Early hydrocortisone replacement in septic shock a randomised controlled pre-clinical trial

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-22
Matthew J Maiden*1, Iain J Clarke2, Marianne J Chapman1, Guy L Ludbrook3, Tim R Kuchel4 and David J Torpy5
1Royal Adelaide Hospital, Australia, 2Monash University, Australia, 3University of Adelaide, Australia, 4SAHMRI, Gilles Plains, Australia, 5Royal Adelaide Hosp, Australia
Title:Early hydrocortisone replacement in septic shock – a randomised controlled pre-clinical trial.

Introduction: Several studies have illustrated that “physiological dose” hydrocortisone (HC) reduces need for vasopressors in patients with established septic shock. However the effect of HC on mortality has been variable and its role in septic shock remains controversial(1,2). The response to HC may depend on timing of administration and some clinical studies suggest benefit when it is given soon after recognition of sepsis(3,4). However it is unknown to what extent HC provided early in sepsis will attenuate septic pathophysiology.

Subjects and Setting:Prospective blinded randomised placebo controlled trial in a validated 24-hour ovine model of septic shock.

Methods: Animal ethics approval was obtained from all institutions. Sixteen ewes were anaesthetised for insertion of carotid arterial line, pulmonary artery catheter, tracheostomy and insertion of cannulae in the coronary sinus, renal vein, hepatic vein, and femoral vein. Sepsis was induced by intravenous E.coli (108 organisms/kg). Animals remained sedated, ventilated and received protocol guided management of parenteral fluids and noradrenaline (NorA) to maintain mean arterial pressure of 75mmHg. Two hours following injection of E.coli, sheep received continuous infusion of HC (0.1mg/kg/hr) or placebo (Pbo) for 24 hours. Primary outcome was the total dose of NorA over 24-hours. Secondary outcomes included haemodynamics, metabolic status, renal function and immunological parameters.

Results: Study groups were evenly matched at baseline (t0) and all animals developed a hyperdynamic septic response. After 24-hours (t24), plasma cortisol levels fell in the Pbo group (nmol/L; t0 395±26 vs. t24 168±43; p<0.01) but were maintained near baseline in the HC group (t0 339±21 vs. t24298±37; p=0.13). There was no difference in the amount of NorA required for the Pbo and HC groups (mg/kg; 208 ±160 vs. 167 ±101; p=0.73). Two animals in the Pbo group died (p=0.14). There was no treatment effect on any haemodynamic variable, temperature, pH, lactate, organ-specific oxygen extraction, renal function, interleukin-6 or haematological variable.

Conclusion: In a 24-hour model of septic shock, HC infusion did not reduce NorA requirement nor alter any other measured physiological variable. Clinical trials of early HC replacement would need to measure longer-term outcomes and require large sample size.

(1)Annane D et al, JAMA, 2002;288(7):862-71. (2)Sprung CL, et al, NEJM, 2008;358(2):111-24. (3)Confalonieri M, et al, Am J Respir Crit Care Med, 2005;171(3):242-8. (4)Nguyen TH, et al, NEJM, 2007;357(24):2431-40.

Nothing to Disclose: MJM, IJC, MJC, GLL, TRK, DJT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Royal Adelaide Hospital, New Investigators Grant; Ms Deidre Tidswell