title: Continuously infused glipizide reverses the hyperdynamic circulation in ovine endotoxemia.
abstract: In advanced sepsis, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Although activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, previous studies demonstrated only a transient increase in mean arterial pressure (MAP) after bolus administration of K(ATP) channel inhibitors. We hypothesized that a continuous infusion of the sulfonylurea glipizide, a K(ATP) channel inhibitor, may reverse cardiovascular dysfunctions in sepsis permanently. Eighteen adult sheep were instrumented for chronic study. After a baseline measurement in healthy ewes, endotoxin (Salmonella typhosa, 10 ng kg(-1) min(-1)) was continuously infused for 19 h. After 16 h of endotoxemia, the surviving sheep (n = 14) were randomly assigned to be treated with either glipizide (5 mg/kg, followed by a continuous infusion of 8 mg kg(-1) h(-1)) or placebo (normal saline; each n = 7). Measurements of cardiopulmonary hemodynamics, global oxygen transport, acid-base status, and urine output were performed in the healthy state, after 16 h of endotoxemia, and during 3 h of glipizide infusion. Continuous infusion of glipizide reversed the endotoxin-induced hyperdynamic circulation, as indicated by significant increases in MAP and systemic vascular resistance index, as well as decreases in cardiac index and heart rate (P < 0.001 each). In addition, glipizide increased urine output as compared with untreated controls (P < 0.001). The anticipated decrease in glucose plasma levels was prevented by infusion of glucose 5%. From these results, we conclude that continuous glipizide infusion may represent a useful therapeutic option in the treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.
authors.affiliation: Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany. lange-m@anit.uni-muenster.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Bone
authors.forename: Hugo
authors.initials: H
authors.lastname: Van Aken
authors.forename: Katrin
authors.initials: K
authors.lastname: Bröking
authors.forename: Andrea
authors.initials: A
authors.lastname: Morelli
authors.forename: Christoph
authors.initials: C
authors.lastname: Hucklenbruch
authors.forename: Fritz
authors.initials: F
authors.lastname: Daudel
authors.forename: Christian
authors.initials: C
authors.lastname: Ertmer
authors.forename: Henning
authors.initials: H
authors.lastname: Stubbe
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.forename: Martin
authors.initials: M
authors.lastname: Westphal
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy*; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D005913:Glipizide / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007022:Hypotension / Q000188:drug therapy*; D007249:Inflammation; D007260:Infusion Pumps; D015221:Potassium Channels / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy; D012756:Sheep; D013577:Syndrome
chemical_list: D004731:Endotoxins; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005913:Glipizide