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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.
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Acetazolamida , Amilorida , Diuréticos , Furosemida , Córtex Renal , Medula Renal , Animais , Furosemida/farmacologia , Acetazolamida/farmacologia , Amilorida/farmacologia , Diuréticos/farmacologia , Ovinos , Feminino , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Oxigênio/metabolismo , Hemodinâmica/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacosRESUMO
BACKGROUND: The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis. METHODS: Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg-1 over 30 min+0.5 g kg-1 h-1 for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70-80 mm Hg. RESULTS: At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] µM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all PTreatment<0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both PGroupxTime<0.01), and increased plasma ascorbate (20 000 [300] µM; PGroup<0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate. CONCLUSIONS: Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.
Assuntos
Ácido Ascórbico , Sepse , Animais , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Sepse/complicações , Sepse/metabolismo , Sepse/tratamento farmacológico , Feminino , Ovinos , Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , Hipóxia/metabolismo , Antioxidantes/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacosRESUMO
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.
Assuntos
Ponte Cardiopulmonar , Metaraminol , Ovinos , Animais , Ponte Cardiopulmonar/efeitos adversos , Oxigênio , Rim , Vasoconstritores , Perfusão , HemoglobinasRESUMO
Patients diagnosed with heart failure have high rates of mortality and morbidity. Based on promising preclinical studies, vagal nerve stimulation has been trialled in these patients using whole nerve electrical stimulation, but the results have been mixed. This is, at least in part, due to an inability to selectively recruit the activity of specific fibres within the vagus with whole nerve electrical stimulation, as well as not knowing which the 'therapeutic' fibres are. This symposium review focuses on a population of cardiac-projecting efferent vagal fibres with cell bodies located within the dorsal motor nucleus of the vagus nerve and a new method of selectively targeting these projections as a potential treatment in heart failure. NEW FINDINGS: What is the topic of this review? Selective efferent vagal stimulation in heart failure. What advances does it highlight? Selectively targeting a population of cardiac-projecting efferent vagal fibres with cell bodies within the dorsal motor nucleus of the vagus using optogenetics slows the progression of heart failure in rats.
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BACKGROUND: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. METHODS: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. RESULTS: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. CONCLUSION: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.
Assuntos
Sepse , Choque Séptico , Humanos , Choque Séptico/complicações , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Austrália , Sepse/complicações , Método Duplo-Cego , Vasoconstritores/uso terapêuticoRESUMO
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.
Assuntos
Ponte Cardiopulmonar , Doenças Neuroinflamatórias , Animais , Feminino , Ponte Cardiopulmonar/efeitos adversos , Citocinas , Interleucina-6 , Doenças Neuroinflamatórias/etiologia , Ovinos , Modelos Animais de DoençasRESUMO
INTRODUCTION: Hemoadsorption has emerged as an adjunctive therapy for sepsis, but its impact on antibiotic levels remains poorly defined. We conducted an in vivo experimental study to investigate the removal of vancomycin and gentamicin during hemoadsorption using the HA380 cartridge, a novel styrene-divinylbenzene copolymer cartridge. METHODS: Six surgically prepared sheep were administered 2 g of vancomycin and 400 mg of gentamicin over 30 min, followed by a continuous infusion of vancomycin (20 mg/h). Hemoadsorption was implemented with a styrene-divinylbenzene copolymer HA380 cartridge at a blood flow of 120 mL/min. The removal ratio, sorbent-based clearance, and the mass removal rate were calculated for each time point. RESULTS: The mean 10-min vancomycin removal ratio exceeded 90% and declined to 68.0% at 30 min; 52.8% at 60 min, and 28.0% by 4 h. Due to constant plasma flow, clearance varied proportionally with the removal ratio. Over 4 hours, the total mass removal was 556 mg (SD 106.3). For gentamicin, the mean 10-min removal ratio was 96.9% and the final ratio at 4 h remained 53.0%, with clearances changing proportionately. The total mass removal of gentamicin was 138 mg (SD 26.6) over 4 h. The sorbent-based clearance of vancomycin was significantly lower than that of gentamicin (Pgroup < 0.0001). CONCLUSION: The novel HA380 sorbent cartridge appears safe and achieves significant vancomycin and gentamicin removal over a four-hour period. This information can be used by clinicians to guide their prescription and consider the additional dosing of at least an extra 25-35% amount in patients receiving HA380 hemoadsorption therapy during sepsis.
