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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 (rSO 2 ) by near-infrared spectroscopy and renal cortical and medullary tissue oxygen tension (PO 2 ), and, in some protocols, brain tissue PO 2 , by phosphorescence lifetime oximetry. During CPB, rSO 2 correlated with mixed venous SO 2 (r = 0.78) and brain tissue PO 2 (r = 0.49) when arterial PO 2 was varied. During the first 30 min of CPB, brain tissue PO 2 , rSO 2 and renal cortical tissue PO 2 did not fall, but renal medullary tissue PO 2 did. Nevertheless, compared with stable anaesthesia, during stable CPB, rSO 2 (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 PO 2 were lower. Both rSO 2 and renal PO 2 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 rSO 2 , but increased renal cortical and medullary PO 2 . Increasing blood haemoglobin concentration increased rSO 2 , but not renal PO 2 . 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., (© 2024 The Authors. Clinical and Experimental Pharmacology and Physiology published by John Wiley & Sons Australia, Ltd.)

Introduction: The use of non-steroidal anti-inflammatory drugs (NSAID) in patients undergoing pleurodesis remains controversial. Although many surgeons are comfortable prescribing NSAIDs post-operatively, some oppose this practice due to concerns of suppressing the inflammatory response and quality of pleurodesis. Only a small body of inconsistent publications exists with respect to guiding therapy in this common clinical scenario., Methods: A retrospective cohort study was undertaken assessing effect of NSAID exposure on pleurodesis outcomes. An institutional thoracic surgery database was reviewed yielding 147 patients who underwent pleurodesis for pneumothorax between 2010 and 2018. Medical records and imaging were reviewed for patient characteristics, NSAID exposure, recurrent pneumothorax and other adverse events., Results: There was no overall difference between rates of recurrence and procedural failure of pleurodesis (Relative Risk [RR] 1.67 [95% CI 0.74-3.77]). However, NSAID exposure of >48 hours was associated with increased risk of recurrent pneumothorax (RR 2.16 [95% CI 1.05-4.45]). There was no increased rate of other adverse events related to NSAID usage., Conclusions: NSAID exposure does not increase failure rates or other adverse events following pleurodesis for pneumothorax. However, prolonged NSAID exposure post-pleurodesis may increase procedural failure rates. Further large volume randomised control trials are required., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α 2 -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 μg.kg -1 .h -1 ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass., (© 2023 Association of Anaesthetists.)

Targeting greater pump flow and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) could potentially alleviate renal hypoxia and reduce the risk of postoperative acute kidney injury (AKI). Therefore, in an observational study of 93 patients undergoing on-pump cardiac surgery, we tested whether intraoperative hemodynamic management differed between patients who did and did not develop AKI. Then, in 20 patients, we assessed the feasibility of a larger-scale trial in which patients would be randomized to greater than normal target pump flow and MAP, or usual care, during CPB. In the observational cohort, MAP during hypothermic CPB averaged 68.8 ± 8.0 mmHg (mean ± SD) in the 36 patients who developed AKI and 68.9 ± 6.3 mmHg in the 57 patients who did not (p = 0.98). Pump flow averaged 2.4 ± 0.2 L/min/m 2 in both groups. In the feasibility clinical trial, compared with usual care, those randomized to increased target pump flow and MAP had greater mean pump flow (2.70 ± 0.23 vs. 2.42 ± 0.09 L/min/m 2 during the period before rewarming) and systemic oxygen delivery (363 ± 60 vs. 281 ± 45 mL/min/m 2 ). Target MAP ≥80 mmHg was achieved in 66.6% of patients in the intervention group but in only 27.3% of patients in the usual care group. Nevertheless, MAP during CPB did not differ significantly between the two groups. We conclude that little insight was gained from our observational study regarding the impact of variations in pump flow and MAP on the risk of AKI. However, a clinical trial to assess the effects of greater target pump flow and MAP on the risk of AKI appears feasible., (© 2023 The Authors. Clinical and Experimental Pharmacology and Physiology published by John Wiley & Sons Australia, Ltd.)

