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

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

Differential responses of cerebral and renal oxygenation to altered perfusion conditions during experimental cardiopulmonary bypass in sheep.

We tested whether the brain and kidney respond differently to cardiopulmonary bypass (CPB) and to changes in perfusion conditions during CPB. Therefore, in ovine CPB, we assessed regional cerebral oxygen saturation (rSO2 ) by near-infrared spectroscopy and renal cortical and medullary tissue oxygen tension (PO2 ), and, in some protocols, brain tissue PO2 , by phosphorescence lifetime oximetry. During CPB, rSO2 correlated with mixed venous SO2 (r = 0.78) and brain tissue PO2 (r = 0.49) when arterial PO2 was varied. During the first 30 min of CPB, brain tissue PO2 , rSO2 and renal cortical tissue PO2 did not fall, but renal medullary tissue PO2 did. Nevertheless, compared with stable anaesthesia, during stable CPB, rSO2 (66.8 decreasing to 61.3%) and both renal cortical (90.8 decreasing to 43.5 mm Hg) and medullary (44.3 decreasing to 19.2 mm Hg) tissue PO2 were lower. Both rSO2 and renal PO2 increased when pump flow was increased from 60 to 100 mL kg-1 min-1 at a target arterial pressure of 70 mm Hg. They also both increased when pump flow and arterial pressure were increased simultaneously. Neither was significantly altered by partially pulsatile flow. The vasopressor, metaraminol, dose-dependently decreased rSO2 , but increased renal cortical and medullary PO2 . Increasing blood haemoglobin concentration increased rSO2 , but not renal PO2 . We conclude that both the brain and kidney are susceptible to hypoxia during CPB, which can be alleviated by increasing pump flow, even without increasing arterial pressure. However, increasing blood haemoglobin concentration increases brain, but not kidney oxygenation, whereas vasopressor support with metaraminol increases kidney, but not brain oxygenation.

Time definition of reintubation most relevant to patient outcomes in critically ill patients: a multicenter cohort study.

BACKGROUND: Reintubation is a common complication in critically ill patients requiring mechanical ventilation. Although reintubation has been demonstrated to be associated with patient outcomes, its time definition varies widely among guidelines and in the literature. This study aimed to determine the association between reintubation and patient outcomes as well as the consequences of the time elapsed between extubation and reintubation on patient outcomes. METHODS: This was a multicenter retrospective cohort study of critically ill patients conducted between April 2015 and March 2021. Adult patients who underwent mechanical ventilation and extubation in intensive care units (ICUs) were investigated utilizing the Japanese Intensive Care PAtient Database. The primary and secondary outcomes were in-hospital and ICU mortality. The association between reintubation and clinical outcomes was studied using Cox proportional hazards analysis. Among the patients who underwent reintubation, a Cox proportional hazard analysis was conducted to evaluate patient outcomes according to the number of days from extubation to reintubation. RESULTS: Overall, 184,705 patients in 75 ICUs were screened, and 1849 patients underwent reintubation among 48,082 extubated patients. After adjustment for potential confounders, multivariable analysis revealed a significant association between reintubation and increased in-hospital and ICU mortality (adjusted hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.359-1.700, and adjusted HR 1.325, 95% CI 1.076-1.633, respectively). Among the reintubated patients, 1037 (56.1%) were reintubated within 24 h after extubation, 418 (22.6%) at 24-48 h, 198 (10.7%) at 48-72 h, 111 (6.0%) at 72-96 h, and 85 (4.6%) at 96-120 h. Multivariable Cox proportional hazard analysis showed that in-hospital and ICU mortality was highest in patients reintubated at 72-96 h (adjusted HR 1.528, 95% CI 1.062-2.197, and adjusted HR 1.334, 95% CI 0.756-2.352, respectively; referenced to reintubation within 24 h). CONCLUSIONS: Reintubation was associated with a significant increase in in-hospital and ICU mortality. The highest mortality rates were observed in patients who were reintubated between 72 and 96 h after extubation. Further studies are warranted for the optimal observation of extubated patients in clinical practice and to strengthen the evidence for mechanical ventilation.

Dynamic responses of renal oxygenation at the onset of cardiopulmonary bypass in sheep and man.

INTRODUCTION: The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. METHODS: We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. RESULTS: In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 ±6 mmHg within 20-30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. CONCLUSIONS: Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.

Incidence and management of metabolic acidosis with sodium bicarbonate in the ICU: An international observational study.

