Differential responses of cerebral and renal oxygenation to altered perfusion conditions during experimental cardiopulmonary bypass in sheep.

We tested whether the brain and kidney respond differently to cardiopulmonary bypass (CPB) and to changes in perfusion conditions during CPB. Therefore, in ovine CPB, we assessed regional cerebral oxygen saturation (rSO2 ) by near-infrared spectroscopy and renal cortical and medullary tissue oxygen tension (PO2 ), and, in some protocols, brain tissue PO2 , by phosphorescence lifetime oximetry. During CPB, rSO2 correlated with mixed venous SO2 (r = 0.78) and brain tissue PO2 (r = 0.49) when arterial PO2 was varied. During the first 30 min of CPB, brain tissue PO2 , rSO2 and renal cortical tissue PO2 did not fall, but renal medullary tissue PO2 did. Nevertheless, compared with stable anaesthesia, during stable CPB, rSO2 (66.8 decreasing to 61.3%) and both renal cortical (90.8 decreasing to 43.5 mm Hg) and medullary (44.3 decreasing to 19.2 mm Hg) tissue PO2 were lower. Both rSO2 and renal PO2 increased when pump flow was increased from 60 to 100 mL kg-1 min-1 at a target arterial pressure of 70 mm Hg. They also both increased when pump flow and arterial pressure were increased simultaneously. Neither was significantly altered by partially pulsatile flow. The vasopressor, metaraminol, dose-dependently decreased rSO2 , but increased renal cortical and medullary PO2 . Increasing blood haemoglobin concentration increased rSO2 , but not renal PO2 . We conclude that both the brain and kidney are susceptible to hypoxia during CPB, which can be alleviated by increasing pump flow, even without increasing arterial pressure. However, increasing blood haemoglobin concentration increases brain, but not kidney oxygenation, whereas vasopressor support with metaraminol increases kidney, but not brain oxygenation.

Associations Between Systemic and Cerebral Inflammation in an Ovine Model of Cardiopulmonary Bypass.

BACKGROUND: Intraoperative inflammation may contribute to postoperative neurocognitive disorders after cardiac surgery requiring cardiopulmonary bypass (CPB). However, the relative contributions of general anesthesia (GA), surgical site injury, and CPB are unclear. METHODS: In adult female sheep, we investigated (1) the temporal profile of proinflammatory and anti-inflammatory cytokines and (2) the extent of microglia activation across major cerebral cortical regions during GA and surgical trauma with and without CPB (N = 5/group). Sheep were studied while conscious, during GA and surgical trauma, with and without CPB. RESULTS: Plasma tumor necrosis factor-alpha (mean [95% confidence intervals], 3.7 [2.5-4.9] vs 1.6 [0.8-2.3] ng/mL; P = .0004) and interleukin-6 levels (4.4 [3.0-5.8] vs 1.6 [0.8-2.3] ng/mL; P = .029) were significantly higher at 1.5 hours, with a further increase in interleukin-6 at 3 hours (7.0 [3.7-10.3] vs 1.8 [1.1-2.6] ng/mL; P < .0001) in animals undergoing CPB compared with those that did not. Although cerebral oxygen saturation was preserved throughout CPB, there was pronounced neuroinflammation as characterized by greater microglia circularity within the frontal cortex of sheep that underwent CPB compared with those that did not (0.34 [0.32-0.37] vs 0.30 [0.29-0.32]; P = .029). Moreover, microglia had fewer branches within the parietal (7.7 [6.5-8.9] vs 10.9 [9.4-12.5]; P = .001) and temporal (7.8 [7.2-8.3] vs 9.9 [8.2-11.7]; P = .020) cortices in sheep that underwent CPB compared with those that did not. CONCLUSIONS: CPB enhanced the release of proinflammatory cytokines beyond that initiated by GA and surgical trauma. This systemic inflammation was associated with microglial activation across 3 major cerebral cortical regions, with a phagocytic microglia phenotype within the frontal cortex, and an inflammatory microglia phenotype within the parietal and temporal cortices. These data provide direct histopathological evidence of CPB-induced neuroinflammation in a large animal model and provide further mechanistic data on how CPB-induced cerebral inflammation might drive postoperative neurocognitive disorders in humans.

Influence of moderate hypothermia on renal and cerebral haemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep.