Machine learning (ML) is increasingly applied to predict adverse postoperative outcomes in cardiac surgery. Commonly used ML models fail to translate to clinical practice due to absent model explainability, limited uncertainty quantification, and no flexibility to missing data. We aimed to develop and benchmark a novel ML approach, the uncertainty-aware attention network (UAN), to overcome these common limitations. Two Bayesian uncertainty quantification methods were tested, generalized variational inference (GVI) or a posterior network (PN). The UAN models were compared with an ensemble of XGBoost models and a Bayesian logistic regression model (LR) with imputation. The derivation datasets consisted of 153,932 surgery events from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) Cardiac Surgery Database. An external validation consisted of 7343 surgery events which were extracted from the Medical Information Mart for Intensive Care (MIMIC) III critical care dataset. The highest performing model on the external validation dataset was a UAN-GVI with an area under the receiver operating characteristic curve (AUC) of 0.78 (0.01). Model performance improved on high confidence samples with an AUC of 0.81 (0.01). Confidence calibration for aleatoric uncertainty was excellent for all models. Calibration for epistemic uncertainty was more variable, with an ensemble of XGBoost models performing the best with an AUC of 0.84 (0.08). Epistemic uncertainty was improved using the PN approach, compared to GVI. UAN is able to use an interpretable and flexible deep learning approach to provide estimates of model uncertainty alongside state-of-the-art predictions. The model has been made freely available as an easy-to-use web application demonstrating that by designing uncertainty-aware models with innately explainable predictions deep learning may become more suitable for routine clinical use., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Penny-Dimri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Objectives: To determine if the administration of norepinephrine to patients recovering from on-pump cardiac surgery is associated with changes in urinary oxygen tension (PO 2 ), an indirect index of renal medullary oxygenation., Design: Single center, prospective observational study., Setting: Surgical intensive care unit (ICU)., Participants: A nonconsecutive sample of 93 patients recovering from on-pump cardiac surgery., Measurements and Main Results: In the ICU, norepinephrine was the most commonly used vasopressor agent (90% of patients, 84/93), with fewer patients receiving epinephrine (48%, 45/93) or vasopressin (4%, 4/93). During the 30-to-60-minute period after increasing the infused dose of norepinephrine (n = 89 instances), urinary PO 2 decreased by (least squares mean ± SEM) 1.8 ± 0.5 mmHg from its baseline level of 25.1 ± 1.1 mmHg. Conversely, during the 30-to-60-minute period after the dose of norepinephrine was decreased (n = 134 instances), urinary PO 2 increased by 2.6 ± 0.5 mmHg from its baseline level of 22.7 ± 1.2 mmHg. No significant change in urinary PO 2 was detected when the dose of epinephrine was decreased (n = 21). There were insufficient observations to assess the effects of increasing the dose of epinephrine (n = 11) or of changing the dose of vasopressin (n <4)., Conclusions: In patients recovering from on-pump cardiac surgery, changes in norepinephrine dose are associated with reciprocal changes in urinary PO 2 , potentially reflecting an effect of norepinephrine on renal medullary oxygenation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 (MPO 2 ) in 24 sheep, and urinary PO 2 (UPO 2 ) as an index of MPO 2 in 92 patients, before and after induction of CPB., Results: In laterally recumbent sheep with a right thoracotomy ( n  = 20), even before CPB commenced MPO 2 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), MPO 2 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, MPO 2 fell abruptly to 24 ±6 mmHg within 20-30 minutes. MPO 2 during CPB was not improved by adding donor blood to the prime ( n  = 13). In patients undergoing cardiac surgery, UPO 2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO 2 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.

