Study design and patient selection
This prospective observational study was approved by the Research Ethics Committee of National Taiwan University Hospital (approval number: 201703011RINA) and registered on the ClinicalTrials.gov protocol registration system (ID: NCT03210818). It was conducted at National Taiwan University Hospital between November 2017 and December 2018. Participants were selected from patients receiving ECMO support on the basis of eligibility screening conducted within 12 hours following ECMO placement. Patients who received VA-ECMO support and were between the ages of 20 and 90 years were included. Patients were excluded if they declined to participate, had received re-implantation of ECMO, died within 12 hours, or had circumstance that prevented sublingual microcirculation from being measured within 24 hours after initiating VA-ECMO, such as those in which placement occurred in the evening or the research nurse was on leave. Informed consent was obtained from patients’ legally authorized representatives before study enrollment.
VA-ECMO components and placement
For all enrolled patients, the placement and principal components of the VA-ECMO were the same as described in our previous study [9]. To avoid possible malperfusion of the distal limb, an antegrade distal perfusion catheter was used when the mean pressure of the superficial femoral artery was below 50 mm Hg [12]. All patients received standard VA-ECMO management and routine intensive care unit (ICU) care. Heparin was continuously administered to maintain an activated clotting time of 160–180 s if no active bleeding or other complications were observed. The following data were recorded: age, gender, height, body weight, sequential organ failure assessment (SOFA) score [13], indications for VA-ECMO, VA-ECMO pump flow rate, heart rate, mean arterial pressure (MAP), lactate level, activated clotting time, hemoglobin level, fluid balance, and inotropic score. The inotropic score was calculated as 100 × epinephrine dose (mcg/kg/min) + 100 × norepinephrine dose (mcg/kg/min) + dopamine dose (mcg/kg/min) + dobutamine dose (mcg/kg/min) [14]. The simultaneous use of intra-aortic balloon pump (IABP) with VA-ECMO support was recorded. The length of ICU and hospital stay, as well as survival status at 28 days were also recorded.
Change in VA-ECMO pump flow rate and recording of sublingual microcirculation images
The ECMO team adjusted the VA-ECMO pump flow rate to maintain an MAP > 60 mm Hg, central venous oxygen saturation >70%, central venous pressure <15 mmHg, and lactate level of <3 mmol/L, and to avoid a urine output of <0.5 mL/kg/h, pulse pressure < 10 mm Hg, and ECMO-induced hemolysis, or to wean the patients off VA-ECMO support. Sublingual microcirculation images were recorded using an incident dark-field video microscope (CytoCam, Braedius Medical, Huizen, Netherlands) [15]. The images were recorded at two time points: within 24 hours (T1) and at 24 to 48 hours (T2) after VA-ECMO placement. At T1 and T2, images were recorded before changing VA-ECMO pump flow rate. After recording, the VA-ECMO pump flow rate was increased or reduced by the ECMO team member according to the treatment plan. The change in pump flow rate was recorded, and images were recorded at 5 minutes after the change.
Measurements of sublingual microcirculation
At each time point, five video sequences (length: 6 s each) were recorded at different sublingual sites and were digitally stored with code numbers to ensure the anonymity of patient information. Subsequent offline analyses were performed by a single observer blinded to patient information according to the international consensus guidelines for performing sublingual microcirculation by a Task Force of the European Society for Intensive Care Medicine [16]. Two or three sequences with appropriate image quality were selected for analysis using the semi-automated analysis software package Automated Vascular Analysis 3.0 [17].
In accordance with the afore mentioned consensus guidelines [16], the following parameters were investigated: (a) total vessel density (TVD; vessels less than 20 μm), (b) perfused vessel density (PVD), (c) proportion of perfused vessels (PPV), and (d) microvascular flow index (MFI) score. The software was used to automatically calculate TVD. The calculation of PVD was semiautomated using the procedure described in our previous study [9]. The MFI scores were semiquantitatively calculated according to the suggestions made at the roundtable conference [18].
Grouping events of changes in VA-ECMO pump flow rate and changes in PVD
Events of changing VA-ECMO pump flow rate at T1 and T2 were divided into the following four groups according to the changes in PVD. Group A included events of increased or sustained PVD after increasing the ECMO pump flow rate; Group B included events of reduced PVD after increasing the ECMO pump flow rate; Group C included events of increased or sustained PVD after decreasing ECMO pump flow rate; and Group D included events of reduced PVD after decreasing ECMO pump flow rate.
Statistical analysis
All statistical analyses were performed using SPSS version 20 (IBM, Armonk, NY, USA). Normally distributed numerical data were expressed as means (standard deviation) and compared using t-tests. Nonnormal distribution of numerical data were expressed as medians (interquartile range) and compared using Mann–Whitney tests. Categorical variables were described as percentages and were compared using chi-square tests or Fisher’s exact tests as appropriate. A p value of < 0.05 indicated a significant difference.