This was a retrospective and observational study of adult patients who underwent ECPR during hospitalization at Samsung Medical Center between May 2010 and December 2016. This study was approved by the Institutional Review Board of Samsung Medical Center (SMC 2017-11-088-002). The requirement for informed consent was waived due to its retrospective nature. Clinical and laboratory data were collected by a trained study coordinator using a standardized case report form. Patients who underwent ECPR during the study period were included. Those who were unconscious (a score of <9 on Glasgow Coma Scale)16) on admission to the hospital after cardiac arrest and those who were given brain CT scan within 48 hours after ECPR were selected. Of these patients, we excluded patients who were under 18 years of age, those who had malignancy whose expected life span was less than one year, those who had insufficient medical records, and those who had a history of head trauma, neurosurgery, or chronic neurological abnormality on ICU admission.

In this study, ECPR was defined as both successful veno-arterial extracorporeal membrane oxygenation (ECMO) implantation and pump-on with cardiac massage during index procedure in patients with cardiac arrest. When a return of spontaneous circulation (ROSC) occurred during ECMO cannulation, practitioners typically did not remove the cannula or stop the ECMO pump-on process^2,13). ECMO pump-on was defined by stopping chest compressions following successful ECMO implantation and activation. ECMO flow was then gradually increased until the patient was hemodynamically stable. Resuscitation was performed in the same way as described in our previous study^16,17). Arrest to ECMO pump-on time was defined as the time from cardiac arrest to the time at which the ECMO pump was turned on. Targeted temperature management (TTM) was performed with surface cooling devices. A commercial temperature regulation system consisting of a hydrogel pad (Arctic Sun^®; Medivance Corp, Louisville, CO, USA) or a cooling blanket was used. Surface cooling and the degree of targeted temperature were determined by each intensivist in the ICU according to the therapeutic hypothermia protocol⁷⁾. The primary outcome was neurological status upon hospital discharge assessed with Glasgow-Pittsburgh Cerebral Performance Categories (CPC) scale (score of 1 to 5)⁴⁾. CPC scores of 1 and 2 indicated good neurological outcome while CPC scores of 3, 4, and 5 indicated poor neurological outcome. Medical records were thoroughly reviewed. Patients were graded on the CPC scale by two independent neurologists.

All recorded brain CT scans were taken within 48 hours after ROSC in this study. After successful ECPR, for patients who had a rapid recovery of mentality and neurological deficits, brain CT scan was not performed. Otherwise, brain CT scan was performed to determine whether control was needed for increased intracranial pressure (ICP). Brain CT scan was also used to exclude intracranial hemorrhage before therapeutic hypothermia by an intensivist. For all CT studies, 64-channel scanners (Light Speed VCT; GE Healthcare, Milwaukee, WI, USA) with a 5-mm slice width were used. Brain CT images were reviewed by two independent neurologists. Investigators who were blinded to clinical information opened these CT scans for each patient using commercial image-viewing software (Centricity RA1000 PACS Viewer; GE Healthcare, Milwaukee, WI, USA). ONSD and eyeball transverse diameter (ETD) were measured using the same initial CT and subsequent scans. The ONSD was measured at a distance of 3 mm behind the eyeball, immediately below the sclera in a perpendicular vector with reference to the linear axis of the nerve (Fig. 1A)^6,9,22). Images were changed to the “chest/abdomen” window (window width 300 & window level 10) and magnified four-fold on the particular image slice that demonstrated the largest diameter of the optic nerve sheath²²⁾. The ONSD was measured from one side of the optic nerve sheath to the other as a section through the center of the optic nerve⁹⁾. The transverse diameter of the eyeball was chosen because the ONSD was usually measured in the transverse plane²⁴⁾. ETD was defined as the maximal transverse diameter of the eyeball measured from one side of the retina to the other (in-to-in, Fig. 1B)^1,24). ONSD_average and the ETD_average measured for the patient’s left and right eyes were averaged to yield mean values⁹⁾. ONSD_index was defined as median ETD (23.0 mm) multiplied by the average value of bilateral ONSDs divided by the average value of bilateral ETDs (23.0×ONSD_average/ETD_average).