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 PO 2 . Moderately hypothermic CPB also did not significantly alter cerebral perfusion, cerebral tissue PO 2 , or cerebral oxygen saturation compared with the standard procedure. Compared with the anesthetized state, the standard procedure reduced renal medullary PO 2 (-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 PO 2 ., 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., (© 2022 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Acute kidney injury (AKI) is a common and serious post-operative complication of cardiac surgery. The value of a predictive biomarker is determined not only by its predictive efficacy, but also by how early this prediction can be made. For a biomarker of cardiac surgery-associated AKI, this is ideally during the intra-operative period. Therefore, in 82 adult patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB), we prospectively compared the predictive efficacy of various blood and urinary biomarkers with that of continuous measurement of urinary oxygen tension (UPO 2 ) at pre-determined intra- and post-operative time-points. None of the blood or urine biomarkers we studied showed predictive efficacy for post-operative AKI when measured intra-operatively. When treated as a binary variable (≤ or > median for the whole cohort), the earliest excess risk of AKI was predicted by an increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) at 3 h after entry into the intensive care unit (odds ratio [95% confidence limits], 2.86 [1.14-7.21], p = 0.03). Corresponding time-points were 6 h for serum creatinine (3.59 [1.40-9.20], p = 0.008), and 24 h for plasma NGAL (4.54 [1.73-11.90], p = 0.002) and serum cystatin C (6.38 [2.35-17.27], p = 0.001). In contrast, indices of intra-operative urinary hypoxia predicted AKI after weaning from CPB, and in the case of a fall in UPO 2 to ≤10 mmHg, during the rewarming phase of CPB (3.00 [1.19-7.56], p = 0.02). We conclude that continuous measurement of UPO 2 predicts AKI earlier than plasma or urinary NGAL, serum cystatin C, or early post-operative changes in serum creatinine., (© 2021 John Wiley & Sons Australia, Ltd.)

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., (Copyright © 2022 American Physiological Society. All rights reserved.)

Background: Acute kidney injury (AKI) is common after cardiac surgery requiring cardiopulmonary bypass. Renal hypoxia may precede clinically detectable AKI. We compared the efficacy of two indices of renal hypoxia, (i) intraoperative urinary oxygen tension (UPO 2 ) and (ii) the change in plasma erythropoietin (pEPO) during surgery, in predicting AKI. We also investigated whether the performance of these prognostic markers varies with preoperative patient characteristics., Methods: In 82 patients undergoing on-pump cardiac surgery, blood samples were taken upon induction of anesthesia and upon entry into the intensive care unit. UPO 2 was continuously measured throughout surgery., Results: Thirty-two (39%) patients developed postoperative AKI. pEPO increased during surgery, but this increase did not predict AKI, regardless of risk of postoperative mortality assessed by EuroSCORE-II. For patients categorized at higher risk by EuroSCORE-II >1.98 (median score for the cohort), UPO 2  ≤10 mmHg at any time during surgery predicted a 4.04-fold excess risk of AKI (p = .04). However, UPO 2 did not significantly predict AKI in lower-risk patients. UPO 2 significantly predicted AKI in patients who were older, had previous myocardial infarction, diabetes, lower preoperative serum creatinine, or shorter bypass times. pEPO and UPO 2 were only weakly correlated., Conclusions: Intraoperative change in pEPO does not predict AKI. However, UPO 2 shows promise, particularly in patients with higher risk of operative mortality. The disparity between these two markers of renal hypoxia may indicate that UPO 2 reflects medullary oxygenation whereas pEPO reflects cortical oxygenation., (© 2021 Wiley Periodicals LLC.)

Using a large national database of cardiac surgical procedures, we applied machine learning (ML) to risk stratification and profiling for cardiac surgery-associated acute kidney injury. We compared performance of ML to established scoring tools. Four ML algorithms were used, including logistic regression (LR), gradient boosted machine (GBM), K-nearest neighbor, and neural networks (NN). These were compared to the Cleveland Clinic score, and a risk score developed on the same database. Five-fold cross-validation repeated 20 times was used to measure the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Risk profiles from GBM and NN were generated using Shapley additive values. A total of 97,964 surgery events in 96,653 patients were included. For predicting postoperative renal replacement therapy using pre- and intraoperative data, LR, GBM, and NN achieved an AUC (standard deviation) of 0.84 (0.01), 0.85 (0.01), 0.84 (0.01) respectively outperforming the highest performing scoring tool with 0.81 (0.004). For predicting cardiac surgery-associated acute kidney injury, LR, GBM, and NN each achieved 0.77 (0.01), 0.78 (0.01), 0.77 (0.01) respectively outperforming the scoring tool with 0.75 (0.004). Compared to scores and LR, shapely additive values analysis of black box model predictions was able to generate patient-level explanations for each prediction. ML algorithms provide state-of-the-art approaches to risk stratification. Explanatory modeling can exploit complex decision boundaries to aid the clinician in understanding the risks specific to individual patients., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

