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.     

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.     

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α₂-agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4–0.8 μg.kg^-1.h^-1) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24–7.23) to 1.56 (0.84–2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33–7.07) to 1.51 (0.33–2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0–3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1–2 [0–3]) vs. 0 (0–0.3 [0–1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.     

Modulatory action of noradrenergic system on spinal motoneurons in humans.

Previous findings in animals demonstrated that the noradrenergic coeruleospinal system exerts a tonic facilitation on spinal reflexes and that activation of alpha2-autoinhibitory receptors can be responsible for a disfacilitation of the spinal activity. To investigate this issue further, we examined whether this system is also involved in descending facilitatory control of spinal motoneurons in healthy humans. The H-reflex technique was utilized to assay the motoneuronal excitability. The ratio between the maximal reflex response (H) and maximal direct response (M) was determined in each subject and was calculated at 10 min intervals before and after i.v. administration of the alpha2-agonist clonidine (0.5 microg/kg). In all subjects a marked decrease of the H/M ratio, due to depression of the H response, occurred 10 min following the clonidine injection and reached its maximum within 30 min. No significant changes of blood pressure values were provoked by drug injections. These results suggest that an autoinhibitory action may be induced by alpha2-receptor activation of locus coeruleus neurons in humans, and that this device may serve as a mechanism for a myotonolytic action on spinal motoneurons.     

Immunohistochemical modifications of vasoactiveneuropeptides and excitatory amino acids in the nervoustissue of the mongolian gerbil after transient cerebralischemia

Modifications in the tissue concentration of vasoactive peptides (Endothelin,Calcitonin Gene Related Peptide, Atrial Natriuretic Peptide) and excitatory amino acids(glutamate, aspartate) were found in the nervous tissue of Mongolian gerbils after transientcerebral ischemia which was induced by unilateral occlusion of the common carotid artery for 30min–4 h. In fact, immunostaining for these peptides was more intense in the ischemic tissue : thegreatest increases of tissue immunoreactivity were observed for Endothelin ; smaller differenceswere found for Calcitonin Gene Related Peptide and Atrial Natriuretic Peptide. Immunostainingfor Neuropeptide Y, another vasoactive neuropeptide, was virtually unchanged. Infarct areas,when present, contained numerous Endothelin-immunoreactive cell bodies. On the contrary, thesame areas were completely void of glutamate- or aspartate-immunostained neurons, normallypresent in the correspondent regions of the control tissue. The present results suggest that severecerebral ischemia is paralleled by an unbalance of local vasoactive factors. The predominance ofvasoconstrictor action of Endothelin might play a major role in the irreversible damage, togetherwith the excitotoxic effect of the extracellular accumulation of excitatory amino acids, probablydue to a leakage from neuronal cell somata, as suggested by the disappearance of glutamate- oraspartate-immunostained neurons.     

Bench-to-bedside review: Chloride in critical illness

Chloride is the principal anion in the extracellular fluid and is the second main contributor to plasma tonicity. Its concentration is frequently abnormal in intensive care unit patients, often as a consequence of fluid therapy. Yet chloride has received less attention than any other ion in the critical care literature. New insights into its physiological roles have emerged together with progress in understanding the structures and functions of chloride channels. In clinical practice, interest in a physicochemical approach to acid-base physiology has directed renewed attention to chloride as a major determinant of acid-base status. It has also indirectly helped to generate interest in other possible effects of disorders of chloraemia. The present review summarizes key aspects of chloride physiology, including its channels, as well as the clinical relevance of disorders of chloraemia. The paper also highlights current knowledge on the impact of different types of intravenous fluids on chloride concentration and the potential effects of such changes on organ physiology. Finally, the review examines the potential intensive care unit practice implications of a better understanding of chloride.