Randomized, double-blind, placebo-controlled crossover pilot study of a potassium channel blocker in patients with septic shock.
BACKGROUND
Marked potassium efflux prevents calcium entry into vascular smooth muscle cells and may be responsible for the "vasoplegia" of septic shock. Blockade of adenosine triphosphate (ATP)-sensitive potassium channels restores vascular tone in animal studies of septic shock. The effect of such potassium channel blockade has not been previously studied in humans.


OBJECTIVE
To test whether the administration of an ATP-sensitive potassium (K(ATP)) channel blocker restores norepinephrine responsiveness in patients with septic shock.


METHODS
Randomized, double-blind, placebo-controlled crossover pilot study.


METHODS
Intensive care unit of a university hospital.


METHODS
Ten patients with septic shock requiring invasive hemodynamic monitoring and infusion of norepinephrine to maintain adequate mean arterial pressure.


METHODS
In addition to standard therapy, patients were randomized to initially receive either the K(ATP) channel blocker glibenclamide (20 mg) or placebo. Then, after 24 hrs, each patient crossed over to receive the alternative therapy.


RESULTS
After the administration of the K(ATP) channel blocker glibenclamide, median norepinephrine requirements decreased from 13 to 4 microg/min compared with a change from 19 to 7 microg/min after placebo. The two changes represented a decrease of 78.9% and 71.1% in dose, respectively (p = .57, not significant). There were also no significant changes in heart rate, mean arterial blood pressure, and lactate concentration when comparing the study drug with placebo. Glibenclamide, however, induced a significant decrease in median blood glucose concentration (5.4 [inter-quartile range, 4.5-7.0] vs. 7.0 mmol/L [5.2-9.3], p < .0001) compared with placebo and increased the need for parenteral glucose administration.


CONCLUSIONS
The K(ATP) channel blocker glibenclamide failed to achieve a greater reduction in norepinephrine dose than placebo in septic shock patients, although it caused a reduced glucose concentration. Our observations suggest that, in such patients, blockade of K(ATP) channels does not have a potent effect on vasomotor tone.
Department of Intensive Care, Austin Hospital, Melbourne, Australia.
Stephen
S
Warrillow
Moritoki
M
Egi
Rinaldo
R
Bellomo
D000368:Aged; D000369:Aged, 80 and over; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005905:Glyburide / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000627:therapeutic use*; D010865:Pilot Projects; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D012772:Shock, Septic / Q000188:drug therapy*
D026902:Potassium Channel Blockers; D005905:Glyburide; D009638:Norepinephrine