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·O 2 min -1  kg -1 ). There were profound reductions in cortical oxygen tension (PO 2 ) (33 ± 13 to 6 ± 6 mmHg) and medullary PO 2 (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·O 2 min -1 kg -1 ) and returned cortical PO 2 to 58 ± 60 mmHg and medullary PO 2 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., (© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

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 (PO 2 , -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 PO 2 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 PO 2 even though it decreased whole kidney oxygen extraction., (© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a "renal reserve," which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.

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.

Aim: Urinary oxygen tension (uPO 2 ) may provide an estimate of renal medullary PO 2 (mPO 2 ) and thus risk of acute kidney injury (AKI). We assessed the potential for variations in urine flow and arterial PO 2 (aPO 2 ) to confound these estimates., Methods: In 28 sheep urine flow, uPO 2 , aPO 2 and mPO 2 were measured during development of septic AKI. In 65 human patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) uPO 2 and aPO 2 were measured continuously during CPB, and in a subset of 20 patients, urine flow was estimated every 5 minutes., Results: In conscious sheep breathing room air, uPO 2 was more closely correlated with mPO 2 than with aPO 2 or urine flow. The difference between mPO 2 and uPO 2 varied little with urine flow or aPO 2 . In patients, urine flow increased abruptly from 3.42 ± 0.29 mL min -1 to 6.94 ± 0.26 mL min -1 upon commencement of CPB, usually coincident with reduced uPO 2 . During hyperoxic CPB high values of uPO 2 were often observed at low urine flow. Low urinary PO 2 during CPB (<10 mm Hg at any time during CPB) was associated with greater (4.5-fold) risk of AKI. However, low urine flow during CPB was not significantly associated with risk of AKI., Conclusions: uPO 2 provides a robust estimate of mPO 2 , but this relationship is confounded by the simultaneous presence of systemic hyperoxia and low urine flow. Urine flow increases and uPO 2 decreases during CPB. Thus, CPB is probably the best time to use uPO 2 to detect renal medullary hypoxia and risk of post-operative AKI., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg -1 min -1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg -1 min -1 , while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg -1 min -1 . CPB at 80 mL kg -1 min -1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po 2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg -1 min -1 further decreased RBF (-16%) and medullary Po 2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg -1 min -1 increased RBF (17%) and medullary Po 2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po 2 from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Acute kidney injury (AKI) is common after cardiac surgery and profoundly affects postoperative mortality and morbidity. There are no validated methods to assess risk of AKI intraoperatively., Methods: We determined the association between postoperative AKI and intraoperative urinary oxygen tension (PO2), measured via a fiber optic probe in the tip of the urinary catheter, in 65 patients undergoing high-risk cardiac surgery requiring cardiopulmonary bypass (CPB). AKI was diagnosed by modified Kidney Disease: Improving Global Outcomes criteria., Results: Urinary PO2 fell during the operation, often reaching its nadir during rewarming or after weaning from CPB. Nadir urinary PO2 was lower in the 26 patients who developed AKI (mean ± SD, 8.9 ± 5.6 mmHg) than in the 39 patients who did not (14.9 ± 10.2 mmHg, P = 0.008). Patients who developed AKI had longer periods of urinary PO2 ≤15 and 10 mmHg than patients who did not. Odds of AKI increased when urinary PO2 fell to ≤10 mmHg {3.60 [95% confidence interval (CI) 1.27-10.21]} or ≤5 mmHg [3.60 (95% CI 1.04-12.42), P = 0.04] during the operation. When urinary PO2 fell to ≤15 mmHg, for more than or equal to  the median duration for all patients (4.8 min/h surgery), the odds of AKI were 4.85 (95% CI 1.64-14.40), P = 0.004. The area under the receiver-operator curve for this parameter alone was 0.69, and was 0.89 when other variables with P ≤ 0.10 in univariable analysis were included in the model., Conclusion: Low urinary PO2 during adult cardiac surgery requiring CPB predicts AKI, so may identify patients in which intervention to improve renal oxygenation might reduce the risk of AKI.

Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts., (© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: The role of perioperative erythropoietin (EPO) for preventing cardiac surgery associated acute kidney injury (CSA-AKI) remains uncertain with published trials producing conflicting results. Perspective into the factors at work is needed, due to ongoing uncertainty., Methods: We undertook the systematic review and meta-analysis of randomised-controlled trials (RCTs) using random-effects modelling. The primary outcome was safety and efficacy of perioperative EPO to prevent CSA-AKI and the secondary outcomes were change in serum creatinine, urinary neutrophil gelatinase-associated lipocalin, time in ICU, rates of postoperative transfusions, haemodialysis, and mortality. Subgroup analysis explored the effect of the timing of the EPO dose in relation to surgery, the dose response, and the impact of the preoperative risk for CSA-AKI for the patient group., Results: Six RCTs were included, which totalled 473 participants. Erythropoietin administration did not reduce the incidence of CSA-AKI compared with controls (OR: 0.69, 95% CI: 0.35 to 1.36, P=0.28; I 2 =64%, P=0.001), however, subgroup analysis suggested administrating EPO before anaesthesia was correlated with a reduction in CSA-AKI (OR: 0.27, 95% CI: 0.13 to 0.54, P=0.0002; I 2 =0%, P=0.98). Additionally, in low risk populations, perioperative EPO administration correlated with significant reduction in CSA-AKI when compared to controls (OR: 0.25, 95% CI: 0.11 to 0.56, P=0.0008; I 2 =0%, P=0.86)., Conclusion: Our findings suggest that administering EPO before anaesthesia is emerging as an important factor for efficacy. Erythropoietin may have a role in preventing CSA-AKI, however, additional high-quality prospective studies are warranted, particularly aimed at describing the methodological components, such as the timing and size of the dose, which potentiate the cytoprotective effect of EPO in the clinical setting., (Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Background: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart defect with limited data on long-term outcomes after surgical intervention., Methods: We conducted a retrospective review of all children (N = 42) who underwent surgical repair of ALCAPA between 1980 and 2014 at the Royal Children's Hospital, Melbourne., Results: Twenty-nine (69% [29 of 42]) patients underwent coronary reimplantation, 12 (29% [12 of 42]) had intrapulmonary baffle (Takeuchi) repair, and 1 (2% [1 of 42]) patient had ligation of the anomalous coronary artery. Nine (21%, 9 of 42) patients had concomitant mitral valve (MV) repair at the time of ALCAPA repair. A left ventricular assist device (LVAD) was used in 36% (15 of 42) of patients. Early mortality was 2.4% (1 of 42 patients). Median follow-up was 14 years (mean, 13 years; range, 4 months-31 years). There were no late deaths. Survival was 98% at 20 years. Freedom from reoperation was 81%, 81%, and 76% at 5, 10, and 20 years after operation, respectively. Eight patients underwent late MV repair or replacement at a median of 3 years (mean, 8 years; range, 2 months-25 years) after operation. Freedom from late MV repair or replacement was 86% at 5 and 10 years and 81% at 20 years after operation. Eleven (26% [11 of 42]) patients had severe mitral regurgitation (MR) preoperatively. Of those 11 patients, 5 (45% [5 of 11]) had concomitant MV repair at the time of ALCAPA repair, 3 (27% [3 of 11]) had late MV repair or replacement, and the remaining 3 (27% [3 of 11]) patients had mild MR at last follow-up. Thirty-six (90% [36 of 41]) patients had normal left ventricular function and 4 (10% [4 of 41]) patients had mildly reduced left ventricular (LV) function at last follow-up., Conclusions: ALCAPA can be operated on with good outcomes. Persistent MR and a moderate rate of late MV repair warrants close follow-up., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Trends towards surgical sub-specialisation to improve patient-outcomes are well-documented and largely supported by evidence. However few studies have examined whether this benefit exists within adult-cardiac surgery. To answer whether sub-specialisation within adult-cardiac surgery improves patient-outcomes, this study assessed the relationship between procedure-specific and total-cardiac surgeon-volume and mortality and morbidity in cardiac-valve and coronary artery bypass grafting (CABG) surgery., Methods: Data came from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) registry from 2001 to 2010 and included 23 hospitals, 109 surgeons, 20,619 patients with isolated-CABG-surgery and 11,536 patients with a valve-procedure. Hierarchical logistic regression using generalised estimating equations was used to analyse outcomes. Measures included operative-mortality and occurrence of a complication (deep sternal wound infection, new stroke, acute kidney injury)., Results: Crude operative mortality (and complication rates) were 1.7% (4.9%) and 4% (11%) in the isolated-CABG and valve-surgical populations respectively. A greater procedure-specific surgeon volume was associated with reduced mortality and complication rates in valve-surgery but not isolated-CABG. There was a 33% decrease in odds of dying for every additional 50 valve procedures performed [OR 0.67, p=0.003]. Conversely, greater total-cardiac surgical volume for individual surgeons did not result in improved outcomes, for both isolated-CABG and valve populations., Conclusions: Our finding of an association between increased valve-specific surgeon volumes with improved valve-surgery outcomes, and absence of an association between these outcomes and annual total-cardiac surgical experience supports the case for sub-specialisation specifically within the field of valve surgery., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background:   Cardiac opioid peptides have been identified to exert important adaptive metabolic signalling for cardioprotection against ischaemia or hypoxia-related injury., Aims:   To determine myocardial methionine-enkephalin content in children with hypoxemic congenital heart defects and to correlate myocardial content of methionine-enkephalin with the extent of arterial oxygen desaturation., Methods:   Children (n= 20, median age of 16 months), undergoing cardiac surgical repair (tetralogy of Fallot, 17/20), were included in this study. Arterial oxygen saturation was measured on admission. Myocardial samples obtained during surgery were assayed via radioimmunochemistry for methionine-enkephalin content., Results:   Greater methionine-enkephalin content was measured in the right ventricles of the patients suffering from recent cyanotic spells compared with those with no recent spells (cyanotic spells: 2418 ± 844 pg/g wet weight tissue, n= 6; no spells: 1175 ± 189 pg/g wet weight tissue, n= 14, P= 0.04). An inverse correlation was evident between the arterial oxygen saturation and myocardial methionine-enkephalin content., Conclusion:   Myocardial methionine-enkephalin levels increase with the severity of hypoxic stress in congenital cardiac disease and may play an important adaptive role in countering adrenergic over-activity and related excess demand on myocardial metabolic capacity., (© 2010 The Authors. Journal compilation © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

