Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis

Yugeesh R. Lankadeva, Lindsea C. Booth, Junko Kosaka, Roger G. Evans, Luc Quintin, Rinaldo Bellomo, Clive N. May

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)e221-e229
JournalCritical care medicine
Volume43
Issue number7
DOIs
Publication statusPublished - Jul 21 2015
Externally publishedYes

Fingerprint

Clonidine
Phenylephrine
Angiotensin II
Sheep
Sepsis
Kidney
Arterial Pressure
Hypotension
Heart Rate
Adrenergic Agonists
Septic Shock
Blood Vessels
Clinical Trials
Escherichia coli
Therapeutics

Keywords

  • Escherichia coli
  • hyperdynamic sepsis
  • sympathetic nerve activity
  • vascular sensitivity
  • α-adrenergic agonist

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Lankadeva, Y. R., Booth, L. C., Kosaka, J., Evans, R. G., Quintin, L., Bellomo, R., & May, C. N. (2015). Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis. Critical care medicine, 43(7), e221-e229. https://doi.org/10.1097/CCM.0000000000000963

Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis. / Lankadeva, Yugeesh R.; Booth, Lindsea C.; Kosaka, Junko; Evans, Roger G.; Quintin, Luc; Bellomo, Rinaldo; May, Clive N.

In: Critical care medicine, Vol. 43, No. 7, 21.07.2015, p. e221-e229.

Research output: Contribution to journalArticle

Lankadeva, Yugeesh R. ; Booth, Lindsea C. ; Kosaka, Junko ; Evans, Roger G. ; Quintin, Luc ; Bellomo, Rinaldo ; May, Clive N. / Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis. In: Critical care medicine. 2015 ; Vol. 43, No. 7. pp. e221-e229.
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AU - Kosaka, Junko

AU - Evans, Roger G.

AU - Quintin, Luc

AU - Bellomo, Rinaldo

AU - May, Clive N.

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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.

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KW - hyperdynamic sepsis

KW - sympathetic nerve activity

KW - vascular sensitivity

KW - α-adrenergic agonist

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