BACKGROUND: Metabolic acidosis is a major complication of critical illness. However, its current epidemiology and its treatment with sodium bicarbonate given to correct metabolic acidosis in the ICU are poorly understood. METHOD: This was an international retrospective observational study in 18 ICUs in Australia, Japan, and Taiwan. Adult patients were consecutively screened, and those with early metabolic acidosis (pH < 7.3 and a Base Excess < -4 mEq/L, within 24-h of ICU admission) were included. Screening continued until 10 patients who received and 10 patients who did not receive sodium bicarbonate in the first 24 h (early bicarbonate therapy) were included at each site. The primary outcome was ICU mortality, and the association between sodium bicarbonate and the clinical outcomes were assessed using regression analysis with generalized linear mixed model. RESULTS: We screened 9437 patients. Of these, 1292 had early metabolic acidosis (14.0%). Early sodium bicarbonate was given to 18.0% (233/1292) of these patients. Dosing, physiological, and clinical outcome data were assessed in 360 patients. The median dose of sodium bicarbonate in the first 24 h was 110 mmol, which was not correlated with bodyweight or the severity of metabolic acidosis. Patients who received early sodium bicarbonate had higher APACHE III scores, lower pH, lower base excess, lower PaCO2, and a higher lactate and received higher doses of vasopressors. After adjusting for confounders, the early administration of sodium bicarbonate was associated with an adjusted odds ratio (aOR) of 0.85 (95% CI, 0.44 to 1.62) for ICU mortality. In patients with vasopressor dependency, early sodium bicarbonate was associated with higher mean arterial pressure at 6 h and an aOR of 0.52 (95% CI, 0.22 to 1.19) for ICU mortality. CONCLUSIONS: Early metabolic acidosis is common in critically ill patients. Early sodium bicarbonate is administered by clinicians to more severely ill patients but without correction for weight or acidosis severity. Bicarbonate therapy in acidotic vasopressor-dependent patients may be beneficial and warrants further investigation.

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

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.

Renal hemodynamics and oxygenation during experimental cardiopulmonary bypass in sheep under total intravenous anesthesia.

Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass (CPB). When performed under volatile (isoflurane) anesthesia in sheep, CPB causes renal medullary hypoxia. There is evidence that total intravenous anesthesia (TIVA) may preserve renal perfusion and renal oxygen delivery better than volatile anesthesia. Therefore, we assessed the effects of CPB on renal perfusion and oxygenation in sheep under propofol/fentanyl-based TIVA. Sheep (n = 5) were chronically instrumented for measurement of whole renal blood flow and cortical and medullary perfusion and oxygenation. Five days later, these variables were monitored under TIVA using propofol and fentanyl and then on CPB at a pump flow of 80 mL·kg-1·min-1 and target mean arterial pressure of 70 mmHg. Under anesthesia, before CPB, renal blood flow was preserved under TIVA (mean difference ± SD from conscious state: -16 ± 14%). However, during CPB renal blood flow was reduced (-55 ± 13%) and renal medullary tissue became hypoxic (-20 ± 13 mmHg versus conscious sheep). We conclude that renal perfusion and medullary oxygenation are well preserved during TIVA before CPB. However, CPB under TIVA leads to renal medullary hypoxia, of a similar magnitude to that we observed previously under volatile (isoflurane) anesthesia. Thus use of propofol/fentanyl-based TIVA may not be a useful strategy to avoid renal medullary hypoxia during CPB.

Systemic haemodynamic, renal perfusion and renal oxygenation responses to changes in inspired oxygen fraction during total intravenous or volatile anaesthesia.

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.

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

Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg-1min-1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg-1min-1, while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg-1min-1. CPB at 80 mL kg-1min-1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary Po2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary Po2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po2 from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol.

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.

Sepsis-induced acute kidney injury: A disease of the microcirculation.

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.

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

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.

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.

Renal perfusion, oxygenation, and sympathetic nerve activity during volatile or intravenous general anaesthesia in sheep.

BACKGROUND: Global and intra-renal perfusion and oxygenation may be affected by the choice of anaesthetic. We compared the effects of isoflurane with those of propofol and fentanyl on renal blood flow (RBF) and intra-renal perfusion and oxygenation, and assessed how these were associated with renal sympathetic nerve activity (RSNA). METHODS: A renal artery flow probe and laser Doppler and oxygen-sensing probes were surgically implanted in the renal medulla and cortex in 20 Merino ewes. RSNA was measured in 12 additional ewes. We compared the effects of volatile or i.v. anaesthesia on global RBF, renal oxygen delivery (RDO2), intra-renal perfusion, and RSNA with the non-anaesthetised state on postoperative day 3 as control reference. RESULTS: Compared with a non-anaesthetised state, volatile anaesthesia reduced global RBF [-76 (82-68)%], RDO2 [-76 (83-71)%], and cortical [-68 (74-54)%] and medullary [-76 (84-72)%] perfusion. I.V. anaesthesia reduced RBF [-55 (67-38)%], RDO2 [-55 (65-44)%], and cortical [-27 (45-6)%] and medullary [-35 (48-30)%] perfusion, but to a lesser extent than volatile anaesthesia. Renal PO2 was not influenced by anaesthesia, whilst RSNA was elevated during volatile, but not during i.v. anaesthesia. CONCLUSIONS: Volatile and i.v. general anaesthesia markedly reduced global RBF, RDO2, and regional kidney perfusion. These effects were greater with volatile anaesthesia, and were paralleled by an increase in RSNA. Our findings suggest a neurogenic modulatory effect of anaesthetics on renal perfusion and oxygenation.

