Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

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.

Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram-negative sepsis.

AIM: Renal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti-inflammatory drug, tempol, may modify these responses. METHODS: Following unilateral nephrectomy, we inserted renal arterial catheters and laser-Doppler/oxygen-sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) Escherichia coli and, at sepsis onset, IV tempol (IVT; 30 mg kg-1 h-1 ), renal arterial tempol (RAT; 3 mg kg-1 h-1 ), or vehicle. RESULTS: Septic sheep receiving vehicle developed renal medullary hypoperfusion (76 ± 16% decrease in perfusion), hypoxia (70 ± 13% decrease in oxygenation), and AKI (87 ± 8% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072 ± 307 to 1005 ± 271 units), oxygenation (46 ± 8 to 43 ± 6 mmHg), and creatinine clearance (61 ± 10 to 66 ± 20 mL min-1 ). Plasma, renal medullary, and cortical tissue malonaldehyde and medullary 3-nitrotyrosine decreased significantly with sepsis but were unaffected by IVT or RAT. Consistent with decreased oxidative/nitrosative stress markers, cortical and medullary nuclear factor-erythroid-related factor-2 increased significantly and were unaffected by IVT or RAT. However, RAT prevented sepsis-induced overexpression of cortical tissue tumor necrosis factor alpha (TNF-α; 51 ± 16% decrease; p = 0.003) and medullary Thr-495 phosphorylation of endothelial nitric oxide synthase (eNOS; 63 ± 18% decrease; p = 0.015). CONCLUSIONS: In ovine Gram-negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF-α expression and uncoupling of eNOS. However, it did not affect markers of oxidative/nitrosative stress, which were significantly decreased by Gram-negative sepsis.

Intraoperative hemodynamics and risk of cardiac surgery-associated acute kidney injury: An observation study and a feasibility clinical trial.

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/m2 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/m2 during the period before rewarming) and systemic oxygen delivery (363 ± 60 vs. 281 ± 45 mL/min/m2 ). 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.

Intraoperative renal desaturation and postoperative acute kidney injury in older patients undergoing liver resection: A prospective cohort study.

STUDY OBJECTIVE: To determine the association between intraoperative renal tissue desaturation as measured using near-infrared spectroscopy and increased likelihood of developing postoperative acute kidney injury (AKI) in older patients undergoing hepatectomy. DESIGN: A multicenter prospective cohort study. SETTING: The study was conducted at two tertiary hospitals in China from September 2020 to October 2021. PATIENTS: 157 older patients (≥ 60 years) undergoing open hepatectomy surgery. INTERVENTIONS AND MEASUREMENTS: Renal tissue oxygen saturation was continuously monitored during operation using near-infrared spectroscopy. The exposure of interest was intraoperative renal desaturation, defined as at least 20% relative decline in renal tissue oxygen saturation from baseline. The primary outcome was postoperative AKI, defined using the Kidney Disease: Improving Global Outcomes criteria according to the serum creatinine criteria. MAIN RESULTS: Renal desaturation occurred in 70 of 157 patients. Postoperative AKI was observed in 23% (16/70) and 8% (7/87) of patients with versus without renal desaturation. Patients with renal desaturation were at higher risk of AKI than patients without renal desaturation (adjusted odds ratio 3.41, 95% confidence interval: 1.12-10.36, p = 0.031). Predictive performance was 65.2% sensitivity and 33.6% specificity for hypotension alone, 69.6% sensitivity and 59.7% specificity for renal desaturation alone, and 95.7% sensitivity and 26.9% specificity for combined use of hypotension and renal desaturation. CONCLUSIONS: Intraoperative renal desaturation occurred in >40% in our sample of older patients undergoing liver resection and was associated with increased risk of AKI. Intraoperative near-infrared spectroscopy monitoring enhances the detection of AKI.

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.

Association Between Changes in Norepinephrine Infusion Rate and Urinary Oxygen Tension After Cardiac Surgery.

OBJECTIVES: To determine if the administration of norepinephrine to patients recovering from on-pump cardiac surgery is associated with changes in urinary oxygen tension (PO2), 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 PO2 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 PO2 increased by 2.6 ± 0.5 mmHg from its baseline level of 22.7 ± 1.2 mmHg. No significant change in urinary PO2 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 PO2, potentially reflecting an effect of norepinephrine on renal medullary oxygenation.

Continuous bladder urinary oxygen tension as a new tool to monitor medullary oxygenation in the critically ill.

Acute kidney injury (AKI) is common in the critically ill. Inadequate renal medullary tissue oxygenation has been linked to its pathogenesis. Moreover, renal medullary tissue hypoxia can be detected before biochemical evidence of AKI in large mammalian models of critical illness. This justifies medullary hypoxia as a pathophysiological biomarker for early detection of impending AKI, thereby providing an opportunity to avert its evolution. Evidence from both animal and human studies supports the view that non-invasively measured bladder urinary oxygen tension (PuO2) can provide a reliable estimate of renal medullary tissue oxygen tension (tPO2), which can only be measured invasively. Furthermore, therapies that modify medullary tPO2 produce corresponding changes in bladder PuO2. Clinical studies have shown that bladder PuO2 correlates with cardiac output, and that it increases in response to elevated cardiopulmonary bypass (CPB) flow and mean arterial pressure. Clinical observational studies in patients undergoing cardiac surgery involving CPB have shown that bladder PuO2 has prognostic value for subsequent AKI. Thus, continuous bladder PuO2 holds promise as a new clinical tool for monitoring the adequacy of renal medullary oxygenation, with its implications for the recognition and prevention of medullary hypoxia and thus AKI.

