Medullary PO2 Research Articles

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.

Chronic intermittent hypoxia promotes glomerular hyperfiltration and potentiates hypoxia-evoked decreases in renal perfusion and PO2.

Introduction: Sleep apnea (SA) is highly prevalent in patients with chronic kidney disease and may contribute to the development and/or progression of this condition. Previous studies suggest that dysregulation of renal hemodynamics and oxygen flux may play a key role in this process. The present study sought to determine how chronic intermittent hypoxia (CIH) associated with SA affects regulation of renal artery blood flow (RBF), renal microcirculatory perfusion (RP), glomerular filtration rate (GFR), and cortical and medullary tissue PO2 as well as expression of genes that could contribute to renal injury. We hypothesized that normoxic RBF and tissue PO2 would be reduced after CIH, but that GFR would be increased relative to baseline, and that RBF, RP, and tissue PO2 would be decreased to a greater extent in CIH vs. sham during exposure to intermittent asphyxia (IA, FiO2 0.10/FiCO2 0.03). Additionally, we hypothesized that gene programs promoting oxidative stress and fibrosis would be activated by CIH in renal tissue. Methods: All physiological variables were measured at baseline (FiO2 0.21) and during exposure to 10 episodes of IA (excluding GFR). Results: GFR was higher in CIH-conditioned vs. sham (p < 0.05), whereas normoxic RBF and renal tissue PO2 were significantly lower in CIH vs. sham (p < 0.05). Reductions in RBF, RP, and renal tissue PO2 during IA occurred in both groups but to a greater extent in CIH (p < 0.05). Pro-oxidative and pro-fibrotic gene programs were activated in renal tissue from CIH but not sham. Conclusion: CIH adversely affects renal hemodynamic regulation and oxygen flux during both normoxia and IA and results in changes in renal tissue gene expression.

The effects of recruitment of renal functional reserve on renal cortical and medullary oxygenation in non-anesthetized sheep.

Recruitment of renal functional reserve (RFR) with amino acid loading increases renal blood flow and glomerular filtration rate. However, its effects on renal cortical and medullary oxygenation have not been determined. Accordingly, we tested the effects of recruitment of RFR on renal cortical and medullary oxygenation in non-anesthetized sheep. Under general anesthesia, we instrumented 10 sheep to enable subsequent continuous measurements of systemic and renal hemodynamics, renal oxygen delivery and consumption, and cortical and medullary tissue oxygen tension (PO2 ). We then measured the effects of recruitment of RFR with an intravenous infusion of 500 ml of a clinically used amino acid solution (10% Synthamin® 17) in the non-anesthetized state. Compared with baseline, Synthamin® 17 infusion significantly increased renal oxygen delivery mean ± SD maximum increase: (from 0.79 ± 0.17 to 1.06 ± 0.16 ml/kg/min, p < 0.001), renal oxygen consumption (from 0.08 ± 0.01 to 0.15 ± 0.02 ml/kg/min, p < 0.001), and glomerular filtration rate (+45.2 ± 2.7%, p < 0.001). Renal cortical tissue PO2 increased by a maximum of 26.4 ± 1.1% (p=0.001) and medullary tissue PO2 increased by a maximum of 23.9 ± 2.8% (p=0. 001). In non-anesthetized healthy sheep, recruitment of RFR improved renal cortical and medullary oxygenation. These observations might have implications for the use of recruitment of RFR for diagnostic and therapeutic purposes.

Effects of changes in inspired oxygen fraction on urinary oxygen tension measurements

