Prognostic value of computed tomography score in patients after extracorporeal cardiopulmonary resuscitation

This was a retrospective, multicenter, observational study of adult patients who underwent ECPR during hospitalization at Hallym University Medical Center (HUMC) and Samsung Medical Center (SMC) between May 2010 and December 2016. This study was approved by the institutional review boards of HUMC (HUMC 2015i128) and SMC (SMC 2017-11-088-002). The requirement for informed consent was waived owing to the study’s retrospective nature. Clinical and laboratory data were collected by a trained study coordinator using a standardized case report form. We included patients who underwent ECPR during the study period. Those who were unconscious (a score < 9 on the Glasgow Coma Scale) [7] upon admission to the hospital after cardiac arrest and those who had a 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 lifespan was less than 1 year; those who had insufficient medical records; and those who had a history of head trauma, neurosurgery, or chronic neurological abnormality upon intensive care unit (ICU) admission. In addition, we excluded patients who had low ASPECTS and were suspected to have brain lesions due to factors other than hypoxic ischemic encephalopathy. We excluded patients for whom we could not define neurological status because of continuous sedation or death of unknown causes or causes other than brain death. Finally, a total of 58 patients with cardiac arrest who were rescued by venoarterial extracorporeal membrane oxygenation (ECMO) were analyzed in this study (Fig. 1).

In this study, ECPR was defined as both successful venoarterial 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 [11, 12]. 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. The resuscitation procedure was performed in the same way as described in our previous study [7, 13]. 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 was performed with surface cooling devices. We used a commercial temperature regulation system consisting of a hydrogel pad (Arctic Sun®; Medivance Corp., Louisville, CO, USA) or a cooling blanket. Surface cooling and the targeted temperature were determined by each intensivist in the ICU according to the therapeutic hypothermia protocol [14]. The primary outcome was neurological status upon hospital discharge assessed with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC) scale (1 to 5) [15]. CPC scores of 1 and 2 were classified as good neurological outcomes. CPC scores of 3, 4, and 5 were considered as poor neurological outcomes. We thoroughly reviewed medical records. Patients were graded on the CPC scale by two independent neurologists. Brain death was confirmed by neurologists. Brain death was diagnosed on the basis of absence of brainstem reflex by neurologic examination, electroencephalography (EEG), and apnea test. Sometimes, transcranial Doppler or brain CT angiography was needed to diagnose brain death when apnea test was impossible due to extracorporeal circulation. Prognostication upon electrocerebral inactivity on EEG and apnea led to termination of therapy or consideration of organ transplant. 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 mental status and neurological deficits, brain CT was not performed. Otherwise, brain CT was performed to determine whether control of increased intracranial pressure was needed. Brain CT was also used to exclude intracranial hemorrhage before therapeutic hypothermia by the intensivist. For all CT studies, 64-channel scanners (at HUMC, SOMATOM Sensation; Siemens, Erlangen, Germany; at SMC, 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 (at HUMC, PiView STAR; INFINITT Healthcare, Seoul, South Korea; at SMC, Centricity RA1000 PACS Viewer; GE Healthcare, Milwaukee, WI, USA). To evaluate the extent of hypoxic-ischemic insult quantitatively, newly modified CT scores were used that are based on the original ASPECTS protocol [8]. The original ASPECTS was used to predict neurological outcomes in this study. Of original ASPECTSs for both hemispheres, the smaller value was used for analysis. To evaluate brain injuries in both hemispheres, bilateral ASPECTS (ASPECTS-b) was extended to both sides based on the original ASPECTS protocol [10]. In addition, modified ASPECTS (mASPECTS) was used in this study. Similar to ASPECTS-b, each MCA territory was scored with 0–10 points. Anterior cerebral artery (ACA) and posterior cerebral artery (PCA) territories had 2 points corresponding to upper and lower levels of each territory. The brainstem and each cerebellar hemisphere had 1 point (Table 1, Fig. 2) [6]. Whenever there were early ischemic findings on CT images such as parenchymal hypoattenuation, cortical swelling with sulcal effacement, and loss of gray-white matter differentiation from each area, new CT scores were calculated by subtracting 1 point from the maximum of 20 (ASPECTS-b) or 31 (mASPECTS) [6, 10]. A brain with diffuse infarction that involved all areas was scored zero.

CPR was led by the hospital’s CPR team, and all data related to the CPR scene were recorded by a bedside nurse according to the Utstein-style guidelines [16]. 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 reversible [17]. 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 for ECPR [17]. The ECMO team at our institution consists of cardiologists, cardiovascular surgeons, intensivists, specialized nurses, and perfusionists. Either the Capiox Emergency Bypass System (Terumo, Tokyo, Japan) or the Prolonged Life Support System (Maquet Cardiopulmonary, Hirrlingen, Germany) was used in all 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 cut-down exposure was performed [17]. The 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 placed [12]. 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, central mixed venous oxygen saturation above 70%, and a mean arterial pressure above 65 mmHg [12]. 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, the necessary steps were taken to treat the underlying cause of cardiac arrest, including percutaneous coronary intervention, coronary artery bypass grafting, heart transplant, and noncardiopulmonary surgery [12].