Assuntos
Sepse , Vancomicina , Humanos , Animais , Ovinos , Gentamicinas , Antibacterianos , Sepse/terapia , EstirenosRESUMO
Perioperative hypotension is common and associated with poor outcomes, including acute kidney injury (AKI). The mechanistic link between perioperative hypotension and AKI is at least partly a consequence of the susceptibility of the kidney, and particularly the renal medulla, to ischaemia and hypoxia. Several critical gaps in our knowledge lead to uncertainty about when and how to intervene to prevent AKI attributable to perioperative hypotension. First, although we know that the risk of AKI varies with both the severity and duration of hypotensive episodes, 'safe' levels of arterial pressure have not been identified. Second, there have been few adequately powered clinical trials of interventions to avoid perioperative hypotension. Thus, most evidence surrounding perioperative hypotension is observational rather than based on randomised clinical trials. This means that the link between perioperative hypotension and AKI may represent association (where both phenomena reflect illness severity) rather than causation. Third, there is little information regarding the relative risks and benefits of various clinically available therapies (e.g. vasoconstrictors, i.v. fluids, or both) to treat and prevent perioperative hypotension, particularly with regard to renal medullary perfusion and oxygenation. Fourth, there are currently no validated, clinically feasible methods for real-time clinical monitoring of renal perfusion or oxygenation. Thus, future developments in perioperative kidney-protective strategies must rely on the development of methods to better monitor renal perfusion and oxygenation in the perioperative period, and thereby guide timing, intensity, type, and duration of interventions.
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Injúria Renal Aguda , Hipotensão , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Pressão Arterial , Humanos , Hipotensão/etiologia , Hipotensão/prevenção & controle , Rim , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Vasoconstritores/uso terapêuticoRESUMO
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.
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Injúria Renal Aguda , Ponte Cardiopulmonar , Animais , Humanos , Hipóxia , Medula Renal/irrigação sanguínea , Oxigênio , OvinosRESUMO
OBJECTIVES: 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. DESIGN: Interventional study. SETTING: Research Institute. SUBJECTS: Adult Merino ewes. INTERVENTIONS: 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). MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.
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Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Bacteriemia/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , OvinosRESUMO
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.
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Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Infecções por Escherichia coli/fisiopatologia , Hipóxia Encefálica/fisiopatologia , Rim/irrigação sanguínea , Consumo de Oxigênio , Oxigênio/sangue , Sepse/fisiopatologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/microbiologia , Injúria Renal Aguda/fisiopatologia , Animais , Ritmo Circadiano , Modelos Animais de Doenças , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/microbiologia , Feminino , Tecnologia de Fibra Óptica , Hipóxia Encefálica/sangue , Hipóxia Encefálica/microbiologia , Circulação Renal , Sepse/sangue , Sepse/microbiologia , Carneiro Doméstico , Fatores de TempoRESUMO
OBJECTIVES: 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. DESIGN: Interventional Study. SETTING: Research Institute. SUBJECTS: Adult Merino ewes. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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%). CONCLUSIONS: 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.
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Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Norepinefrina/farmacologia , Sepse/complicações , Vasoconstritores/farmacologia , Vasopressinas/farmacologia , Animais , Pressão Arterial , Modelos Animais de Doenças , Feminino , Hemodinâmica , Rim/irrigação sanguínea , Testes de Função Renal , OvinosRESUMO
Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a "renal reserve," which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.
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Injúria Renal Aguda/fisiopatologia , Aminoácidos/metabolismo , Proteínas Alimentares/metabolismo , Taxa de Filtração Glomerular , Rim/irrigação sanguínea , Rim/metabolismo , Circulação Renal , Insuficiência Renal Crônica/fisiopatologia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Adaptação Fisiológica , Aminoácidos/administração & dosagem , Animais , Humanos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/metabolismoRESUMO
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.
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Injúria Renal Aguda/etiologia , Anestesia Intravenosa , Ponte Cardiopulmonar/efeitos adversos , Hemodinâmica , Hipóxia/etiologia , Medula Renal/irrigação sanguínea , Oxigênio/sangue , Propofol/administração & dosagem , Circulação Renal , Injúria Renal Aguda/sangue , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/prevenção & controle , Anestésicos Intravenosos/administração & dosagem , Animais , Biomarcadores/sangue , Fentanila/administração & dosagem , Hipóxia/sangue , Hipóxia/fisiopatologia , Hipóxia/prevenção & controle , Modelos Animais , Fatores de Proteção , Fatores de Risco , Carneiro Doméstico , Fatores de TempoRESUMO
BACKGROUND: Anaesthesia-induced changes in renal perfusion are dependent on the choice of anaesthetic agent. However, the effects of varying inspired oxygen fraction (FiO2) on renal perfusion and oxygenation during TIVA (propofol + fentanyl) or volatile anaesthesia (VA; isoflurane) are unknown. METHODS: In 16 Merino ewes, we surgically implanted a renal artery flow probe and laser-Doppler and oxygen-sensing probes in the renal medulla and cortex. We compared the systemic and renal effects of graded alterations in FiO2 (0.21, 0.40, 0.60, and 1.0) during TIVA or VA and compared the changes with those in the non-anaesthetised state. RESULTS: Compared with the non-anaesthetised state, TIVA and VA decreased renal blood flow (-50% vs -75%), renal oxygen delivery (-50% vs -80%), and renal cortical (-40% vs -60%) and medullary perfusion (-50% vs -75%). At an FiO2 of 0.21, both anaesthetic regimens induced similar reductions in cortical (-58 vs -65%) and medullary (-37% vs -38%) oxygenation. At higher concentrations of FiO2, renal blood flow and renal tissue perfusion were not changed, but intrarenal oxygenation improved similarly under TIVA and VA. In particular, at an FiO2 of ≥0.40 and ≤0.60, cortical and medullary oxygen tension were similar to the non-anaesthetised state. CONCLUSIONS: Irrespective of FiO2, TIVA decreased renal and intrarenal perfusion less than VA, but at low FiO2 concentrations both led to equivalent reductions in renal cortical and medullary oxygenation. However, with FiO2 between 0.40 and 0.60 during TIVA or VA, both cortical and medullary oxygenation was maintained at normal physiological levels.