AIM: Cardiac surgery requiring cardiopulmonary bypass (CPB) can result in renal and cerebral injury. Intraoperative tissue hypoxia could contribute to such organ injury. Hypothermia, however, may alleviate organ hypoxia. Therefore, we tested whether moderate hypothermia (30°C) improves cerebral and renal tissue perfusion and oxygenation during ovine CPB. METHODS: Ten sheep were studied while conscious, under stable anesthesia, and during 3 h of CPB. In a randomized within-animal cross-over design, five sheep commenced CPB at a target body temperature of 30°C (moderate hypothermia). After 90 min, the body temperature was increased to 36°C (standard procedure). The remaining five sheep were randomized to the opposite order of target body temperature. RESULTS: Compared with the standard procedure, moderately hypothermic CPB reduced renal oxygen delivery (-34.8% ± 19.6%, P = 0.003) and renal oxygen consumption (-42.7% ± 35.2%, P = 0.04). Nevertheless, moderately hypothermic CPB did not significantly alter either renal cortical or medullary tissue PO2 . Moderately hypothermic CPB also did not significantly alter cerebral perfusion, cerebral tissue PO2 , or cerebral oxygen saturation compared with the standard procedure. Compared with the anesthetized state, the standard procedure reduced renal medullary PO2 (-21.0 ± 13.8 mmHg, P = 0.014) and cerebral oxygen saturation (65.0% ± 7.0% to 55.4% ± 9.6%, P = 0.022) but did not significantly alter either renal cortical or cerebral PO2 . CONCLUSION: Ovine experimental CPB leads to renal medullary tissue hypoxia. Moderately hypothermic CPB did not improve cerebral or renal tissue oxygenation. In the kidney, this is probably because renal tissue oxygen consumption is matched by reduced renal oxygen delivery.

Dynamic responses of renal oxygenation at the onset of cardiopulmonary bypass in sheep and man.

INTRODUCTION: The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. METHODS: We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. RESULTS: In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 ±6 mmHg within 20-30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. CONCLUSIONS: Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.

Reversal of renal tissue hypoxia during experimental cardiopulmonary bypass in sheep by increased pump flow and arterial pressure.

AIM: Renal tissue hypoxia during cardiopulmonary bypass could contribute to the pathophysiology of acute kidney injury. We tested whether renal tissue hypoxia can be alleviated during cardiopulmonary bypass by the combined increase in target pump flow and mean arterial pressure. METHODS: Cardiopulmonary bypass was established in eight instrumented sheep under isoflurane anaesthesia, at a target continuous pump flow of 80 mL·kg-1 min-1 and mean arterial pressure of 65 mmHg. We then tested the effects of simultaneously increasing target pump flow to 104 mL·kg-1 min-1 and mean arterial pressure to 80 mmHg with metaraminol (total dose 0.25-3.75 mg). We also tested the effects of transitioning from continuous flow to partially pulsatile flow (pulse pressure ~15 mmHg). RESULTS: Compared with conscious sheep, at the lower target pump flow and mean arterial pressure, cardiopulmonary bypass was accompanied by reduced renal blood flow (6.8 ± 1.2 to 1.95 ± 0.76 mL·min-1 kg-1) and renal oxygen delivery (0.91 ± 0.18 to 0.24 ± 0.11 mL·O2 min-1 kg-1). There were profound reductions in cortical oxygen tension (PO2) (33 ± 13 to 6 ± 6 mmHg) and medullary PO2 (31 ± 12 to 8 ± 8 mmHg). Increasing target pump flow and mean arterial pressure increased renal blood flow (to 2.6 ± 1.0 mL·min-1 kg-1) and renal oxygen delivery (to 0.32 ± 0.13 mL·O2 min-1kg-1) and returned cortical PO2 to 58 ± 60 mmHg and medullary PO2 to 28 ± 16 mmHg; levels similar to those of conscious sheep. Partially pulsatile pump flow had no significant effects on renal perfusion or oxygenation. CONCLUSIONS: Renal hypoxia during experimental CPB can be corrected by increasing target pump flow and mean arterial pressure within a clinically feasible range.

Influence of blood haemoglobin concentration on renal haemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep.