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.

Risk factors for incident cardiovascular events among adults in low- and middle-income countries: A systematic review and meta-analysis of prospective cohort studies.

The relative contributions of risk factors for cardiovascular events at a population level has received little attention in low- and middle-income countries (LMICs). We estimated the population attributable fraction (PAF) of risk factors associated with incident cardiovascular events in LMICs. We searched six databases for relevant articles, supplemented with a manual search of reference lists. Articles included in the meta-analyses were those based on prospective community-based cohorts and incorporating adjusted hazard ratios (HR) or relative risks with 95% confidence intervals (95% CI) for associations between risk factors and a composite cardiovascular and/or stroke endpoint. Pooled HRs and 95% CI were calculated using the random effects model. We assessed heterogeneity using the I2 test and study quality using the Newcastle-Ottawa Scale. We calculated the PAF of each associated risk factor. The protocol was registered in PROSPERO (CRD42019122741). We identified 18 cohorts from LMICs with 1,125,846 participants, 77,045 composite cardiovascular events and 42,216 strokes. Substantial proportions of incident cardiovascular events were attributable to hypertension (HR [95% CI], 2.23 [2.01-2.48], PAF = 28%); current smoking (1.44 [1.31-1.58], PAF = 10%); and diabetes mellitus (1.93 [1.67-2.23], PAF = 8%). Other risk factors identified included number of children, depression, bone mineral density, and air pollution. A substantial proportion of incident cardiovascular events were linked to traditional metabolic and behavioural modifiable risk factors. However, other novel risk factors also appear to contribute. Targeting of these established and novel risk factors has the potential to reduce the burden of CVD in LMICs.

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.

Intra-operative and early post-operative prediction of cardiac surgery-associated acute kidney injury: Urinary oxygen tension compared with plasma and urinary biomarkers.

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 (UPO2 ) 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 UPO2 to ≤10 mmHg, during the rewarming phase of CPB (3.00 [1.19-7.56], p = 0.02). We conclude that continuous measurement of UPO2 predicts AKI earlier than plasma or urinary NGAL, serum cystatin C, or early post-operative changes in serum creatinine.

Renal and Cerebral Hypoxia and Inflammation During Cardiopulmonary Bypass.

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.

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.

Intraoperative renal hypoxia and risk of cardiac surgery-associated acute kidney injury.

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 (UPO2 ) 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. UPO2 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), UPO2 ≤10 mmHg at any time during surgery predicted a 4.04-fold excess risk of AKI (p = .04). However, UPO2 did not significantly predict AKI in lower-risk patients. UPO2 significantly predicted AKI in patients who were older, had previous myocardial infarction, diabetes, lower preoperative serum creatinine, or shorter bypass times. pEPO and UPO2 were only weakly correlated. CONCLUSIONS: Intraoperative change in pEPO does not predict AKI. However, UPO2 shows promise, particularly in patients with higher risk of operative mortality. The disparity between these two markers of renal hypoxia may indicate that UPO2 reflects medullary oxygenation whereas pEPO reflects cortical oxygenation.

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.

Factors that confound the prediction of renal medullary oxygenation and risk of acute kidney injury from measurement of bladder urine oxygen tension.

AIM: Urinary oxygen tension (uPO2 ) may provide an estimate of renal medullary PO2 (mPO2 ) and thus risk of acute kidney injury (AKI). We assessed the potential for variations in urine flow and arterial PO2 (aPO2 ) to confound these estimates. METHODS: In 28 sheep urine flow, uPO2 , aPO2 and mPO2 were measured during development of septic AKI. In 65 human patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) uPO2 and aPO2 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, uPO2 was more closely correlated with mPO2 than with aPO2 or urine flow. The difference between mPO2 and uPO2 varied little with urine flow or aPO2 . 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 uPO2 . During hyperoxic CPB high values of uPO2 were often observed at low urine flow. Low urinary PO2 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: uPO2 provides a robust estimate of mPO2 , but this relationship is confounded by the simultaneous presence of systemic hyperoxia and low urine flow. Urine flow increases and uPO2 decreases during CPB. Thus, CPB is probably the best time to use uPO2 to detect renal medullary hypoxia and risk of post-operative AKI.

Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury.

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-1min-1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg-1min-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-1min-1. CPB at 80 mL kg-1min-1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary Po2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary Po2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po2 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.

Urinary hypoxia: an intraoperative marker of risk of cardiac surgery-associated acute kidney injury.

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.