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.

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.

Risk factors for incident cardiovascular events and their population attributable fractions in rural India: The Rishi Valley Prospective Cohort Study.

OBJECTIVE: We prospectively determined incident cardiovascular events and their association with risk factors in rural India. METHODS: We followed up with 7935 adults from the Rishi Valley Prospective Cohort Study to identify incident cardiovascular events. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) with 95% confidence intervals (95% CI) for associations between potential risk factors and cardiovascular events. Population attributable fractions (PAFs) for risk factors were estimated using R ('averisk' package). RESULTS: Of the 4809 participants without prior cardiovascular disease, 57.7% were women and baseline mean age was 45.3 years. At follow-up (median of 4.9 years, 23,180 person-years [PYs]), 202 participants developed cardiovascular events, equating to an incidence of 8.7 cardiovascular events/1000 PYs. Incidence was greater in those with hypertension (hazard ratio [HR] [95% CI] 1.73 [1.21-2.49], adjusted PAF 18%), diabetes (1.96 [1.15-3.36], 4%) or central obesity (1.77 [1.23, 2.54], 9%) which together accounted for 31% of the PAF. Non-traditional risk factors such as night sleeping hours and number of children accounted for 16% of the PAF. CONCLUSIONS: Both traditional and non-traditional cardiovascular risk factors are important contributors to incident cardiovascular events in rural India. Interventions targeted to these factors could assist in reducing the incidence of cardiovascular events.

Comparison of the performance of cardiovascular risk prediction tools in rural India: the Rishi Valley Prospective Cohort Study.

AIMS: We compared the performance of cardiovascular risk prediction tools in rural India. METHODS AND RESULTS: We applied the World Health Organization Risk Score (WHO-RS) tools, Australian Risk Score (ARS), and Global risk (Globorisk) prediction tools to participants aged 40-74 years, without prior cardiovascular disease, in the Rishi Valley Prospective Cohort Study, Andhra Pradesh, India. Cardiovascular events during the 5-year follow-up period were identified by verbal autopsy (fatal events) or self-report (non-fatal events). The predictive performance of each tool was assessed by discrimination and calibration. Sensitivity and specificity of each tool for identifying high-risk individuals were assessed using a risk score cut-off of 10% alone or this 10% cut-off plus clinical risk criteria of diabetes in those aged >60 years, high blood pressure, or high cholesterol. Among 2333 participants (10 731 person-years of follow-up), 102 participants developed a cardiovascular event. The 5-year observed risk was 4.4% (95% confidence interval: 3.6-5.3). The WHO-RS tools underestimated cardiovascular risk but the ARS overestimated risk, particularly in men. Both the laboratory-based (C-statistic: 0.68 and χ2: 26.5, P = 0.003) and non-laboratory-based (C-statistic: 0.69 and χ2: 20.29, P = 0.003) Globorisk tools showed relatively good discrimination and agreement. Addition of clinical criteria to a 10% risk score cut-off improved the diagnostic accuracy of all tools. CONCLUSION: Cardiovascular risk prediction tools performed disparately in a setting of disadvantage in rural India, with the Globorisk performing best. Addition of clinical criteria to a 10% risk score cut-off aids assessment of risk of a cardiovascular event in rural India. LAY SUMMARY: In a cohort of people without prior cardiovascular disease, tools used to predict the risk of cardiovascular events varied widely in their ability to accurately predict who would develop a cardiovascular event.The Globorisk, and to a lesser extent the ARS, tools could be appropriate for this setting in rural India.Adding clinical criteria, such as sustained high blood pressure, to a cut-off of 10% risk of a cardiovascular event within 5 years could improve identification of individuals who should be monitored closely and provided with appropriate preventive medications.

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.

Effects of postovipositional hypoxia and hyperoxia on leatherback turtle reproductive success and hatchling performance.