BackgroundContinuous measurement of urinary PO2 (PuO2) is being applied to indirectly monitor renal medullary PO2. However, when applied to critically ill patients with shock, its measurement may be affected by changes in FiO2 and PaO2 and potential associated O2 diffusion between urine and ureteric or bladder tissue. We aimed to investigate PuO2 measurements in septic shock patients with a fiberoptic luminescence optode inserted into the urinary catheter lumen in relation to episodes of FiO2 change. We also evaluated medullary and urinary oxygen tension values in Merino ewes at two different FiO2 levels.ResultsIn 10 human patients, there were 32 FiO2 decreases and 31 increases in FiO2. Median pre-decrease FiO2 was 0.36 [0.30, 0.39] and median post-decrease FiO2 was 0.30 [0.23, 0.30], p = 0.006. PaO2 levels decreased from 83 mmHg [77, 94] to 72 [62, 80] mmHg, p = 0.009. However, PuO2 was 23.2 mmHg [20.5, 29.0] before and 24.2 mmHg [20.6, 26.3] after the intervention (p = 0.56). The median pre-increase FiO2 was 0.30 [0.21, 0.30] and median post-increase FiO2 was 0.35 [0.30, 0.40], p = 0.008. PaO2 levels increased from 64 mmHg [58, 72 mmHg] to 71 mmHg [70, 100], p = 0.04. However, PuO2 was 25.0 mmHg [IQR: 20.7, 26.8] before and 24.3 mmHg [IQR: 20.7, 26.3] after the intervention (p = 0.65). A mixed linear regression model showed a weak correlation between the variation in PaO2 and the variation in PuO2 values. In 9 Merino ewes, when comparing oxygen tension levels between FiO2 of 0.21 and 0.40, medullary values did not differ (25.1 ± 13.4 mmHg vs. 27.9 ± 15.4 mmHg, respectively, p = 0.6766) and this was similar to urinary oxygen values (27.1 ± 6.17 mmHg vs. 29.7 ± 4.41 mmHg, respectively, p = 0.3192).ConclusionsChanges in FiO2 and PaO2 within the context of usual care did not affect PuO2. Our findings were supported by experimental data and suggest that PuO2 can be used as biomarker of medullary oxygenation irrespective of FiO2.

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

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. Ten sheep were studied while conscious, under stable anesthesia, and during 3h 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. 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 . 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.

Rapid and persistent decrease in brain tissue oxygenation in ovine gram-negative sepsis.

The changes in brain perfusion and oxygenation in critical illness, which are thought to contribute to brain dysfunction, are unclear due to the lack of methods to measure these variables. We have developed a technique to chronically measure cerebral tissue perfusion and oxygen tension in unanesthetized sheep. Using this technique, we have determined the changes in cerebral perfusion and Po2 during the development of ovine sepsis. In adult Merino ewes, fiber-optic probes were implanted in the brain, renal cortex, and renal medulla to measure tissue perfusion, oxygen tension (Po2), and temperature, and flow probes were implanted on the pulmonary and renal arteries. Conscious sheep were infused with live Escherichia coli for 24 h, which induced hyperdynamic sepsis; mean arterial pressure decreased (from 85.2 ± 5.6 to 71.5 ± 8.7 mmHg), while cardiac output (from 4.12 ± 0.70 to 6.15 ± 1.26 L/min) and total peripheral conductance (from 48.9 ± 8.5 to 86.8 ± 11.5 mL/min/mmHg) increased (n = 8, all P < 0.001) and arterial Po2 decreased (from 104 ± 8 to 83 ± 10 mmHg; P < 0.01). Cerebral perfusion tended to decrease acutely, although this did not reach significance, but there was a significant and sustained decrease in cerebral tissue Po2 (from 32.2 ± 10.1 to 18.8 ± 11.7 mmHg) after 3 h and to 22.8 ± 5.2 mmHg after 24 h of sepsis (P < 0.02). Sepsis induced large reductions in both renal medullary perfusion and Po2 but had no effect in the renal cortex. In ovine sepsis, there is an early decrease in cerebral Po2 that is maintained for 24 h despite minimal changes in cerebral perfusion. Cerebral hypoxia may be one of the factors causing sepsis-induced malaise and lethargy.

