Translation of previous animal studies into human ICU clinical trials has frequently produced negative results. Most of these animal studies have had high baseline mortality and have not employed standardised management of sepsis as usually provided in an ICU. The aim of this study was to develop a large animal model of septic shock receiving standardised intensive care management, thus replicating the management of septic shock in humans.
Eleven Marino ewes (weight 60 to 70 kg, hemiazygous vein ligated) were anaesthetised and had radiological guided catheters inserted into the iliac, renal, and hepatic veins, coronary sinus, and the pulmonary and carotid arteries. Tracheostomy tubes were inserted and the animals mechanically ventilated while supported in a sling. Six sheep were administered intravenous E. coli (ATCC 25922) 1.0 × 108 orgs/kg over 1 hour (septic sheep), five received placebo (nonseptic sheep). For 24 hours, animals were monitored and received sedation (midazolam + ketamine), ventilation, fluids and inotropes according to a protocol. Primary end-point was noradrenaline (NA) dose to maintain mean arterial pressure (MAP) of 75 mmHg. Secondary end-points included haemodynamic variables, respiratory, hepatic, and renal function, haematology, acid-base status and global, hind-limb, renal, hepatic and coronary oxygen extraction ratio (OER).
Sheep were successfully instrumented, monitored and supported for 24 hours. Septic sheep required NA (mean dose 0.28 μg/kg/min vs 0.00, P < 0.001), developed a higher cardiac index (6.6 l/m2 vs 4.3, P < 0.05) and lower SVRI (769 dynes/m2 vs 1,804, P < 0.05). At 24 hours, septic sheep had renal impairment (creatinine 286 mmol/l vs 76, P < 0.05; urea 12 mmol/l vs 7, P < 0.05), metabolic acidosis (pH 7.21 vs 7.39, P < 0.05; lactate 10.9 mmol/l vs 1.2, P < 0.01; pCO2 32 vs 31, P = 0.63), coagulopathy (INR 5.9 vs 1.9, P < 0.05; fibrinogen 0.9 g/l vs 2.7, P < 0.05) but preserved respiratory and hepatic function. Global OER was lower in septic sheep (0.16 vs 0.29, P < 0.05) as was coronary OER (0.36 vs 0.68, P < 0.05). OER did not change with sepsis in the kidney (0.09 vs 0.11, P = 0.52), liver (0.24 vs 0.31, P = 0.48) and hind-limb (0.31 vs 0.42, P = 0.23).
We have developed a large animal model of septic shock that receives intensive care support and standardised management. This model replicates much of the pathophysiology and management that occurs in human septic shock. It allows a large range of physiological parameters to be assessed when investigating new therapies for sepsis.