Leatherback egg clutches typically experience lower hatching success (~50%) than those of other sea turtle species (>70%). The majority of embryonic death (>50%) occurs at early stages of development, possibly because embryos fail to break preovipositional embryonic arrest after oviposition. The embryonic arrest is maintained by hypoxia in the oviduct and following oviposition increased availability of oxygen is the trigger that breaks arrest in all turtle species studied to date. We conducted an ex situ incubator experiment and an in situ hatchery experiment to examine the influence of oxygen availability on hatching success and hatchling traits in leatherbacks. After oviposition, eggs (n = 1005) were incubated in either normoxia (21% O2 ), hyperoxia (32%-42% O2 ) for 5 days, or hypoxia (1% O2 ) for 3 or 5 days. As with other turtles, hypoxic incubation maintained embryos in arrest, equivalent to the time spent in hypoxia. However, extending arrest for 5 days resulted in greater early-stage death and a significant decrease in hatching success (4% 5-day hypoxia vs. 72% normoxia). Eggs placed in incubators had greater hatching success than those placed into hatchery nests (67% vs. 47%, respectively). We found no impact of hyperoxia on the stage of embryonic death, hatching success, hatchling phenotype, exercise performance, or early dispersal. Our findings indicate that delayed nesting and the subsequent extension of embryonic arrest may negatively impact embryonic development and therefore the reproductive success of leatherbacks. They also indicate that incubation under hyperoxic conditions is unlikely to be a useful method to improve hatching success in this species.

Maybe the various forms of kidney disease are not so mechanistically different?

Sieckmann and colleagues provide evidence of a common abnormality in polyamine metabolism in 11 different rodent models of acute kidney injury and chronic kidney disease, and in human renal transplantation. The abnormality is characterized by downregulation of enzymes involved in polyamine synthesis and/or upregulation of enzymes involved in polyamine metabolism. Therefore, polyamine metabolism is a potential target for development of pharmacotherapies for a broad range of kidney diseases.

Combining general and central measures of adiposity to identify risk of hypertension: a cross-sectional survey in rural India.

AIM: In three socioeconomically diverse regions of rural India, we determined the optimal cut-offs for definition of overweight, the prevalence of overweight, and the relationships between measures of overweight and risk of hypertension. SUBJECTS AND METHODS: Villages were randomly sampled within rural Trivandrum, West Godavari, and Rishi Valley. Sampling of individuals was stratified by age group and sex. Cut-offs for measures of adiposity were compared using area under the receiver operating characteristic curve. Associations between hypertension and definitions of overweight were assessed by logistic regression. RESULTS: Of 11 657 participants (50 % male; median age 45 years), 29.8 % had hypertension. Large proportions were overweight as defined by body mass index (BMI) ≥ 23 kg/m2 (47.7 %), waist circumference (WC) ≥ 90 cm for men or ≥ 80 cm for women (39.6 %), waist-hip ratio (WHR) ≥ 0.9 for men or ≥ 0.8 for women (65.6 %), waist-height ratio (WHtR) ≥ 0.5 (62.5 %), or by BMI plus either WHR, WC or WHtR (45.0 %). All definitions of overweight were associated with hypertension, with optimal cut-offs being at, or close to, the World Health Organization (WHO) Asia-Pacific standards. Having overweight according to both BMI and a measure of central adiposity was associated with approximately twice the risk of hypertension than overweight defined by only one measure. CONCLUSIONS: Overweight, as assessed by both general and central measures, is prevalent in rural southern India. WHO standard cut-offs are appropriate in this setting for assessing risk of hypertension. However, combining BMI with a measure of central adiposity identifies risk of hypertension better than any single measure. The risk of hypertension is significantly greater in those centrally and generally overweight than those overweight by a single measure.

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.

Morbidity and utilisation of healthcare services among people with cardiometabolic disease in three diverse regions of rural India.