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

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. Cardiopulmonary bypass was established in eight instrumented sheep under isoflurane anaesthesia, at a target continuous pump flow of 80mL·kg-1min-1 and mean arterial pressure of 65mmHg. We then tested the effects of simultaneously increasing target pump flow to 104mL·kg-1min-1 and mean arterial pressure to 80mmHg with metaraminol (total dose 0.25-3.75mg). We also tested the effects of transitioning from continuous flow to partially pulsatile flow (pulse pressure ~15mmHg). 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±0.76mL·min-1kg-1) and renal oxygen delivery (0.91±0.18 to 0.24±0.11mL·O2 min-1kg-1). There were profound reductions in cortical oxygen tension (PO2) (33±13 to 6±6mmHg) and medullary PO2 (31±12 to 8±8mmHg). Increasing target pump flow and mean arterial pressure increased renal blood flow (to 2.6±1.0mL·min-1kg-1) and renal oxygen delivery (to 0.32±0.13mL·O2 min-1kg-1) and returned cortical PO2 to 58±60mmHg and medullary PO2 to 28±16mmHg; levels similar to those of conscious sheep. Partially pulsatile pump flow had no significant effects on renal perfusion or oxygenation. 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.

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 ~7g dL-1 to ~9g dL-1 improves renal tissue oxygenation. Ten sheep were studied while conscious, under stable isoflurane anaesthesia, and during 3hours of CPB. In a randomized cross-over design, 5 sheep commenced bypass at a high target [Hb], achieved by adding 600mL donor blood to the priming solution. After 90minutes 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 90minutes of CPB, 800-900mL of donor blood was given to achieve a high target [Hb]. 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±6mmHg change, P>.99) or cortex (-19±13mmHg change, P=.08) was detected with high [Hb]. In experimental CPB blood transfusion to increase Hb concentration from ~7g dL-1 to ~9g dL-1 did not improve renal cortical or medullary tissue PO2 even though it decreased whole kidney oxygen extraction.

Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C.

Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis. Interventional study. Research Institute. Adult Merino ewes. Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg). Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours. IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients.

Beneficial Effects of Vasopressin Compared With Norepinephrine on Renal Perfusion, Oxygenation, and Function in Experimental Septic Acute Kidney Injury

To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury. Interventional Study. Research Institute. Adult Merino ewes. Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis. Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%). In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

Analysis of the critical determinants of renal medullary oxygenation.

We have previously developed a three-dimensional computational model of oxygen transport in the renal medulla. In the present study, we used this model to quantify the sensitivity of renal medullary oxygenation to four of its major known determinants: medullary blood flow (MBF), medullary oxygen consumption rate (V̇o2,M), hemoglobin (Hb) concentration in the blood, and renal perfusion pressure. We also examined medullary oxygenation under special conditions of hydropenia, extracellular fluid volume expansion by infusion of isotonic saline, and hemodilution during cardiopulmonary bypass. Under baseline (normal) conditions, the average medullary tissue Po2 predicted for the whole renal medulla was ~30 mmHg. The periphery of the interbundle region in the outer medulla was identified as the most hypoxic region in the renal medulla, which demonstrates that the model prediction is qualitatively accurate. Medullary oxygenation was most sensitive to changes in renal perfusion pressure followed by Hb, MBF, and V̇o2,M, in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po2 when multiple parameters changed simultaneously. Hydropenia did not induce a significant change in medullary oxygenation compared with the baseline state, while volume expansion resulted in a large increase in inner medulla tissue Po2 (by ~15 mmHg). Under conditions of cardiopulmonary bypass, the renal medulla became severely hypoxic, due to hemodilution, with one-third of the outer stripe of outer medulla tissue having a Po2 of <5 mmHg.

Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO2 (40 to 21 mmHg) and creatinine clearance (2.50 to 0.78 mL/Kg/min). Norepinephrine restored baseline mean arterial pressure (to 83 mmHg) but worsened medullary hypoperfusion (to 330 perfusion units) and medullary hypoxia (to 9 mmHg). Dexmedetomidine (0.5 μg/kg/h) co-administration significantly reduced the norepinephrine dose (0.8 to 0.4 μg/kg/min) required to restore baseline mean arterial pressure, attenuated medullary hypoperfusion (to 606 perfusion units), decreased medullary tissue hypoxia (to 29 mmHg), and progressively increased creatinine clearance (to 1.8 mL/Kg/min). Compared with vehicle time-control, dexmedetomidine given alone significantly prevented the temporal reduction in mean arterial pressure, but had no significant effects on medullary perfusion and oxygenation or creatinine clearance. Thus, in experimental septic acute kidney injury, dexmedetomidine reduced norepinephrine requirements, attenuated its adverse effects on the renal medulla, and maintained renal function.