Effect of Furosemide on Urinary Oxygenation in Patients with Septic Shock.

BACKGROUND: Renal medullary hypoxia precedes the development of acute kidney injury in experimental sepsis and can now be assessed by continuous measurement of urinary oxygen tension (PuO2). OBJECTIVES: We aimed to test if PuO2 measurements in patients with septic shock would be similar to those shown in experimental sepsis and would detect changes induced by the administration of furosemide. METHOD: Pilot prospective observational cohort study in a tertiary intensive care unit (ICU). Seven adult patients with septic shock admitted to ICU had PuO2 measurements recorded minutely. There were 29 episodes of intravenous furosemide (20 mg n = 19; 40 mg n = 10). RESULTS: The median pre-furosemide PuO2 was low at 21.2 mm Hg (interquartile range [IQR] 17.73-24.86) and increased to 26 mm Hg (IQR 20.27-29.95) at 20 min (p < 0.01), to 27.5 mm Hg (IQR 24.06-33.18) at 40 min (p < 0.01) and to 28.5 mm Hg (IQR 22.65-31.03) at 60 min (p < 0.01). The increase in PuO2 was greater in episodes with a diuretic response >2 mL/kg/h than during episodes without such a response (p < 0.01). CONCLUSIONS: PuO2 measurements in patients are reflective of the low values reported in experimental models of sepsis. PuO2 values increased following furosemide administration with a response independently associated with greater diuresis.

Alterations in regional kidney oxygenation during expansion of extracellular fluid volume in conscious healthy sheep.

Expansion of extracellular fluid volume with crystalloid solutions is a common medical intervention, but its effects on renal cortical and medullary oxygenation are poorly understood. Therefore, we instrumented sheep under general anesthesia to enable continuous measurement of systemic and renal hemodynamics, global renal oxygen delivery and consumption, and intrarenal tissue perfusion and oxygen tension (Po2) in conscious animals ( n = 7). The effects of three sequential intermittent infusions of 500 ml of compound sodium lactate solution, administered at hourly intervals, were determined. Volume expansion induced transient increases in mean arterial pressure (+7 ± 2%), central venous pressure (+50 ± 19%), and cardiac output (+15 ± 3%). There were sustained increases in renal medullary tissue Po2 (+35 ± 10%) despite increases in global renal oxygen consumption (+66 ± 18%) and renal oxygen extraction (+64 ± 8%). Volume expansion did not significantly alter renal blood flow, renal oxygen delivery, or medullary perfusion. The sustained increase in medullary Po2 was paralleled by increased bladder urine Po2 (34 ± 4%). Cortical perfusion and Po2 did not change significantly. Our findings indicate that extracellular fluid volume expansion can increase renal medullary oxygenation, providing a potential mechanistic basis for its use as prophylaxis against iatrogenic acute kidney injury. They also indicate that continuous measurement of bladder urine Po2 could be used to monitor the effects of volume expansion on medullary oxygenation. However, the mechanisms mediating increased medullary oxygenation during volume expansion remain to be determined.

Neutrophil gelatinase-associated lipocalin and liver-type fatty acid-binding protein as biomarkers for acute kidney injury after organ transplantation.