Assuntos
Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Hemodinâmica/efeitos dos fármacos , Oxigênio/metabolismo , Circulação Renal/efeitos dos fármacos , Animais , Feminino , Fentanila , Isoflurano/farmacologia , Modelos Animais , Propofol/farmacologia , OvinosRESUMO
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.
Assuntos
Injúria Renal Aguda/prevenção & controle , Ponte Cardiopulmonar/efeitos adversos , Medula Renal/irrigação sanguínea , Complicações Pós-Operatórias/prevenção & controle , Vasoconstritores/administração & dosagem , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Pressão Arterial/efeitos dos fármacos , Ponte Cardiopulmonar/instrumentação , Ponte Cardiopulmonar/métodos , Hipóxia Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Medula Renal/patologia , Metaraminol/administração & dosagem , Oxigênio/metabolismo , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia , OvinosRESUMO
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.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Agonistas alfa-Adrenérgicos/uso terapêutico , Dexmedetomidina/uso terapêutico , Norepinefrina/uso terapêutico , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Citocinas/sangue , Dexmedetomidina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Escherichia coli , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Norepinefrina/farmacologia , Oxigênio/metabolismo , Sepse/complicações , OvinosRESUMO
AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48 hours, the defects may be functional rather than structural in nature. For example, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α2 -adrenergic receptor agonists (clonidine and dexmedetomidine) may be feasible adjunct therapies for catecholamine-resistant vasodilatory shock. In this review, we outline the recent progress made in understanding how these drugs may influence the renal microcirculation, which represents a crucial step toward developing better approaches for the circulatory management of patients with septic AKI.
Assuntos
Injúria Renal Aguda/etiologia , Microcirculação , Sepse/complicações , Injúria Renal Aguda/mortalidade , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Humanos , Rim/irrigação sanguínea , Rim/fisiopatologia , Sepse/mortalidade , Vasoconstritores/uso terapêuticoRESUMO
OBJECTIVES: 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. DESIGN: Interventional study. SETTING: Research institute. SUBJECTS: Adult Merino ewes. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Injúria Renal Aguda/terapia , Hidratação , Oxigênio/metabolismo , Circulação Renal , Sepse/terapia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/microbiologia , Animais , Pressão Sanguínea , Débito Cardíaco , Pressão Venosa Central , Creatinina/análise , Modelos Animais de Doenças , Escherichia coli , Infecções por Escherichia coli/complicações , Rim/metabolismo , Sepse/microbiologia , OvinosRESUMO
In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α1-adrenoceptors. In conscious sheep with mild HF (ejection fraction 35%-40%), renal blood flow (276 ± 13 to 185 ± 18 mL/min) and renal vascular conductance (3.8 ± 0.2 to 3.1 ± 0.2 mL·min-1·mmHg-1) were decreased compared with healthy sheep. There were increases in the burst frequency of RSNA (27%), renal norepinephrine spillover (377%), and plasma renin activity (141%), whereas the density of renal medullary angiotensin type-1 receptors decreased. In anesthetized sheep with HF, the renal vasoconstrictor responses to electrical stimulation of the renal nerves or to phenylephrine were attenuated. Irbesartan improved the responses to nerve stimulation, but not to phenylephrine, in HF and reduced the responses in normal sheep. In summary, in HF, the increases in renal norepinephrine spillover and plasma renin activity are augmented compared with the increase in RSNA. The vasoconstrictor effect of the increased renal norepinephrine and angiotensin II is offset by reduced levels of renal angiotensin type-1 receptors and reduced renal vasoconstrictor responsiveness to α1-adrenoceptor stimulation.