5 mg/kg). Anaesthesia was induced with 5% isoflurane [selected since the effect of this anaesthetic on AChE activity is well characterised (Dorandeu et al., 2007)] in oxygen delivered via facemask. The trachea was intubated and anaesthesia maintained to a clinically acceptable depth using isoflurane in oxygen delivered via a circle breathing system. Regorafenib concentration Intermittent positive pressure ventilation (IPPV) was provided as necessary using a minute volume divider (Manley Pulmovent, Harlow, UK) adjusted to maintain normocapnia. Inspired and expired carbon dioxide, oxygen and isoflurane concentrations

were monitored. Heart rate, oesophageal and peripheral temperature, electrocardiogram, and percentage of saturated haemoglobin were recorded (Datex, USA). Temperature was maintained as close to physiological values as possible by the use of forced warm air blankets (Bair Hugger, Arizant UK) or heat pads and a high

ambient temperature. Ten ml/kg/h lactated Ringer’s solution was administered for the first 30 min after induction of anaesthesia and then at 5 ml/kg/h for the remainder of the study. Fluid administration was increased as necessary during the study to maintain urine output and raise the central venous pressure. A central arterial catheter was placed surgically into the carotid artery for continuous arterial pressure monitoring. A central venous catheter was placed into the external jugular vein for infusion of drugs and monitoring of central venous pressure. The catheters were SGI-1776 purchase connected to a pressure manometer (Datex, USA) zeroed at the level of the base of the heart to give arterial and CVP pressure readings. Lithium dilution cardiac output (LiDCO, London, UK) was used to assess beat-to-beat cardiac output, arterial blood pressure,

and systemic vascular resistance (SVR). A urine catheter was placed by mini-laparotomy; urine output was measured every 60–120 min. An orogastric tube was placed for poison gavage. IPPV was withdrawn every 30 min to assess the isometheptene pig’s ability to breathe spontaneously. The time to return of spontaneous ventilation (SV) and the EtCO2 after 30 s of SV were recorded. IPPV was then re-imposed to help maintain cardiovascular stability. Mechanomyography was established using the deep peroneal nerve/tibialis posterior nerve/muscle group. Train of four stimulations was applied at 2 Hz, at intervals greater than 10 s, as per standard protocols (Fuchs-Buder et al., 2009). After arterial catheter insertion, 60 min was allowed to pass before poisoning during which time baseline observations were recorded. Minipigs were randomly allocated to each group. Pigs were administered 2.5 ml/kg of dimethoate 40% emulsifiable concentrate (EC40; BASF SE, Ludwigs-hafen, Germany), 2.