We describe the determinants of urinary oxygen tension (Po2) and the potential for use of urinary PO2 as a "physiological biomarker" of the risk of acute kidney injury (AKI) in hospital settings. We also identify knowledge gaps required for clinical translation of bedside monitoring of urinary PO2. Hypoxia in the renal medulla is a hallmark of AKI of diverse etiology. Urine in the collecting ducts would be expected to equilibrate with the tissue PO2 of the inner medulla. Accordingly, the PO2 of urine in the renal pelvis changes in response to stimuli that would be expected to alter oxygenation of the renal medulla. Oxygen exchange across the walls of the ureter and bladder will confound measurement of the PO2 of bladder urine. Nevertheless, the PO2 of bladder urine also changes in response to stimuli that would be expected to alter renal medullary oxygenation. If confounding influences can be understood, urinary bladder PO2 may provide prognostically useful information, including for prediction of AKI after cardiopulmonary bypass surgery. To translate bedside monitoring of urinary PO2 into the clinical setting, we require 1) a more detailed knowledge of the relationship between renal medullary oxygenation and the PO2 of pelvic urine under physiological and pathophysiological conditions; 2) a quantitative understanding of the impact of oxygen transport across the ureteric epithelium on urinary PO2 measured from the bladder; and 3) a simple, robust medical device that can be introduced into the bladder via a standard catheter to provide reliable and continuous measurement of urinary PO2.

