Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

Lankadeva, Yugeesh R.; Ma, Shuai; Iguchi, Naoya; Evans, Roger G.; Hood, Sally G.; Farmer, David G.S.; Bailey, S. R.; Bellomo, Rinaldo; May, Clive

doi:10.1016/j.kint.2019.06.013

Cited by 46 publications

(51 citation statements)

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“…As alpha-2 agonist, dexmedetomidine may increase the risk of hypotension and bradycardia [14,15] and, in patients with septic shock, this may be both dangerous and harmful. However, experimental data also suggest that dexmedetomidine can be administered in septic shock and may even have catecholamine-sparing effects [5,[16][17][18][19][20][21]. Our findings are consistent with such experimental observations.…”

Section: Discussionsupporting

confidence: 90%

“…In animal models of sepsis, high doses of central alpha2-agonists increase vasopressor responsiveness [5]. Moreover, dexmedetomidine reduces noradrenaline requirements and maintains renal function in experimental septic acute kidney injury [17]. In healthy volunteers, dexmedetomidine decreases plasma levels of both noradrenaline and adrenaline [9].…”

Section: Discussionmentioning

confidence: 99%

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The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial

et al. 2020

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Background: Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting. Methods: In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [μg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4). Results: Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] μg/kg/min in the DEX group and 0.04 [0.01, 0.16] μg/kg/min in the usual care group (p = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial

et al. 2020

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“…After 12 h of baseline measurements, bacteraemia was induced in conscious sheep by an intravenous bolus infusion of live E. coli (2.8 × 10 9 colony-forming units over 30 min). E. coli was cultured from stock derived from a human septic patient, as used in previous studies in this laboratory 18 – 20 , 25 , 26 . Following infusion of E. coli , all sheep received an infusion of isotonic sodium chloride (Baxter, Old Toongabbie, NSW, Australia; 1 mL −1 kg −1 h −1 ) as fluid supplementation.…”

Section: Methodsmentioning

confidence: 99%

Sympathetic nerves control bacterial clearance

Lankadeva

May

McKinley

et al. 2020

Sci Rep

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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.

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“…DEX has shown its anti-inflammatory and antiapoptotic effects in multiple animal models [46][47][48][49][50][51]. As we mentioned above, the anti-inflammatory effect of DEX is achieved by inhibiting the TLR4/NF-κB [47], JAK2-STAT3 [25,50], and NF-κB/COX-2 pathways [27,52]; activating the ERK1/2 pathway [53]; and releasing acetylcholine (ACh) through antisympathetic effects via the cholinergic pathway [13]. At the same time, DEX also reduces neuronal apoptosis through a variety of mechanisms that enhance the viability of the neurocyte.…”

Section: Anti-inflammatory and Antiapoptoticmentioning

confidence: 97%

“…Since then, DEX's organ-protective effects as an anti-inflammatory have become a popular topic. In summary, the anti-inflammatory effects of DEX function through the following means: inhibition of TLR4/NF-κB [13,[22][23][24], JAK2-STAT3 [25,26], and NF-κB/COX-2 [27] pathways. DEX also promotes the release of acetylcholine (ACh) through an antisympathetic effect; this combines with α7nAChR on immune cytomembranes and exerts anti-inflammatory effects via the cholinergic pathway (as in Figure 1) [13,26,28].…”

Section: The Main Biological Effects Of Using Dexmedetomidine For Orgmentioning

confidence: 99%

Organ-Protective Effects and the Underlying Mechanism of Dexmedetomidine

Bao

Tang

2020

Mediators of Inflammation

102

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Dexmedetomidine (DEX) is a highly selective α2 adrenergic receptor (α2AR) agonist currently used in clinical settings. Because DEX has dose-dependent advantages of sedation, analgesia, antianxiety, inhibition of sympathetic nervous system activity, cardiovascular stabilization, and significant reduction of postoperative delirium and agitation, but does not produce respiratory depression and agitation, it is widely used in clinical anesthesia and ICU departments. In recent years, much clinical study and basic research has confirmed that DEX has a protective effect on a variety of organs, including the nervous system, heart, lungs, kidneys, liver, and small intestine. It acts by reducing the inflammatory response in these organs, activating antiapoptotic signaling pathways which protect cells from damage. Therefore, based on wide clinical application and safety, DEX may become a promising clinical multiorgan protection drug in the future. In this article, we review the physiological effects related to organ protection in α2AR agonists along with the organ-protective effects and mechanisms of DEX to understand their combined application value.

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Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

Cited by 46 publications

References 46 publications

The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial

The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial

Sympathetic nerves control bacterial clearance

Organ-Protective Effects and the Underlying Mechanism of Dexmedetomidine

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