increased renal oxygen extraction during CPB (B). As discussed in the text, it appears that CPB leads to redistribution of blood flow away from the kidney and thus leads to decreased RDO2 although the DO2 is maintained. CPB 30′, 30 min after the start of CPB, CPB 60′, 60 min after the start of CPB. ***P < 0.001 and *P < 0.05 are for comparisons with pre‐CPB values. Redrawn, with permission, from Lannemyr L, et al., 2017 225.


Figure 8. Renal function and efficiency of oxygen utilization for sodium reabsorption during transition to experimental cardiopulmonary bypass in sheep. Data are from the studies depicted in Figure 4. Columns and error bars show mean and 95% confidence intervals for n = 35 for creatinine clearance and sodium reabsorption (TNa+). However, due to equipment failure n = 25 for the ratio of sodium reabsorption to renal oxygen consumption (TNa+/Vo2). *P ≤ 0.05, **P ≤ 0.01 compared with “Conscious” by Student's paired t‐test with a Dunn‐Sidak correction to control risk of type 1 error (three comparisons).


Figure 9. Effects of altered perfusion conditions on renal hemodynamics and tissue perfusion during experimental cardiopulmonary bypass in sheep. Pump flow was decreased from 80 to 60 mL/kg/min (Pump Flow Down) or increased from 80 to 100 mL/kg/min (Pump Flow Up) while arterial pressure was maintained at a target of 70 mmHg through titration of the vasopressor metaraminol (n = 9–12) 218. Arterial pressure was increased either by infusion of the vasopressor metaraminol at a dose of 0.2 mg/min while maintaining pump flow constant (Pressor, n = 9–11) 218 or by increasing pump flow from 80 to 104 mL/kg/min and then only giving metaraminol if target arterial pressure was not met (Flow, n = 7–8) 219. The effects of partially pulsatile flow (Pulse, n = 7–8) 219 and increasing blood hemoglobin concentration from approximately 7 to 9 g/dL ([Hb], n = 9–10) are also shown. Data are mean ± 95% confidence intervals. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 by single‐sample t‐test.


Figure 10. Effects of altered perfusion conditions on renal and systemic oxygenation during experimental cardiopulmonary bypass in sheep. The various interventions, data presentation, and statistical symbols are as for Figure 9. DO2, oxygen delivery; Vo2, oxygen consumption. The number of observations for each dataset varies from 5 to 12.


Figure 11. Effects of altered perfusion conditions on renal function and efficiency of oxygen utilization for sodium reabsorption during experimental cardiopulmonary bypass in sheep. The various interventions, data presentation, and statistical symbols are as for Figure 9. TNa+, sodium reabsorption; Vo2, oxygen consumption. The number of observations for each dataset varies from 5 to 12.


Figure 12. Renal oxygen extraction (%) before and during cardiopulmonary bypass (CPB) at pump flows of 2.4, 2.7, and 3.0 liter/min/m2. Renal oxygen extraction was significantly increased during transition to CPB at a pump flow of 2.4 liter/min/m2. However, progressively increasing pump flow to 2.7 and then to 3.0 liter/min/m2 was found to significantly decrease renal oxygen extraction. Data are expressed as mean ± standard deviation. The P values are post hoc t tests of the difference versus a pump flow of 2.4 liter/min/m2. Redrawn, with permission, from Lannemyr L, et al., 2019 224.


Figure 13. The influence of goal‐directed perfusion during cardiopulmonary bypass on the incidence of postoperative acute kidney injury (AKI). Goal‐directed perfusion, aiming to maintain systemic oxygen delivery ≥280 mL/min/m2 during cardiopulmonary bypass, was associated with significantly lesser incidence of postoperative AKI (15.4%) compared with the usual care group (24.7%) who were perfused at a pump flow of 2.4 liter/min/m2. Redrawn, with permission, from Ranucci M, et al., 2018 312.


Figure 14. The impact of cardiopulmonary bypass (CPB) on the kidney and brain. CPB leads to development of hypoxia in the renal medulla and cerebral cortex. It also induces systemic and local inflammatory responses. Renal and cerebral tissue hypoxia and inflammation contribute to the development of cardiac surgery‐associated acute kidney injury (AKI) and brain injury. Increasing either pump flow or mean arterial pressure (MAP) or both during CPB mitigate (‐) the risk of renal medullary hypoxia during CPB and therefore have the potential to reduce the risk of cardiac surgery‐associated AKI. Transfusion of blood and maintaining MAP at higher level during CPB increases cerebral oxygen delivery or cerebral blood flow and hence could potentially mitigate (‐) cerebral hypoxia during CPB and the risk of postoperative brain injury. Anti‐inflammatory agents including corticosteroids, dexmedetomidine, erythropoietin, melatonin, and statins attenuate (‐) the inflammatory response to CPB. However, as discussed in the text, there is limited evidence that these pharmacological therapies improve postoperative kidney and brain functions. Blue lines indicate pathways leading to tissue hypoxia, inflammation, and injury. Red lines indicate potential mitigating strategies and therapies.
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Article Title: Renal and Cerebral Hypoxia and Inflammation During Cardiopulmonary Bypass
 

How to Cite

Alemayehu H. Jufar, Yugeesh R. Lankadeva, Clive N. May, Andrew D. Cochrane, Bruno Marino, Rinaldo Bellomo, Roger G. Evans. Renal and Cerebral Hypoxia and Inflammation During Cardiopulmonary Bypass. Compr Physiol 2021, 12: 2799-2834. doi: 10.1002/cphy.c210019