CPR was led by the hospital’s CPR team. All data related to the CPR scene were recorded by a bedside nurse according to the Utstein-style guidelines³⁾. The on-call ECMO team leader was called when CPR was performed for longer than 10 minutes or in the event of unstable vital signs or recurrent cardiac arrest. The ECMO team leader along with the CPR leader assessed the patient and decided whether to institute ECPR. ECPR was performed when a witnessed arrest was confirmed, the arrest persisted despite at least 10 minutes of conventional CPR, and the underlying cause of the arrest was considered reversible¹⁵⁾. Cases in which ECPR was deferred included a short life expectancy (<6 months), terminal malignancy, an unwitnessed collapse, limited physical activity, an unprotected airway, or CPR undertaken for longer than 60 minutes at the time of initial contact. Age alone did not constitute a contraindication of ECPR¹⁵⁾. The ECMO team at our institution consisted of cardiologists, cardiovascular surgeons, intensivists, specialized nurses, and perfusionists. Either a Capiox Emergency Bypass System (Terumo, Tokyo, Japan) or a Prolonged Life Support System (Maquet Cardiopulmonary, Hirrlingen, Germany) was used in these cases. A crystalloid solution such as normal saline or balanced solution was used for priming. No patient in this study underwent blood-primed ECMO. A percutaneous vascular approach was tried initially in all cases using the Seldinger technique. If percutaneous cannulation failed, a surgical cutdown exposure was performed¹⁵⁾. Femoral vessels were the most common sites of vascular access and 14 to 17 French arterial cannulas and 20 to 24 French venous cannulas were placed¹³⁾. Cardiac compression was stopped once ECMO initiation was deemed successful. Anticoagulation was accomplished with a bolus injection of unfractionated heparin followed by a continuous intravenous heparin infusion to maintain an activated clotting time between 150 and 180 seconds. The initial number of revolutions per minute of the ECMO device was adjusted to achieve an ideal cardiac index greater than 2.2 L/min/m² of body surface area, a central mixed venous oxygen saturation above 70%, and a mean arterial pressure above 65 mmHg¹³⁾. Blood pressure was monitored continuously through an arterial catheter and an artery in the right arm was used for arterial blood gas analysis to estimate cerebral oxygenation. After ECMO was established, necessary steps were taken to treat the underlying cause of cardiac arrest, including percutaneous coronary intervention, coronary artery bypass grafting, heart transplantation, and non-cardiopulmonary surgery¹³⁾.

All data are presented as medians and interquartile ranges (IQRs) for continuous variables and numbers (percentages) for categorical variables. Data were compared using Mann-Whitney U test for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. Predictive performances of ONSDs and their modification were assessed using area under the curve (AUC) of the receiver operating characteristic (ROC) curves for sensitivity vs. 1-specificity. AUCs were compared using the nonparametric approach published by DeLong et al.⁵⁾ for two correlated AUCs. Optimal cut-off values of ONSDs for predicting poor neurological outcome were obtained by ROC curve and Youden index^14,20). All tests were two-sided and p-values <0.05 were considered statistically significant. Data were analyzed using IBM SPSS statistics version 20 (IBM, Armonk, NY, USA).

A total of 52 patients with cardiac arrest who were rescued by veno-arterial ECMO were analyzed. Their median age was 53.0 years (IQR: 40.5–64.5 years). Of 52 patients, 39 (75.0%) were males. A cardiac cause of arrest was verified in 46 (88.5%) patients. Thirty-nine (75.0%) patients experienced cardiac arrest in the hospital while 13 (25.0%) patients had cardiac arrest in an out-of-hospital setting. The median time from arrest to ECMO pump-on was 43.0 minutes (IQR: 27.0–53.0 minutes). TTM was performed in 25 (48.1%) patients using surface cooling devices. Baseline characteristics of ECPR patients are presented in Table 1. Characteristics of cardiac arrest are shown in Table 2. There were no significant differences in baseline or arrest-related characteristics between the two neurological outcome groups except hemoglobin level before ECMO. Successful ECMO weaning was achieved in 29 (55.8%) patients. Survival to discharge was identified in 19 (36.5%) patients. Of these 19 survivors, 13 (25.0%) had good neurological outcomes (CPC score of 1 or 2).

In this study, ONSDs and ONSD_index in the poor neurological outcome group were significantly greater than those in the good neurological outcome group (Table 3). However, ETD was not significantly different between the two groups (p=0.770). In ROC curve analysis for predicting poor neurological outcome (Fig. 2), the C-statistic of ONSD_average was 0.856 (95% CI: 0.731 to 0.938). A cut-off >5.79 mm had a sensitivity of 71.8% (95% CI: 55.1% to 85.0%) and a specificity of 92.3% (95% CI: 64.0% to 99.8%). The C-statistic of ONSD_max was 0.778 (95% CI: 0.641 to 0.882). A cut-off >6.24 mm had a sensitivity of 51.3% (95% CI: 34.8% to 67.6%) and a specificity of 100% (95% CI: 75.3% to 100%). The C-statistic of ONSD_index was 0.860 (95% CI: 0.736 to 0.941). A cut-off >5.91 had a sensitivity of 71.8% (95% CI: 55.1% to 85.0%) and a specificity of 100% (95% CI: 75.3% to 100%). However, ONSDs and their modification showed similar performances for predicting poor neurological outcome. The predictive performance of ONSD_index for poor neurological outcome was not significantly different from that of ONSD_average or ONSD_max (p=0.913 and p=0.138, respectively).