Abstract
BackgroundSeptic shock remains associated with significant mortality rates. Arginine vasopressin (AVP) and analogs with V1A receptor agonist activity are increasingly used to treat fluid-resistant vasodilatory hypotension, including catecholamine-refractory septic shock. Clinical studies have been restricted to healthy volunteers and catecholamine-refractory septic shock patients excluding subjects with cardiac co-morbidities because of presumed safety issues. The novel selective V1A receptor agonist selepressin, with short half-life, has been designed to avoid V2 receptor-related complications and long-term V1A receptor activation. Cardiovascular safety of selepressin, AVP, and the septic shock standard of care norepinephrine was investigated in a rabbit model of early-stage atherosclerosis.MethodsAtherosclerosis was established in New Zealand White rabbits using a 1% cholesterol-containing diet. Selepressin, AVP, or norepinephrine was administered as cumulative intravenous infusion rates to atherosclerotic and non-atherosclerotic animals.ResultsSelepressin and AVP induced a slight dose-dependent increase in arterial pressure (AP) associated with a moderate decrease in heart rate, no change in stroke volume, and a moderate decrease in aortic blood flow (ABF). In contrast, norepinephrine induced a marked dose-dependent increase in AP associated with a lesser decrease in the heart rate, an increase in stroke volume, and a moderate increase in ABF. For all three vasopressors, there was no difference in responses between atherosclerotic and non-atherosclerotic animals.ConclusionFurther studies should be considered using more advanced atherosclerosis models, including with septic shock, before considering septic shock clinical trials of patients with comorbidities. Here, selepressin and AVP treatments did not display relevant cardiovascular risk in early-stage rabbit atherosclerosis.
Highlights
Septic shock remains associated with mortality rates of 20–50% in critical care medicine despite some improvements in recent years [1−4]
Norepinephrine induced a marked dose-dependent increase in arterial pressure (AP) associated with a lesser decrease in the heart rate, an increase in stroke volume, and a moderate increase in aortic blood flow (ABF)
Shock is the result of a systemic inflammatory response syndrome (SIRS) inducing systemic vasodilatation and increased vascular permeability, both leading to hypotension that becomes unresponsive to fluid resuscitation
Summary
Septic shock remains associated with mortality rates of 20–50% in critical care medicine despite some improvements in recent years [1−4]. The neuroendocrine hormone arginine vasopressin (AVP) and analogs with selective V1A receptor-agonist activity are increasingly used to treat catecholamine-refractory septic shock and the irreversible phase of fluid-resuscitated hemorrhagic shock, another form of distributive shock like septic shock [6]. Both decreased and increased mortality rates have been reported in association with AVP treatment of these two forms of distributive shock. A retrospective study of acute trauma patients in the irreversible phase of hemorrhagic shock showed that AVP administration was associated with increased mortality compared to patients receiving other vasopressors [7]. Cardiovascular safety of selepressin, AVP, and the septic shock standard of care norepinephrine was investigated in a rabbit model of early-stage atherosclerosis
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