SAT-143 MILD HYPERCAPNIA DURING MAJOR SURGERY, A POSSIBLE STRATEGY TO PREVENT RENAL MEDULLARY HYPOXIA AND THE DEVELOPMENT ACUTE KIDNEY INJURY

Acute kidney injury (AKI) is a common complication of major surgery that increases short- and long-term morbidity and mortality. There is emerging evidence that decreased renal medullary perfusion, resulting in hypoxia, contributes to the development of AKI during prolonged surgery. Since hypercapnia can provide a degree of organ protection, possibly due to its vasodilator effects, we investigated whether increases in arterial carbon dioxide level (PaCO2) improve global and regional kidney oxygenation in anesthetised sheep. In addition, positive end expiratory pressure (PEEP) is used to increase oxygenation, but it also decreases cardiac output and may therefore reduce renal perfusion and oxygenation. Thus, we determined the effects of PEEP (0, 5, 10, 15 and 20 cmH2O for 15 min), and PEEP with mild hypercapnia (PaCO2 45-55mmHg), on renal perfusion and oxygenation. In Merino ewes, surgery was performed to implant pulmonary and renal artery flow probes and laser-Doppler and oxygen-sensing probes in the renal medulla and cortex and to cannulate a renal vein. In anaesthetised sheep (isoflurane 2.5%), FiO2 was held at 0.4 and respiratory rate was changed to achieve target PaCO2 (normocapnia 35-45, mild hypercapnia 45-55 and severe hypercapnia 55-65 mmHg) for periods of 20 minutes, in random order. PEEP was held at (0, 5, 10, 15 and 20 cm H2O) for periods of 15 min during normocapnia and mild hypercapnia. Increases in PaCO2 from normocapnia, to mild and severe hypercapnia significantly increased medullary PO2 (39.1±5.5, 48.6±4.2 and 51.9±4.8 mmHg, respectively) and perfusion (336±66, 449±72 and 453±82 blood perfusion units, respectively). There were no changes in cortical perfusion or PO2, renal blood flow or renal oxygen delivery. During normocapnia, PEEP decreased cardiac output, renal blood flow, renal oxygen delivery, medullary perfusion (342±101 to 243±64 blood perfusion units (BPU)) and medullary PO2 (33.5±5.4 to 22.6±8.9 mmHg). Mild hypercapnia, for 30 min before and during PEEP, prevented the PEEP-induced decreases in medullary perfusion (586±165 to 491±93 BPU) and PO2 (54.6±7.8 to 57.4±7.6 mmHg), despite reductions in cardiac output and renal blood flow. Under volatile anaesthesia, increases in PaCO2 caused progressive increases in renal medullary perfusion and oxygenation. PEEP had detrimental effects on cardiac output, renal blood flow and medullary perfusion and PO2. Mild hypercapnia prevented the PEEP-induced decreases in medullary perfusion and PO2. During prolonged major surgery, increasing PaCO2 to prevent decreases in renal medullary PO2 may be a useful strategy to reduce the incidence of post-operative AKI.

SUN-162 EFFECTS OF INTRAVENOUS FUROSEMIDE ON URINARY OXYGEN TENSION IN PATIENTS IN THE INTENSIVE CARE UNIT AFTER CARDIAC SURGERY

Continuous measurement of urinary oxygen tension (PO2) in patients undergoing cardiac surgery may allow prediction of post-operative acute kidney injury (AKI). The predictive efficacy of urinary PO2 may be because it provides a good estimate of renal medullary PO2. Medications given during the perioperative period, particularly diuretics, could potentially alter medullary and/or urinary PO2. Thus, administration of furosemide may reduce the utility of urinary PO2 in predicting AKI. Therefore, we tested the effects of furosemide on urinary PO2 in patients recovering in the intensive care unit (ICU) after open heart surgery requiring cardiopulmonary bypass.