PURPOSE: Neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) are promising early biomarkers for acute kidney injury (AKI). In organ transplant recipients, AKI predictability based on NGAL and L-FABP remains to be elucidated. Furthermore, the association between serial NGAL and L-FABP measurements and AKI outcome is unknown. Therefore, we conducted a study to evaluate the ability of NGAL and L-FABP to predict AKI after organ transplantation and investigate the association between NGAL, L-FABP and AKI outcome. METHODS: Twenty-five organ transplant recipients admitted to the intensive care unit (ICU) immediately after transplant surgery were studied prospectively. Plasma NGAL (P-NGAL), urinary NGAL (U-NGAL) and L-FABP were measured from ICU admission to ICU discharge. U-NGAL and L-FABP were corrected for dilution/concentration by calculating U-NGAL/urine creatinine ratios (U-NGAL/Cr) and L-FABP/urine creatinine ratios (L-FABP/Cr). AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria. RESULTS: AKI occurred in 11 patients. P-NGAL, U-NGAL/Cr and L-FABP/Cr upon ICU admission were unrelated to AKI development (p = 0.24, 0.22, and 0.53, respectively). There were no differences in P-NGAL, U-NGAL/Cr, and L-FABP/Cr levels from day 1 to day 6 between patients who did not recover from AKI and patients who recovered from AKI (p = 0.82, 0.26, and 0.61, respectively). CONCLUSION: Our findings suggest that NGAL and L-FABP upon ICU admission are not predictive of AKI and serial NGAL and L-FABP measurements may be ineffective for monitoring the status and treatment of post-transplantation AKI.

Effects of adherence to ventilator-associated pneumonia treatment guidelines on clinical outcomes.

Two guidelines are currently available to guide Japanese clinicians caring for patients with ventilator-associated pneumonia (VAP): the 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines or the 2008 Japanese Respiratory Society (JRS) guidelines. We aimed to measure compliance with guideline recommendations for VAP in Japanese intensive care units (ICUs) and to assess the effects of guideline-compliant treatment on outcomes. We retrospectively reviewed the records of all patients with microbiologically confirmed VAP in five Japanese ICUs between January 1, 2006, and December 31, 2009. We evaluated whether empiric antibiotic prescriptions were guideline compliant and correlated compliance with clinical outcomes. Among the 95 patients with VAP who were included, 85 patients received empiric antibiotics. Of these, therapy of 62 patients (73 %) was appropriate based on in vitro sensitivity testing. Using ATS/IDSA criteria, 16 patients (19 %) received guideline-compliant therapy and 69 patients (81 %) received noncompliant treatment. Using JRS criteria, 24 patients (28 %) received guideline-compliant therapy and 61 patients (72 %) received noncompliant treatment. All-cause 28-day mortality was 24 %. When compared to patients who received noncompliant therapy, there were no differences in 28-day mortality rates for patients who received ATS/IDSA guideline-compliant regimens (25 vs. 25 %, p = 1.00) or JRS guideline-compliant regimens (21 vs. 26 %, p = 0.78). Our study demonstrates poor compliance with guideline-recommended antibiotic therapy for VAP in Japanese ICUs. Compliance with current VAP guidelines was not associated with increased rates of appropriate antibiotic treatment or improved 28-day mortality.

Association between tracheostomy and survival in patients with coronavirus disease 2019 who require prolonged mechanical ventilation for more than 14 days: A multicenter cohort study.

OBJECTIVE: Tracheostomy is a common procedure with potential prognostic advantages for patients who require prolonged mechanical ventilation (PMV). Early recommendations for patients with coronavirus disease 2019 (COVID-19) suggested delayed or limited tracheostomy considering the risk for viral transmission to clinicians. However, updated guidelines for tracheostomy with appropriate personal protective equipment have revised its indications. This study aimed to evaluate the association between tracheostomy and prognosis in patients with COVID-19 requiring PMV. METHODS: This was a multicenter, retrospective cohort study using data from the nationwide Japanese Intensive Care PAtient Database. We included adult patients aged ≥16 years who were admitted to the intensive care unit (ICU) due to COVID-19 and who required PMV (for >14 days or until performance of tracheostomy). The primary outcome was hospital mortality, and the association between implementation of tracheostomy and patient prognosis was assessed using weighted Cox proportional hazards regression analysis with inverse probability of treatment weighting (IPTW) using the propensity score to address confounders. RESULTS: Between January 2020 and February 2021, 453 patients with COVID-19 were observed. Data from 109 patients who required PMV were analyzed: 66 (60.6%) underwent tracheostomy and 38 (34.9%) died. After adjusting for potential confounders using IPTW, tracheostomy implementation was found to significantly reduce hospital mortality (hazard ratio [HR]: 0.316, 95% confidence interval [CI]: 0.163-0.612). Patients who underwent tracheostomy had a similarly decreased ICU and 28-day mortality (HR: 0.269, 95% CI: 0.124-0.581; HR 0.281, 95% CI: 0.094-0.839, respectively). A sensitivity analysis using different definitions of PMV duration consistently showed reduced mortality in patients who underwent tracheostomy. CONCLUSION: The implementation of tracheostomy was associated with favorable patient prognosis among patients with COVID-19 requiring PMV. Our findings support proactive tracheostomy in critically ill patients with COVID-19 requiring mechanical ventilation for >14 days.