AIM: Blood transfusion may improve renal oxygenation during cardiopulmonary bypass (CPB). In an ovine model of experimental CPB, we tested whether increasing blood haemoglobin concentration [Hb] from ~7 g dL-1 to ~9 g dL-1 improves renal tissue oxygenation. METHODS: Ten sheep were studied while conscious, under stable isoflurane anaesthesia, and during 3 hours of CPB. In a randomized cross-over design, 5 sheep commenced bypass at a high target [Hb], achieved by adding 600 mL donor blood to the priming solution. After 90 minutes of CPB, PlasmaLyte® was added to the blood reservoir to achieve low target [Hb]. For the other 5 sheep, no blood was added to the prime, but after 90 minutes of CPB, 800-900 mL of donor blood was given to achieve a high target [Hb]. RESULTS: Overall, CPB was associated with marked reductions in renal oxygen delivery (-50 ± 12%, mean ± 95% confidence interval) and medullary tissue oxygen tension (PO2 , -54 ± 29%). Renal fractional oxygen extraction was 17 ± 10% less during CPB at high [Hb] than low [Hb] (P = .04). Nevertheless, no increase in tissue PO2 in either the renal medulla (0 ± 6 mmHg change, P > .99) or cortex (-19 ± 13 mmHg change, P = .08) was detected with high [Hb]. CONCLUSIONS: In experimental CPB blood transfusion to increase Hb concentration from ~7 g dL-1 to ~9 g dL-1 did not improve renal cortical or medullary tissue PO2 even though it decreased whole kidney oxygen extraction.

Renal hemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep under total intravenous anesthesia.

Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass (CPB). When performed under volatile (isoflurane) anesthesia in sheep, CPB causes renal medullary hypoxia. There is evidence that total intravenous anesthesia (TIVA) may preserve renal perfusion and renal oxygen delivery better than volatile anesthesia. Therefore, we assessed the effects of CPB on renal perfusion and oxygenation in sheep under propofol/fentanyl-based TIVA. Sheep (n = 5) were chronically instrumented for measurement of whole renal blood flow and cortical and medullary perfusion and oxygenation. Five days later, these variables were monitored under TIVA using propofol and fentanyl and then on CPB at a pump flow of 80 mL·kg-1·min-1 and target mean arterial pressure of 70 mmHg. Under anesthesia, before CPB, renal blood flow was preserved under TIVA (mean difference ± SD from conscious state: -16 ± 14%). However, during CPB renal blood flow was reduced (-55 ± 13%) and renal medullary tissue became hypoxic (-20 ± 13 mmHg versus conscious sheep). We conclude that renal perfusion and medullary oxygenation are well preserved during TIVA before CPB. However, CPB under TIVA leads to renal medullary hypoxia, of a similar magnitude to that we observed previously under volatile (isoflurane) anesthesia. Thus use of propofol/fentanyl-based TIVA may not be a useful strategy to avoid renal medullary hypoxia during CPB.

Agreement between radial and femoral arterial blood pressure measurements during orthotopic liver transplantation.

OBJECTIVE: To study agreement between radial and femoral arterial pressure measurements in orthotopic liver transplantation (OLTx) surgery to determine whether arterial cannulation sites are interchangeable. DESIGN, SETTING AND PARTICIPANTS: Prospective observational study of 25 patients undergoing OLTx surgery. METHODS: Radial and femoral arteries were cannulated with standardised arterial line kits. Radial and femoral mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and pulse pressure (PP) were measured at four time points (30 minutes after induction of anaesthesia, 30 minutes after the start of the anhepatic phase, 30 minutes after liver graft reperfusion and 30 minutes after the start of bile duct anastomosis). MAIN OUTCOME MEASURES: The bias, precision and limits of agreement between radial and femoral arterial pressures were calculated in accordance with Bland-Altman statistics. RESULTS: Radial-femoral differences in MAP (mean difference, 4.8 mmHg [SD, 4.5 mmHg]), limits of agreement (- 13.6 and 8.8, P < 0.001) and DAP showed clinically acceptable agreement between measurement sites across all time points. However, clinically significant differences between radial and femoral SAPs (mean difference, - 14.9 mmHg [SD, 24.8 mmHg]) and limits of agreement (- 63.5 and 33.7, P < 0.001) occurred overall. This difference started after portal vein clamping and remained significant throughout the remainder of the operation. CONCLUSION: Radial artery SAP underestimates femoral artery measurements significantly but unpredictably. As femoral measurement is more likely to reflect central arterial pressure, radial SAP measurement is not reliable in adults undergoing OLTx.

Outcomes of Aortic Arch Replacement Performed Without Circulatory Arrest or Deep Hypothermia.