SUN-166 FACTORS THAT CONFOUND THE PREDICTION OF RENAL MEDULLARY OXYGENATION AND RISK OF ACUTE KIDNEY INJURY FROM MEASUREMENT OF BLADDER URINE OXYGEN TENSION

Urinary oxygen tension (PO2) may provide a useful estimate of renal medullary PO2 and thus risk of acute kidney injury (AKI). However, the relationship between urinary PO2 and medullary PO2 could be confounded by variations in urine flow and arterial PO2. In the current study we exploited data we had previously generated, from experimental studies in ovine septic AKI and in patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB), to perform a detailed analysis of the influences of urine flow and arterial PO2 on urinary PO2.

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

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. 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 5minutes. 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±0.29mL min-1 to 6.94±0.26mL 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 (<10mm 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. 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.

Furosemide reverses medullary tissue hypoxia in ovine septic acute kidney injury.

In experimental sepsis, the rapid development of renal medullary hypoxia precedes the development of acute kidney injury (AKI) and may contribute to its pathogenesis. We investigated whether inhibiting active sodium transport and oxygen consumption in the medullary thick ascending limb with furosemide attenuates the medullary hypoxia in experimental septic AKI. Sheep were instrumented with flow probes on the pulmonary and renal arteries and fiber optic probes to measure renal cortical and medullary perfusion and oxygen tension (Po2). Sepsis and AKI were induced by infusion of live Escherichia coli. At 24 h of sepsis there were significant decreases in renal medullary tissue perfusion (1,332 ± 233 to 698 ± 159 blood perfusion units) and Po2 (44 ± 6 to 19 ± 6 mmHg) (both P < 0.05). By 5 min after intravenous administration of furosemide (20 mg), renal medullary Po2 increased to 43 ± 6 mmHg and remained at this normal level for 8 h. Furosemide caused transient increases in fractional excretion of sodium and creatinine clearance, but medullary perfusion, renal blood flow, and renal oxygen delivery were unchanged. Urinary F2-isoprostanes, an index of oxidative stress, were not significantly changed at 24 h of sepsis but tended to transiently decrease after furosemide treatment. In septic AKI, furosemide rapidly restored medullary Po2 to preseptic levels. This effect was not accompanied by changes in medullary perfusion or renal oxygen delivery but was accompanied by a transient increase in fractional sodium excretion, implying decreased oxygen consumption as a mechanism.

Adjusting cardiopulmonary bypass flow or arterial pressure to maintain renal medullary oxygen

Cardiopulmonary bypass leads to renal hypoperfusion, resulting in medullary hypoxia and acute kidney injury. In instrumented sheep subjected to cardiopulmonary bypass, Lankadeva etal. found that medullary perfusion and tissue oxygen tension (PO2) was maintained at low-dose metaraminol, an α1-adrenoceptor agonist, because low-dose metaraminol increased perfusion pressure without affecting renal vascular resistance. Lankadeva etal. developed a fiber-optic catheter to measure bladder urine PO2. Urine PO2 tracks medullary PO2, and low urine PO2 predicts acute kidney injury. Adjusting cardiopulmonary bypass to maintain urine PO2 may help avoid acute kidney injury.

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 ata pump flow of 80 mL kg-1min-1 and target MAP of70mmHg. Pump flow was then set at 60 and 100mLkg-1min-1, while MAP was maintained at approximately 70mmHg.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 mmHg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary Po2 from 25 to 14 mmHg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary Po2 from 20 to 29 mmHg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mmHg, RBF (47%), and medullary Po2 from 19 to 39 mmHg. 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.

Effects of Fluid Bolus Therapy on Renal Perfusion, Oxygenation, and Function in Early Experimental Septic Kidney Injury.

To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury. Interventional study. Research institute. Adult Merino ewes. Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann's solution over 15 min) was administered. In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (-48% ± 5%), medullary PO2 (-56% ± 4%), and urinary PO2 (-54% ± 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary PO2 (+280% ± 90%), urinary PO2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2. In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention.