This retrospective multicenter study showed that, while all patients in the HSI-presence group had poor neurological outcomes, 24.5% of those in the HSI-absence group also had false-negative findings with poor neurological outcomes. In our cohort, prolonged low-flow time, longer ROSC to DW-MRI scan-interval, and non-shockable rhythm were independently associated with HSI-presence. Optimal cut-off values for predicting HSI-presence accurately were a ROSC to DW-MRI scan-interval ≥ 2.2 h and a low-flow time > 21 min. In particular, when predicting poor neurological outcomes using clinical factors related to OHCA based on the ROSC to DW-MRI scan-interval, the predictive performance was higher when the interval was ≥ 2.2 h than when it was < 2.2 h, in all groups.
DW-MRI serves as the initial imaging sequence to depict changes in HIBI, typically revealing HSIs in areas such as the cerebral cortex (particularly the perirolandic and visual cortices), deep gray matter (basal ganglia and thalami), and hippocampus[27–30]. HSIs on ultra-early DW-MRI scan indicate an irreversible progression to severe HIBI, regardless of its location and extent[14–18]. This interpretation differs from that of a post-TTM DW-MRI, where the neurological outcome varies depending on the location and extent of HSI[10, 14–18, 29–31].
The optimal timing for ultra-early DW-MRI in OHCA-survivors remains unknown. An ischemic attack-to-DW-MRI scan-interval ≥ 2 h reduces false-negatives in transient ischemic attacks and cerebral infarction[31–33]. In this study, the cut-off value for the ROSC to DW-MRI scan-interval was 2.2 h. This finding was similar to that related to ischemic attacks. The DW-MRI changes post-cardiac arrest are expected to show time-dependent patterns.
Ultra-early DW-MRI signal alterations can differ based on the severity of hypoxia during cardiac arrest and the scanning time[14, 15, 34]. Unlike cerebral infarction, ultra-early DW-MRI is performed after the blood flow is restored throughout the brain following cardiac arrest-induced HIBI. Cytotoxic edema, hemodynamic changes, and altered substance diffusion speed, which progress throughout the entire brain, are critical factors in the early stages of HIBI[5, 18]. Cytotoxic edema involves increased cell membrane permeability, leading to temporary reduction in diffusion and potentially smaller or absent lesions on DW-MRI scans[31, 32]. Hemodynamic changes can disrupt the blood flow, further impacting substance diffusion around the injury site[35, 36]. Moreover, slower substance diffusion rates in the whole brain may also contribute to the DW-MRI presentation of a smaller HSI[35, 36]. However, the potential occurrence of false-negative findings on ultra-early DW-MRI due to these factors can be overcome by adjusting the scan timing[35, 36]. In this study, these factors showed a clear pattern in which false-negative findings decreased as the severity of hypoxia increased (e.g., longer low-flow time and non-shockable rhythm). Additionally, these false negative findings were reduced as the ROSC to DW-MRI scan-interval increased. Therefore, these factors and DW-MRI scan timing might collectively play a significant role in false-negative findings on ultra-early DW-MRI.
In this study, the cut-off value for the low-flow time of HSI-presence was > 21 min, supporting the findings of previous studies reporting poor neurological outcomes for low-flow durations of ≥ 20 min or > 30 min[19–21, 37–40]. Particularly, in the patients with low-flow time > 30 min in the poor neurological outcome group, all but one patient exhibited HSI-presence. However, favorable outcomes were observed in some cases with prolonged low-flow time of > 30 min. HSI was absent in all of them. Moreover, non-shockable rhythm indicated poor neurological outcomes[24, 37–39]. However, favorable outcomes have also been observed in a significant number of non-shockable cases. Therefore, for OHCA survivors with low-flow time > 21 min or a non-shockable rhythm, the significance of ultra-early DW-MRI becomes more evident. The presence or absence of HSI provides adequate data for predicting neurological outcomes. Thus, in cases with a low-flow time of > 21 min and a non-shockable rhythm, the integration of ultra-early DW-MRI into objective neurological outcome predictions seems to be warranted.
When the ROSC to DW-MRI scan-interval was ≥ 2.2 h, ultra-early DW-MRI exhibited excellent performance in predicting poor neurological outcomes, notably in patients with a low-flow time of > 21 min or a non-shockable rhythm. Moreover, a ROSC to DW-MRI scan-interval of < 2.2 h still provided adequate prediction of neurological prognosis. However, for patients with a low-flow time ≤ 21 min or a shockable rhythm, a minimum ROSC to DW-MRI scan-interval of 2.2 h was essential. If the ROSC to DW-MRI scan-interval was < 2.2 h, the neurological outcome predictions were less reliable. Thus, ultra-early DW-MRI conducted beyond 2.2 h were found to be more dependable, particularly in patients with a low-flow time of ≤ 21 min or a shockable rhythm.
These results indicated that increased hypoxic severity increases the likelihood of detecting HSI on ultra-early DW-MRI, which suggests poor neurological outcomes, particularly in prolonged low-flow time and non-shockable rhythm scenarios. Moreover, in less severe hypoxic situations, such as a short low-flow time or shockable rhythm, the timing of ultra-early DW-MRI becomes more pivotal. Ultra-early DW-MRI can potentially enhance the diagnostic precision for OHCA survivors by optimizing the scan timing, particularly in relation to low-flow time and first monitored rhythm. Therefore, as low-flow time and first monitored rhythm are uncontrollable factors, refining ultra-early DW-MRI timing based on these factors is crucial for a more accurate prediction of neurological outcomes.
The strengths of our study include its multicenter design and the training provided at each site. Despite advancements in this field, ultra-early DW-MRI is less commonly used in clinical settings than is post-TTM DW-MRI, partly because of the lack of established guidelines for imaging timing, and particularly concerning factors such as low-flow time and first monitored rhythm. Therefore, once validated, our data may contribute to future evidence-based guidelines for employing ultra-early DW-MRI for prognostication before TTM.
This study also had some limitations. First, as this was a retrospective study with a limited sample size, a larger prospective study is needed to ensure generalizability of the results. Second, a self-fulfilling prophecy bias might have occurred because the treating physicians had access to the DW-MRI results. However, WLST was not permitted in South Korea before February 2018, and during TTM in this study, WLST was not applied in any patient. Third, the analysis of no-flow time data was not included. In unwitnessed cases, determining the precise no-flow time was not feasible[40, 41]. Therefore, prolonged no-flow time could potentially impact the severity and affect HSI-presence[40, 41]. Fourth, we were unable to include qualitative aspects of basic life support and advanced cardiovascular life support in our analysis[42–45]. These could influence the severity of HIBI, thereby affecting HSI-presence. Finally, this study may have been affected by selection bias. While our protocol dictates performing DW-MRI before TTM, 261 patients had undergone TTM during the study, and 68 (21.1%) were excluded, possibly causing selection bias, and limiting the generalizability of our findings.
In conclusion, our study indicated that a longer ROSC to DW-MRI scan-interval is necessary with a shorter low-flow time or shockable rhythm. However, with a longer low-flow time or non-shockable rhythm, the urgency for the ROSC to DW-MRI scan-interval diminishes. Therefore, we recommend an optimal timing for ultra-early DW-MRI of ≥ 2.2 h, and particularly in cases with a low-flow time of ≤ 21 min or shockable rhythm. These findings warrant further validation via a prospective multicenter study to confirm their reliability and generalizability.