All data are presented as median and interquartile range (IQR) for continuous variables and number (percent) for categorical variables. Data were compared using the Mann-Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. The predictive performance of each brain CT marker was assessed using AUC of the ROC curve for sensitivity vs. 1 − specificity. AUCs were compared using the nonparametric approach published by DeLong et al. [18] for two correlated AUCs. The optimal cut-off value of each brain CT marker for predicting poor neurological outcome was obtained by the ROC curve and Youden index [19, 20]. Intraclass correlation coefficient (ICC) was used to analyze interrater reliability of ASPECTS-b and mASPECTS [21]. ICC was estimated using a single-measurement absolute-agreement and two-way mixed-effects model [21]. All tests were two-sided, and p values < 0.05 were considered statistically significant. Data were analyzed using IBM SPSS statistics version 20 software (IBM, Armonk, NY, USA).

The median age of patients was 52 years (IQR, 37–58 years). Of 58 patients, 44 (75.9%) were males. A cardiac cause of arrest was verified in 49 (84.5%) patients. Thirty-one (53.4%) patients experienced cardiac arrest in the hospital, and 27 (46.6%) patients had cardiac arrest in an out-of-hospital setting. The median time from arrest to ECMO pump-on was 47.5 minutes (IQR, 29.0–63.0 minutes). Targeted temperature management was performed in 40 (69.0%) patients using surface cooling devices. Only one patient had ROSC during cannulation. Baseline characteristics of ECPR patients are presented in Table 2. Characteristics of cardiac arrest are shown in Table 3. There were no significant differences in baseline or arrest-related characteristics between the two neurological outcome groups. Successful ECMO weaning was achieved in 35 (60.3%) patients. Survival to discharge was identified in 25 (43.1%) patients. Of these 25 survivors, 19 (32.8%) had good neurological outcomes (CPC score of 1 or 2) (Fig. 1).

In this study, interrater reliabilities of CT scores were excellent. ICCs of ASPECTS, ASPECTS-b, and mASPECTS were 0.918 (95% CI, 0.865–0.950), 0.918 (95% CI, 0.866–0.951), and 0.915 (95% CI, 0.860–0.949), respectively. CT scores of ASPECTS, ASPECTS-b, and mASPECTS in the poor neurological outcome group were significantly lower than those in the good neurological outcome group (all p < 0.001) (Table 4, Fig. 3a). In ROC curve analysis for the prediction of poor neurological outcome, the C-statistic of ASPECTS was 0.812 (95% CI, 0.688–0.902). A cutoff ≤ 3 had a sensitivity of 59.0% (95% CI, 42.1–74.4%) and a specificity of 100% (95% CI, 82.4–100%). The C-statistic of ASPECTS-b was 0.818 (95% CI, 0.694–0.907). A cutoff ≤ 14 had a sensitivity of 66.7% (95% CI, 49.8–80.9%) and a specificity of 94.7% (95% CI, 74.0–99.9%). The C-statistic of mASPECTS was 0.922 (95% CI, 0.821–0.976). A cutoff ≤ 25 had a sensitivity of 84.6% (95% CI, 69.5–94.1%) and a specificity of 89.5% (95% CI, 66.9–98.7%). The predictive performance of mASPECTS for poor neurological outcome was better than that of ASPECTS or ASPECTS-b (p = 0.004 and p = 0.003, respectively). Among three regions (cortex, subcortex/basal ganglia, and brainstem/cerebellum) for mASPECTS, the score of cortex had the best predictive performance for poor neurological outcome after ECPR (Fig. 3b).

There were only ten patients for whom follow-up CT scans were performed within 7 days (three good neurological outcomes and seven poor neurological outcomes) during ECMO support. Four patients had lower CT scores than previous scans, and another six patients had the same scores as for previous scans. All four patients who had lower CT scores than on previous scans had poor neurological outcomes.

Portable EEG was performed in 30 patients within 7 days after ECPR. Continuous slow (36.7%) and background suppression (23.3%) were the most common EEG findings. One-half of patients received continuous intravenous sedatives during EEG monitoring. Therefore, EEG findings might have reflected the use of sedatives as well as hypoxic brain injury. All patients who had well-known malignant EEG patterns such as electrocerebral inactivity, burst suppression, or generalized periodic epileptiform discharges had poor neurological outcomes. The EEG findings are shown in Additional file 1.