TY - JOUR
T1 - Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis
AU - Lankadeva, Yugeesh R.
AU - Booth, Lindsea C.
AU - Kosaka, Junko
AU - Evans, Roger G.
AU - Quintin, Luc
AU - Bellomo, Rinaldo
AU - May, Clive N.
PY - 2015/7/21
Y1 - 2015/7/21
N2 - Objectives: In sepsis, prolonged, sympathetic overstimulation may lead to vasopressor-refractory hypotension. We therefore examined the effects of the α2-adrenergic agonist clonidine on mean arterial pressure, renal sympathetic nerve activity, and pressor responsiveness to phenylephrine and angiotensin II during hypotensive sepsis in conscious sheep. Design: Interventional study. Setting: Research institute. Subjects: Twelve adult Merino ewes (n = 6 per group). Interventions: Sepsis was induced by IV infusion of Escherichia coli for 32 hours. Pressor responses to increasing doses of phenylephrine and angiotensin II were measured at baseline and at 24, 28, and 32 hours of sepsis. Sheep were treated with clonidine (1 μg/kg/hr) or saline-vehicle from 24 to 32 hours of sepsis. Measurements and Main Results: Sepsis was characterized by hypotension (∼12 mm Hg), increased heart rate (∼80 beats/min), increased renal sympathetic nerve activity (∼70%), and blunted pressor responses to phenylephrine and angiotensin II. In vehicle-treated sheep, mean arterial pressure progressively declined from 25 to 32 hours of sepsis (73 ± 3 to 66 ± 3 mm Hg; p = 0.013) while the elevations in heart rate and renal sympathetic nerve activity and reduced pressor responsiveness to vasopressors persisted. Clonidine treatment prevented the further decline in mean arterial pressure, substantially reduced heart rate and renal sympathetic nerve activity and restored pressor responsiveness to both phenylephrine and angiotensin II toward preseptic levels. Conclusions: Administration of clonidine during hypotensive sepsis reduced renal sympathetic nerve activity, restored vascular sensitivity to both phenylephrine and angiotensin II, and resulted in better preservation of arterial pressure. Considering these findings, a clinical trial for the use of clonidine in the treatment of persistent vasopressor-refractory hypotension in patients with septic shock would be worthwhile.
AB - Objectives: In sepsis, prolonged, sympathetic overstimulation may lead to vasopressor-refractory hypotension. We therefore examined the effects of the α2-adrenergic agonist clonidine on mean arterial pressure, renal sympathetic nerve activity, and pressor responsiveness to phenylephrine and angiotensin II during hypotensive sepsis in conscious sheep. Design: Interventional study. Setting: Research institute. Subjects: Twelve adult Merino ewes (n = 6 per group). Interventions: Sepsis was induced by IV infusion of Escherichia coli for 32 hours. Pressor responses to increasing doses of phenylephrine and angiotensin II were measured at baseline and at 24, 28, and 32 hours of sepsis. Sheep were treated with clonidine (1 μg/kg/hr) or saline-vehicle from 24 to 32 hours of sepsis. Measurements and Main Results: Sepsis was characterized by hypotension (∼12 mm Hg), increased heart rate (∼80 beats/min), increased renal sympathetic nerve activity (∼70%), and blunted pressor responses to phenylephrine and angiotensin II. In vehicle-treated sheep, mean arterial pressure progressively declined from 25 to 32 hours of sepsis (73 ± 3 to 66 ± 3 mm Hg; p = 0.013) while the elevations in heart rate and renal sympathetic nerve activity and reduced pressor responsiveness to vasopressors persisted. Clonidine treatment prevented the further decline in mean arterial pressure, substantially reduced heart rate and renal sympathetic nerve activity and restored pressor responsiveness to both phenylephrine and angiotensin II toward preseptic levels. Conclusions: Administration of clonidine during hypotensive sepsis reduced renal sympathetic nerve activity, restored vascular sensitivity to both phenylephrine and angiotensin II, and resulted in better preservation of arterial pressure. Considering these findings, a clinical trial for the use of clonidine in the treatment of persistent vasopressor-refractory hypotension in patients with septic shock would be worthwhile.
KW - Escherichia coli
KW - hyperdynamic sepsis
KW - sympathetic nerve activity
KW - vascular sensitivity
KW - α-adrenergic agonist
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U2 - 10.1097/CCM.0000000000000963
DO - 10.1097/CCM.0000000000000963
M3 - Article
C2 - 25860204
AN - SCOPUS:84937544827
VL - 43
SP - e221-e229
JO - Critical Care Medicine
JF - Critical Care Medicine
SN - 0090-3493
IS - 7
ER -