title: Clonidine Restores Pressor Responsiveness to Phenylephrine and Angiotensin II in Ovine Sepsis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Interventional study.
  
  
  METHODS
  Research institute.
  
  
  METHODS
  Twelve adult Merino ewes (n = 6 per group).
  
  
  METHODS
  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.
  
  
  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.
authors: 1Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia. 2Department of Physiology, Monash University, VIC, Australia. 3Department of Physiology, University of Lyon, Lyon, France. 4Department of Intensive Care, Austin Health, Heidelberg, VIC, Australia. 5Department of Medicine, Austin Health, Heidelberg, VIC, Australia. 6The Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
authors: Yugeesh R
authors: YR
authors: Lankadeva
authors: Lindsea C
authors: LC
authors: Booth
authors: Junko
authors: J
authors: Kosaka
authors: Roger G
authors: RG
authors: Evans
authors: Luc
authors: L
authors: Quintin
authors: Rinaldo
authors: R
authors: Bellomo
authors: Clive N
authors: CN
authors: May
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology*; D005260:Female; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology*; D007668:Kidney / Q000294:innervation; D010656:Phenylephrine / Q000494:pharmacology*; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D012756:Sheep; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D003000:Clonidine