Effects of the dual endothelin receptor antagonist tezosentan and hypertonic saline/dextran on porcine endotoxin shock.
OBJECTIVE
To evaluate the haemodynamic effects of the dual endothelin receptor antagonist tezosentan, both alone and combined with hypertonic saline/dextran (HSD), on porcine endotoxin shock, with focus on cardiopulmonary circulation. The effects on gas exchange and short-term survival were also studied.


METHODS
A prospective, randomized experimental study was carried out. Thirty-two anaesthetized pigs underwent pulmonary and carotid artery catheterization. Following haemodynamic stabilization and baseline measurements, endotoxaemia was induced by an Escherichia coli-endotoxin infusion over 180 min and the animals observed another 120 min. After 60 min of endotoxaemia, directly before intervention, animals were randomized into four groups: a tezosentan group, an HSD group, a combined tezosentan/HSD group and a control group. The consequent haemodynamic effects and blood gas results were recorded.


RESULTS
The endotoxin infusion reduced mean arterial blood pressure from 111 +/- 14 (mean +/- standard deviation) to 77 +/- 27 mmHg and cardiac index from 126.9 +/- 27.2 to 109.3 +/- 22.6 mL min(-1) kg(-1) within 90 min in the control group. In addition, endotoxin simultaneously increased mean pulmonary artery pressure from 24 +/- 17 to 38 +/- 19 mmHg and reduced arterial oxygenation from 18.9 +/- 2.0 to 12.2 +/- 5.3 kPa. Tezosentan, alone and combined with HSD, reversed the pulmonary hypertension and prevented the reduction in cardiac index and arterial oxygenation, resulting in reduced metabolic acidosis. Additionally, in the tezosentan group, the mean arterial blood pressure was reduced to the same level as in controls, an effect not prevented by the addition of HSD. It was found that all three interventions improved survival rates.


CONCLUSIONS
Tezosentan, alone and in combination with HSD, improved cardiac index and arterial oxygenation. The addition of HSD to tezosentan treatment did not improve the endotoxin-induced hypotension, but beneficial effects on microcirculation and systemic oxygenation were seen despite low perfusion pressure, as indicated by increased SvO(2) and reduced metabolic acidosis.
Somell
A
A
Departments of Anaesthesiology & Intensive Care, Karolinska University Hospital, Stockholm, Sweden. anna.somell@karolinska.se
Weitzberg
E
E
Suneson
A
A
Sollevi
A
A
Hjelmqvist
H
H
D000136:Acid-Base Equilibrium / Q000187:drug effects / Q000502:physiology; D000138:Acidosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001775:Blood Circulation / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003911:Dextrans / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D004731:Endotoxins; D004926:Escherichia coli; D005260:Female; D007022:Hypotension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011659:Pulmonary Gas Exchange / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D012462:Saline Solution, Hypertonic / Q000494:pharmacology / Q000627:therapeutic use*; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D003911:Dextrans; D065128:Endothelin Receptor Antagonists; D004731:Endotoxins; D011725:Pyridines; D012462:Saline Solution, Hypertonic; D013777:Tetrazoles; C120582:tezosentan