Emerging benefits and drawbacks of alpha(2)-adrenoceptor agonists in the management of sepsis and critical illness

Agonists of α₂ -adrenoceptors are increasingly being used for the provision of comfort, sedation and the management of delirium in critically ill patients, with and without sepsis. In this context, increased sympathetic and inflammatory activity are common pathophysiological features linked to multi-organ dysfunction, particularly in patients with sepsis or those undergoing cardiac surgery requiring cardiopulmonary bypass. Experimental and clinical studies support the notion that the α₂ -adrenoceptor agonists, dexmedetomidine and clonidine, mitigate sympathetic and inflammatory overactivity in sepsis and cardiac surgery requiring cardiopulmonary bypass. These effects can protect vital organs, including the cardiovascular system, kidneys, heart and brain. We review the pharmacodynamic mechanisms by whichα₂-adrenoceptor agonists might mitigate multi-organ dysfunction arising from pathophysiological conditions associated with excessive inflammatory and adrenergic stress in experimental studies. We also outline recent clinical trials that have examined the use of dexmedetomidine in critically ill patients with and without sepsis and in patients undergoing cardiac surgery.Yugeesh R. Lankadeva, Yahya Shehabi, Adam M. Deane, Mark P. Plummer, Rinaldo Bellomo, Clive N. Ma

Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass

Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts

Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies

Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2 Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2 Both intravenous infusion of [Phe(2),Ile(3),Orn(8)]-vasopressin and infusion of N(G)-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8-17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po2 during these stimuli correlated strongly with changes in medullary Po2 (within-rabbit r(2) = 0.87-0.90). Differences in the Po2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po2 in the pelvic ureter (presumed to reflect medullary Po2) from known values of bladder urine Po2, urine flow, and arterial Po2 Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1-0.5 ml/min for a single kidney), a change in bladder urine Po2 explains 10-50% of the change in pelvic urine/medullary Po2 Thus, it is possible to infer changes in medullary Po2 from changes in urinary Po2, so urinary Po2 may have utility as a real-time biomarker of risk of acute kidney injury

Sympathetic nerves control bacterial clearance

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection

Urinary and renal oxygenation during dexmedetomidine infusion in critically ill adults with mechanistic insights from an ovine model

Purpose: Examine effects of dexmedetomidine on bladder urinary oxygen tension (PuO₂) in critically ill patients and delineate mechanisms in an ovine model. Materials and methods: In 12 critically ill patients: oxygen-sensing probe inserted in the bladder catheter and dexmedetomidine infusion at a mean (SD) rate of 0.9 ± 0.3 μg/kg/h for 24-h. In 9 sheep: implantation of flow probes around the renal and pulmonary arteries, and oxygen-sensing probes in the renal cortex, renal medulla and bladder catheter; dexmedetomidine infusion at 0.5 μg/kg/h for 4-h and 1.0 μg/kg/h for 4-h then 16 h observation. Results: In patients, dexmedetomidine decreased bladder PuO2at 2 (−Δ11 (95% CI 7–16)mmHg), 8 (−Δ 7 (0.1–13)mmHg) and 24 h (−Δ 11 (0.4–21)mmHg). In sheep, dexmedetomidine at 1 μg/kg/h reduced renal medullary oxygenation (−Δ 19 (14–24)mmHg) and bladder PuO2 (−Δ 12 (7–17)mmHg). There was moderate correlation between renal medullary oxygenation and bladder PuO2; intraclass correlation co-efficient 0.59 (0.34–0.80). Reductions in renal medullary oxygenation were associated with reductions in blood pressure, cardiac output and renal blood flow (P < 0.01). Conclusions: Dexmedetomidine decreases PuO₂in critically ill patients and in sheep. In sheep this reflects a decrease in renal medullary oxygenation, associated with reductions in cardiac output, blood pressure and renal blood flow.Mark P. Plummer, Yugeesh R. Lankadeva, Mark E. Finnis, Anatole Harrois, Charlie Harding, Rachel M. Peiris, Nobuki Okazaki, Clive N. May, Roger G. Evans, Christopher M. Macisaac, Deborah Barge, Rinaldo Bellomo, Adam M. Dean