Background: Gastrointestinal (GI) complications after cardiac surgery are uncommon, but are associated with high morbidity and mortality as well as significant hospital resource utilization., Methods: We analysed a prospectively collected database containing all adult cardiac surgery procedures performed from July 2001 to March 2011 at Monash Medical Centre and Jessie McPherson Private Hospital. Patients with post-operative GI complications were compared to patients without GI complications who were operated in the same period., Results: The incidence of GI complications was 1.1% (61 out of 5382 patients) with an overall 30-day mortality of 33% (versus 3% in the non-GI complication group). The most common complications were GI bleeding, gastroenteritis and bowel ischaemia. Patients who had GI complications were significantly older, had higher incidence of renal impairment, chronic lung disease and anticoagulation therapy and were more likely to be in cardiogenic shock. Emergency procedures, combined coronary artery bypass grafting and valve surgery and aortic dissection cases were more common in the GI complication group. The GI complication group also had higher incidence of return to theatre, renal failure, stroke, septicaemia and multi-organ failure., Conclusions: GI complications after cardiac surgery remain an uncommon but dreadful complication associated with high mortality. Our findings should prompt a high degree of clinical vigilance in order to make an early diagnosis especially in high risk patients. Further studies aiming to identify independent predictors for GI complications after cardiac surgery are warranted., (© 2013 The Authors. ANZ Journal of Surgery © 2013 Royal Australasian College of Surgeons.)

Background: In women under the age of 40, over 50% of type A aortic dissections occur in the obstetric population. This is a complex situation, with potential catastrophic outcomes for mother and child. Time to diagnosis is often delayed by a low degree of suspicion, atypical presentation and difficulties investigating pregnant women. Management requires early involvement of multiple teams and appreciation of potential complications. We report our experience (the largest series described) and describe our surgical strategy., Methods: A retrospective search of the cardiothoracic surgical database at our centre from 2002 to 2010 identified five pregnant women with type A dissections., Results: Median time to diagnosis was 18.5 h (range 5.5-150 h) and median time from diagnosis to arrival in the operating theatre was 1.5 h (range 0.5-54 h). Four patients underwent concomitant Caesarean section and dissection repair. There was one maternal death and one unrelated foetal death., Conclusion: Occurrence of type A aortic dissection in pregnant women is uncommon but potentially catastrophic. A high index of suspicion and timely investigations are necessary to expedite definitive management. Sound surgical strategies and collaboration with appropriate teams are necessary to optimise outcome., (Copyright © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Objectives: To report our experience with the use of the Amplatzer muscular ventricular septal defect (VSD) occluder, using direct right ventricle free wall puncture for primary closure of muscular VSDs in infants., Background: Young infants with heart failure due to large or multiple muscular VSDs often require intervention at a stage when percutaneous device closure is impractical due to delivery system limitations. There are considerable benefits to avoiding bypass in these infants., Methods: Patients with suitable muscular VSDs, considered too small for transvenous closure, underwent periventricular muscular VSD closure under transesophageal echo (TEE) guidance., Results: Eight infants underwent the procedure. The median age was 14 weeks (2-41) with median weight of 4 kg (3-6.6). Four patients had additional VSDs and one patient had previous repair of coarctation. One patient had dextrocardia and severe left ventricular impairment due to an associated cardiomyopathy. The median VSD size was 8 mm (range, 4-10 mm). A single device (6-12 mm) was deployed in each patient, the size chosen being 1-2 mm larger than the TEE measurement. Two patients had subsequent pulmonary artery banding, with absorbable bands, because of moderate residual shunting through additional VSDs. The latest echo study at a median of 7.2 weeks (0.5-66) post device implantation revealed no patients with a hemodynamically significant shunt., Conclusion: Perventricular muscular VSD closure can be safely and effectively undertaken in small infants with suitable muscular defects, and this strategy can avoid the need for bypass., (Copyright 2008 Wiley-Liss, Inc.)