Effect of hydrocortisone on phenylephrine--mean arterial pressure dose-response relationship in septic shock.
BACKGROUND
Septic shock is characterized by decreased responsiveness to catecholamines. Because endogenous steroids are known to play a role in the modulation of vasomotor tone, the purpose of our study was to investigate the phenylephrine-mean arterial pressure dose-response relationship in patients with septic shock and the effect of a physiological dose of hydrocortisone on it.


METHODS
Twelve patients meeting usual criteria for septic shock and 12 age-matched control subjects were investigated before and 1 hour after receiving 50 mg intravenous hydrocortisone. Sixteen incremental doses of phenylephrine (microg/kg/min) were infused, and the effects on mean arterial pressure (mm Hg) were recorded. A sigmoid model, E = E0 + [Emax x Dgamma/(ED50gamma + Dgamma)], was fitted to individual data. In this model, E is the predicted effect and D is the dose of phenylephrine infused. E0 represents the basal value of effect (ie, the value of mean arterial pressure without drug), Emax is the maximum theoretical effect, ED50 is the dose of phenylephrine for which an effect of 50% of Emax is observed, and gamma is the Hill coefficient which accounts for the sigmoidicity of the curve.


RESULTS
As compared with in control subjects, in patients, E0 was decreased before (58 +/- 8 versus 73 +/- 7 mm Hg) and after (64 +/- 12 versus 82 +/- 10 mm Hg) administration of hydrocortisone (P = .0001 for group), Emax was reduced before (39 +/- 17 versus 84 +/- 18 mm Hg) and after (77 +/- 26 versus 106 +/- 21 mm Hg) administration of hydrocortisone (P = .0001 for group), ED50 was not modified, and gamma was increased before (3.5 +/- 1.8 versus 1.3 +/- 0.3) and after (1.9 +/- 1.1 versus 1.3 +/- 0.3) administration of hydrocortisone (P = .0010 for group). Hydrocortisone similarly increased E0 in both groups (P = .0003 for sequence, P = .2883 for interaction), increased more Emax in patients than in control subjects (P < .0001 for sequence; P = .0280 for interaction), did not change ED50, and decreased y in patients but not in control subjects (P = .0025 for sequence, P = .0025 for interaction).


CONCLUSIONS
In patients with septic shock, the Emax of phenylephrine is decreased, whereas its ED50 is not modified, both before and after administration of hydrocortisone. A physiological dose of hydrocortisone tends to normalize the relationship.
Bellissant
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Laboratoire de Pharmacologie Expérimentale et Clinique, Faculté de Médecine, Université de Rennes I, France. Eric.Bellissant@univ-rennes1.fr
Annane
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D000704:Analysis of Variance; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000145:classification / Q000188:drug therapy* / Q000401:mortality
D000893:Anti-Inflammatory Agents; D002316:Cardiotonic Agents; D010656:Phenylephrine; D006854:Hydrocortisone