BACKGROUND: Aortic arch replacement using standard techniques, including deep hypothermic circulatory arrest and selective antegrade cerebral perfusion, is still associated with significant mortality and cerebral morbidity. We have previously described the "branch-first" technique that avoids circulatory arrest or profound hypothermia with excellent outcomes. We now describe our clinical experience with a larger cohort of patients as well as follow-up of our earlier results. We also describe a further technical simplification to this technique. METHODS: From 2005 to 2010, 43 patients underwent a "branch-first continuous perfusion" technique for aortic arch replacement. In this technique, arterial perfusion is peripheral, usually by femoral inflow. Disconnection of each arch branch and anastomosis to a perfused trifurcation graft proceeds sequentially from the innominate to the left subclavian artery, with uninterrupted perfusion of the heart and viscera by the peripheral cannula. In the first cohort perfusion to the trifurcation graft was by right axillary cannulation. Since 2009, a modification was introduced such that perfusion is supplied directly by a sidearm on the trifurcation graft. This was used in the last 18 patients of this series. After reconstruction of the debranched arch and ascending aorta, the common stem of the trifurcation graft is anastomosed to the arch graft. In this series, there were 27 males, and mean age was 63 ± 13 years. Fifteen cases (35%) were performed with urgent/emergent priority. Nineteen patients (44%) were operated for aortic dissection, and the remainder for aneurysms. Seven patients (16%) had previously undergone a cardiac surgical procedure. RESULTS: There were two (4.7%) early mortalities while one patient (2.3%) experienced a permanent stroke. One patient (2%) required mechanical support while three (7%) required hemofiltration for renal support. Extubation was achieved within 24 hours in 21 patients (49%) while 19 (42%) were discharged from the Intensive Care Unit (ICU) within two days. Eight patients (19%) did not require any transfusion of red cells or platelets. Mean follow-up duration was 21 ± 19 months and was 100% complete. At three years, survival was 95 ± 3.2%. No patients required subsequent aortic reoperation during this early follow-up period. CONCLUSIONS: This modified branch-first continuous perfusion technique brings us closer to the goal of arch surgery without cerebral or visceral circulatory arrest and the morbidity of deep hypothermia. Our early experience is encouraging although greater numbers and longer follow-up will reveal the full potential of this approach.

Branch-first aortic arch replacement with no circulatory arrest or deep hypothermia.

BACKGROUND: For aortic arch surgery, the potential risks of deep hypothermic circulatory arrest with or without antegrade cerebral perfusion have been widely documented. We hereby describe our early experience with a "branch-first continuous perfusion" technique that, by avoiding deep hypothermia and circulatory arrest, has the potential to reduce morbidity and mortality. METHODS: Arterial perfusion is peripheral using femoral and axillary inflows. Disconnection of each arch branch, and anastomosis to the trifurcation graft, proceeds sequentially from the innominate to the left subclavian artery, with continuous perfusion of the heart and viscera by lower body and brain by upper body arterial return. After the descending aorta is clamped, the debranched arch may then be replaced and connected to the ascending aorta before the common stem of the trifurcation graft is joined to the arch graft. Thirty patients underwent this technique. Twelve patients were operated on for aortic dissection and the remainder for aneurysms. RESULTS: With experience, minimum pump temperature rose from 16°C to 34°C. There was 1 (3.3%) death, and 2 (6.7%) patients had neurological dysfunction. Extubation was achieved within 24 hours in 12 (40%) patients, whereas 14 (47%) left the intensive care unit within 2 days. Ten (33%) patients were discharged from the hospital within 7 days. Eight (27%) patients required no transfusion of blood or blood products. CONCLUSIONS: This technique brings us closer to the goal of arch surgery without cerebral or visceral circulatory arrest and the morbidity of deep hypothermia. Early results are encouraging.

Noninvasive measurement of intrapulmonary shunting.

OBJECTIVE: To investigate the accuracy and precision of a noninvasive approach to measurement of pulmonary shunt fraction using simultaneous application of 2 fundamental respiratory mixing equations: the direct Fick equation for oxygen and the shunt equation of Berggren. This can be performed without mixed venous blood sampling and requires measurement of oxygen uptake and pulmonary blood flow. DESIGN: Comparison with invasive shunt fraction measured using mixed venous blood sampling and with estimated shunt fraction using an assumed arteriovenous O(2) content difference. SETTING: Major teaching hospital. PARTICIPANTS: Nine patients undergoing anesthesia for cardiac surgery. INTERVENTIONS: Pulmonary blood flow was measured using an indirect Fick technique (nitrous oxide throughflow) and by bolus thermodilution for comparison. MEASUREMENTS AND MAIN RESULTS: The mean shunt fraction measured by the invasive method was 0.145 (range 0.057-0.263). When pulmonary blood flow was measured using an indirect Fick technique (nitrous oxide throughflow), the absolute mean bias for noninvasive shunt fraction was -0.005 with a standard deviation of 0.012. Correlation was excellent (r(2) = 0.95, p < 0.001). Agreement was less precise when pulmonary blood flow was measured using thermodilution (mean bias + 0.001 with a standard deviation of 0.018). CONCLUSIONS: The noninvasive method is an accurate substitute for invasive shunt fraction measurement with mixed venous blood sampling.