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.

Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis.

Increased cardiac sympathetic nerve activity (CSNA) is a key feature of heart failure (HF) and is associated with poor outcome. There is evidence that central angiotensinergic mechanisms contribute to the increased CSNA in HF, but the central sites involved are unknown. In an ovine, rapid pacing model of HF, we investigated the contribution of the lamina terminalis and area postrema to the increased CSNA and also the responses to fourth ventricular infusion of the angiotensin type 1 receptor antagonist losartan. Ablation of the area postrema or sham lesion (n = 6/group), placement of lamina terminalis lesion electrodes (n = 5), and insertion of a cannula into the fourth ventricle (n = 6) were performed when ejection fraction was ~ 50%. When ejection fraction was < 40%, recording electrodes were implanted, and after 3 days, resting CSNA and baroreflex control of CSNA were measured before and following lesion of the lamina terminalis, in groups with lesion or sham lesion of the area postrema and before and following infusion of losartan (1.0 mg/h for 5 h) into the fourth ventricle. In conscious sheep with HF, lesion of the lamina terminalis did not significantly change CSNA (91 ± 2 vs. 86 ± 3 bursts/100 heart beats), whereas CSNA was reduced in the group with lesion of the area postrema (89 ± 3 to 45 ± 10 bursts/100 heart beats, P < 0.01) and following fourth ventricular infusion of losartan (89 ± 3 to 48 ± 8 bursts/100 heartbeats, P < 0.01). These findings indicate that the area postrema and brainstem angiotensinergic mechanisms may play an important role in determining the increased CSNA in HF.