OBJECTIVES: To assess the prevalence and determinants of cardiometabolic disease (CMD), and the factors associated with healthcare utilisation, among people with CMD. METHODS: Using a cross-sectional design, 11,657 participants were recruited from randomly selected villages in 3 regions located in Kerala and Andhra Pradesh from 2014 to 2016. Multivariable logistic regression was used to identify factors independently associated with CMD and healthcare utilisation (public or private). RESULTS: Thirty-four per cent (n = 3629) of participants reported having ≥1 CMD, including hypertension (21.6%), diabetes (11.6%), heart disease (5.0%) or chronic kidney disease (CKD) (1.6%). The prevalence of CMD was progressively greater in regions of greater socio-economic position (SEP), ranging from 19.1% to 40.9%. Among those with CMD 41% had sought any medical advice in the last month, with only 19% utilising public health facilities. Among people with CMD, those with health insurance utilised more healthcare (age-gender adjusted odds ratio (AOR) (95% confidence interval (CI)): 1.31 (1.13, 1.51)) as did those who reported accessing private rather than public health services (1.43 (1.23, 1.66)). DISCUSSION: The prevalence of CMD is high in these regions of rural India and is positively associated with indices of SEP. The utilisation of outpatient health services, particularly public services, among those with CMD is low.

Cardiovascular and renal profiles in rat offspring that do not undergo catch-up growth after exposure to maternal protein restriction.

Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non 'growth' (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension.

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

AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Evolution of the glomerulus in a marine environment and its implications for renal function in terrestrial vertebrates.

Nearly a century ago, Homer Smith proposed that the glomerulus evolved to meet the challenge of excretion of water in freshwater vertebrates. This hypothesis has been repeatedly restated in the nephrology and renal physiology literature, even though we now know that vertebrates evolved and diversified in marine (saltwater) environments. A more likely explanation is that the vertebrate glomerulus evolved from the meta-nephridium of marine invertebrates, with the driving force for ultrafiltration being facilitated by the apposition of the filtration barrier to the vasculature (in vertebrates) rather than the coelom (in invertebrates) and the development of a true heart and the more complex vertebrate vascular system. In turn, glomerular filtration aided individual regulation of divalent ions like magnesium, calcium, and sulfate compatible with the function of cardiac and skeletal muscle required for mobile predators. The metabolic cost, imposed by reabsorption of the small amounts of sodium required to drive secretion of these over-abundant divalent ions, was small. This innovation, developed in a salt-water environment, provided a preadaptation for life in freshwater, in which the glomerulus was co-opted to facilitate water excretion, albeit with the additional metabolic demand imposed by the need to reabsorb the majority of filtered sodium. The evolution of the glomerulus in saltwater also provided preadaptation for terrestrial life, where the imperative is conservation of both water and electrolytes. The historical contingencies of this scenario may explain why the mammalian kidney is so metabolically inefficient, with ∼80% of oxygen consumption being used to drive reabsorption of filtered sodium.

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.

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

BACKGROUND: Continuous 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. RESULTS: In 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). CONCLUSIONS: Changes 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.

Increasing hypoxia progressively slows early embryonic development in an oviparous reptile, the green turtle, Chelonia mydas.

Green turtle (Chelonia mydas) embryos are in an arrested state of development when the eggs are laid, but in the presence of oxygen, arrest is broken and development resumes within 12-16 h. However, the precise oxygen level at which embryos break arrest and continue development is not known. To better understand the impact of oxygen concentration on breaking of arrest and early embryonic development, we incubated freshly laid eggs of the green sea turtle for three days at each of six different oxygen concentrations (less than or equal to 1%, 3%, 5%, 7%, 9% and 21%) and monitored the appearance and growth of white spots on the shell, indicative of embryonic development. As reported previously, white spots did not develop on eggs incubated in anoxia (less than or equal to 1% oxygen). For all other treatments, mean time to white spot detection and white spot growth rate varied inversely with oxygen concentration. In nearly all cases the difference between eggs at different oxygen levels was statistically significant (p ≤ 0.05). This suggests that sea turtle embryonic development may respond to oxygen in a dose-dependent manner. Our results indicate that the development of green turtle embryos may be slowed if they are exposed to the most hypoxic conditions reported in mature natural nests.