Study design
We conducted a retrospective study in two centres, the Alfred Hospital (Melbourne, Australia) and the Hospital of Besançon (France). The Alfred Hospital is a teaching hospital affiliated to Monash University, which provides heart and lung transplantation services for the states of Victoria, South Australia and Tasmania. It has an intensive care unit (ICU) with a 45-bed capacity and is the referral centre for adult trauma and ECMO in Victoria. The Hospital of Besançon is a teaching hospital affiliated to the University of Franche-Comté; its 21-bed medical ICU has long-standing experience in ECMO support.
All adults admitted to ICU between January 2010 and June 2013 at the Alfred Hospital and between January 2013 and December 2013 at the Hospital of Besançon and who underwent ECMO were included.
The study was approved by the Alfred Health Human Research Ethics Committee (202/11) and by the Ethics Committee of Besançon Hospital.
ECMO haemostatic practice
Both hospitals had anticoagulation protocols and local guidelines for haemostatic management for patients undergoing ECMO, and these protocols were similar for VV and VA ECMO. In both centres, systemic anticoagulation with a heparin infusion targeting an activated partial thromboplastin time (aPTT) between 50 and 70 s was standard practice, unless patients were bleeding or at increased risk of bleeding (usually related to peri-operative and traumatic injuries). Red blood cell (RBC) transfusion was given to maintain a haemoglobin (Hb) concentration above 8 g/dL. Prophylactic blood products were not routinely given for coagulation abnormalities, with the exception of severe thrombocytopenia (<50,000 platelets/mm3). In the case of bleeding, platelets were administered to maintain a platelet count ≥80,000/mm3, fresh frozen plasma (FFP) to maintain the international normalised ratio (INR) ≤1.5 or prothrombin (PT) >70 %, and cryoprecipitate or fibrinogen concentrate to maintain fibrinogen plasma concentration ≥1.5 g/L. Coagulation factor concentrates, antifibrinolytic agents (tranexamic acid), antithrombin III and protamine were administered when deemed appropriate by the intensivist in charge. Heparin was the anticoagulant of choice; however, alternatives (warfarin, lepirudin) were used if necessary. ECMO circuits were phosphorylcholine and heparin bonded in both centres. Circuit membrane was changed at the Alfred Hospital if there was evidence of systemic fibrinolysis presumed to be due to circuit or clot in the oxygenator and at both sites in cases of poor oxygenator function and increases in trans-oxygenator pressure. Proton pump inhibitors were routinely administered to ECMO patients. At the Alfred Hospital, both cannulae of VA and VV ECMO were percutaneously inserted, while at Hospital of Besançon cannula of VA ECMO was surgically inserted.
Clinical and biological data
Medical history and clinical charts were retrospectively reviewed, and the following data were collected: demographics, comorbidities, ICU and hospital admission and discharge dates, diagnosis and Acute Physiology and Chronic Health Evaluation (APACHE III) score at admission. Treatment with aspirin, clopidogrel or vitamin K antagonist, surgery or cardiopulmonary resuscitation prior to ECMO initiation was recorded. The Sequential Organ Failure Assessment (SOFA) scores prior to ECMO initiation and on the third day of ECMO were calculated. Requirement for renal replacement therapy (RRT), mechanical ventilation (MV) or intra-aortic balloon pump while on ECMO were also collected. The daily highest and lowest values of the following biological data were recorded for each day on ECMO: Hb on formal full blood examination, platelet count, aPTT, INR, PT and fibrinogen level. The lowest temperature, the lowest value of arterial pH and ionised calcium, the highest D-dimer, urea, bilirubin and free Hb were also collected for each day on ECMO.
ECMO data
ECMO data included the commencement and cessation date, whether the ECMO was initiated in another hospital, the main indication for ECMO and the type of ECMO [veno-venous (VV) or veno-arterial (VA) including central and peripheral VA ECMO]. The following data were also recorded: outcomes of ECMO, status at ICU and hospital discharge and location of hospital discharge.
Bleeding events and thromboembolic events
Daily information on blood product and haemostatic agent use, including type and dose of anticoagulant, was collected for the duration of ECMO.
Bleeding events were defined according to the Extracorporeal Life Support Organisation (ELSO) definition [15]: we defined a bleeding event if there was clinically overt bleeding recorded in the medical and/or nursing charts associated with either administration of 2 or more RBC units in 24 h or a drop in haemoglobin greater than 2 g/L over 24 h, or if there was a haemothorax, central nervous system or retroperitoneal bleeding, or if bleeding required an intervention. If there were consecutive days with the same primary source of bleeding as preceding days, these were considered the same bleeding event. When a patient had more than one bleeding source on the same day, this was also recorded.
Thromboembolic complications, including deep venous thrombosis, ischaemic stroke, intra-cardiac thrombus, pulmonary embolism and membrane circuit clotting requiring membrane change, were collected from the medical record.
Statistical analysis
All analyses were performed using Stata 12.0 (College Station, Texas). Descriptive statistics are reported as mean (standard deviation) or median (inter-quartile range, IQR) according to data distribution. Hypothesis testing for patient level data was performed using Chi-square for categorical variables, Student’s t test for normally distributed data and Wilcoxon’s rank sum for non-normally distributed data. For comparisons between ECMO days with and without bleeding, to account for the repeated measures per patient (with bleeding recorded on each day of ECMO treatment), a repeated measures mixed model was performed for continuous variables and random effects logistic model for binomial variables. Mean and 95 % confidence interval (CI) are reported adjusted for repeated measures.
Survival curves were plotted using the Kaplan–Meier method, and groups were compared using the log-rank test. Multivariable analysis for predictors of survival was performed using a Cox proportional hazard regression model, including those variables that were associated with the outcome with a P < 0.2. As the relationship between bleeding and survival was time dependent (with bleeding occurring at different times during the course of ECMO treatment), bleeding variables were treated as time-varying covariates in the Cox proportional hazard models. The final models were assessed for proportionality using the proportional hazards assumption test.
To investigate predictors of bleeding, multiple logistic regression modelling was performed. Initially, a backward stepwise logistic model was performed, which only included variables recorded prior to the day of bleeding (e.g. highest aPTT on the day prior to the bleeding event, anticoagulation on the day prior to the bleeding event, etc.). aPTT was categorised into quartiles for the multivariable analysis. To account for the repeated measures per patient, variables that were found to be independently associated with the bleeding outcomes in the stepwise logistic model were then included in a multi-level logistic regression model, with each patient now modelled as a random effect. Subgroup analyses were performed in patients undergoing non-post-surgical VA ECMO.