Extracorporeal lessons from sheep

Abstract

Background Extracorporeal circulation (ECC), the diversion of blood flow through a circuit located outside of the body, has been one of the major advances in modern medicine. Cardio‐pulmonary bypass (CPB), renal dialysis, apheresis and extracorporeal membrane oxygenation (ECMO) are all different forms of ECC. Despite its major benefits, when blood comes into contact with foreign material, both the coagulation and inflammation cascades are activated simultaneously. Short periods of exposure to ECC e.g. CPB (∼2 h duration), are known to be associated with haemolysis, coagulopathies, bleeding and inflammation which demand blood product support. Therefore, it is not unexpected that these complications would be exaggerated with prolonged periods of ECC such as in ECMO (days to weeks duration). The variability and complexities of the underlying pathologies of patients requiring ECC makes it difficult to study the cause and effect of these complications. To overcome this problem we developed an ovine (sheep) model of ECC. Method Healthy female sheep (1–3 y.o.) weighing 40–50 kg were fasted overnight, anaesthetised, intubated and ventilated [1]. Half the group received smoke induced acute lung injury (S‐ALI group) (n = 8) and the other half did not (healthy group) (n = 8). Sheep were subsequently cannulated (Medtronic Inc, Minneapolis, MN, USA) and veno‐venous ECMO commenced using PLS ECMO circuit and Quadrox D oxygenator (Maquet Cardiopulmonary AG, Hechinger Straße, Germany). There was continuous physiological monitoring and blood was collected at specified time intervals for full blood counts, platelet function analysis (by Multiplate®), routine coagulation and assessment of clot formation and lysis (by ROTEM®). Preliminary results Full blood counts and routine coagulation results from normal healthy sheep were comparable to those of normal human adults. Within 15 min of initiating of ECMO, PT, PTT and EXTEM clot formation time increased, whilst EXTEM maximum clot firmness decreased in both cohorts. Discussion & Conclusions Preliminary results of sheep from both 2 h ECMO cohorts showed that the anatomy, haematology and coagulation parameters of an adult sheep are comparable to that a human adult. Experiments are currently underway with healthy (n = 8) and S‐ALI (n = 8) sheep on ECMO for 24 h. In addition to characterising how ECMO alters haematology and coagulation parameters, we hope that it will also define which blood components will be most effective to correct bleeding or clotting complications during ECMO support.

A comprehensive ovine model of blood transfusion

“…However, canines are generally smaller in size, which may restrict the volume and number of samples collected during a study. Therefore, an ovine model was selected as it has also been used extensively in medical research [26,27] and has comparable size and anatomy [28] to humans thus providing good surgical accessibility. They also have comparative plasma and tissue pharmacokinetics [29], pulmonary circulation [30] and a placid nature, which is extremely useful during long in vivo studies [31].…”

The Complex Relationship of Extracorporeal Membrane Oxygenation and Acute Kidney Injury: Causation or Association?

“…The institution of salvage ECMO is often reserved for patients with a predicted mortality rate in excess of 80% [ 7 ]. Improvements in clinical application and device design with a more precise appreciation of the patient-device interface, particularly with regard to haematological changes, have improved the risk : benefit ratio of ECMO [ 8 – 10 ].…”

Sick patients, starved circuits and sticky drugs: understanding pharmacokinetics during extracorporeal membrane oxygenation to optimise drug dosing and improve patient outcomes

“…In the setting of pneumonia or sepsis and severe cardiac dysfunction, where feasible, VV ECMO with inotropic support should be the initial perfusion strategy [53]. Septic myocardial depression may improve with management of the sepsis, improved oxygenation and normalisation of respiratory acidosis [54].…”

“…This research will characterise the PK of 18 important drugs (Chapter 4) used during ECMO utilising validated ex vivo and large animal models of ECMO 52,53 ,efficient drug and metabolite assays 54 and a multi-national population PK collaboration 55 . This mechanistic data can be translated into clinical practice rapidly, facilitating optimal pharmacotherapy, minimizing the risk of therapeutic failure and the rise of antibiotic resistance from sub-therapeutic concentrations.…”

“…Evidence-based practices such as use of sedation protocols [52], allowing lighter sedation with daily interruptions [52][53][54] and minimizing administration of paralytic agents, have all been shown to reduce morbidity in critically ill patients. However, these practices may not always be practical in a critically ill patient on ECLS.…”