Scientific Papers

Quantitative analysis of early apparent diffusion coefficient values from MRIs for predicting neurological prognosis in survivors of out-of-hospital cardiac arrest: an observational study | Critical Care


In this retrospective analysis, the group with poor neurological outcomes had lower mean whole brain ADC values and higher ADC-PercentValue thresholds in all ranges (250 to 1150 × 10−6 mm2/s). The mean whole brain ADC value and ADC-PercentValue between 350 and 650 × 10−6 mm2/s showed better prognostic performance than the GWR value. Of these, the mean whole brain ADC value was the best predictor (AUC 0.83; sensitivity 51% when FPR was 0%) of poor neurological outcomes. Multivariable regression analysis of cardiac arrest characteristics showed that mean whole brain ADC values and the ADC-PercentValues 600 and 650 × 10−6 mm2/s were independently associated with poor neurological outcomes. In predicting neurological outcomes, the multimodal assessment that combined the absence of PLR, serum NSE levels, and mean whole brain ADC value had the highest accuracy (0.91) and sensitivity (51%), at an FPR of 0%, in predicting poor neurological outcomes (CPC 3–5) 6 months after OHCA.

International guidelines for post-cardiac arrest care recommend predicting prognosis 72 h after ROSC to prevent inappropriate WLST in patients with good neurological outcomes [5, 27]. However, the recent COVID-19 pandemic sparked significant discussion regarding the appropriate distribution of medical resources, and several research findings have been reported on the utility of early neurological outcome prediction (i.e. within 6 h after ROSC) in survivors of cardiac arrest [7, 11, 28]. Particularly, early neurological outcome prediction could be helpful when there is a reluctance to provide therapeutic interventions to patients unlikely to benefit, or when treating a patient with an intervention lasting at least 72 h seems unwarranted due to minimal chances of recovery. Nevertheless, despite the potential advantages of early prognostication and our significant findings in this study, it remains insufficient to justify making a clinical decision (i.e. WLST) based entirely on early neurological outcome prediction. It would be pertinent to justify early decision-making for the appropriate allocation of medical resources through early neurological outcome prediction only after confirmatory prospective multicentre evaluation in an unbiased and reproducible setting and after renewed ethical consideration. Therefore, an important ethical consideration in the early prediction of prognosis was to allocate treatment opportunities, such as intensive care units, to survivors of cardiac arrest who were predicted to have good neurological outcomes, rather than making early decisions for withdrawal of life-sustaining treatment (WLST).

In this study, CT-based GWR values obtained within 6 h after the ROSC mostly had poor prognostic prediction performance compared to MRI-based ADC metrics. In the case of CT, observational studies in severe HIBI patients have shown that GWR gradually decreases over time, resulting in poor predictive performance in early CT scans (within 6 h after ROSC) (AUC 0.70), which improved in late CT scans (after > 24 h of ROSC) (AUC 0.80) [29]. Therefore, they reported that CT scans performed after 24 h of ROSC remain an important option in the multimodal approach to neuroprognostication. In contrast, cytotoxic oedema due to HIBI after acute cardiac arrest displays high-signal intensity (HSI) with low ADC much earlier (within 6 h after ROSC) in DW-MRI [1, 2, 5, 13]. Prognostic studies using the presence of HSI on DW-MRI have shown varying sensitivity and specificity, probably due to inconsistency between studies or the lack of a precise definition of HSI [7,8,9, 18, 19]. Although analysed by the same scanner and neuroradiologist as in our previous study, studies using DW-MRI performed within 6 h and 72 to 96 h after ROSC demonstrated differences in prognostic performance and sensitivity between 0.87 versus 0.97 and 74% versus 93%, respectively [7, 8]. However, the ADC enables quantitative measurement of diffusion changes in brain MRI, with low ADC values indicating restricted diffusion. Yet, there is no consensus on the ideal technique for evaluating the decrease in ADC value in the brain after HIBI [20,21,22,23].

When the number of voxels with an ADC value of less than 650 × 10−6 mm2/s exceeded 10% of the total voxels in the brain, it was associated with poor neurological outcomes, with a specificity of 91% and sensitivity of 72% in predicting those outcomes [20, 21]. Furthermore, a prospective cohort study conducted to validate the threshold of this research, reported a predictive value of 0.79 when the specificity was 96% and sensitivity was 63% [22]. Contrarily, another study did not confirm the prediction of poor neurological outcomes when applying the same threshold criteria (AUC 0.59) [23]. However, they reported that the proportion of brain voxels below 650 × 10−6 mm2/s, which is required to predict a poor neurological outcome with 100% specificity, was similar at 23.4% compared to 22% in the study by Hirsch et al. [20].

Additionally, a systematic review reported that all studies identified ADC thresholds for the FPR of 0%, often with a sensitivity greater than 50%, including the mean global or regional ADC value of the brain, the proportion of voxels with low ADC value, and a maximum size of MRI clusters with minimum ADC [1, 30]. In the present study, the mean whole brain ADC value demonstrated the best predictive performance (AUC 0.83; sensitivity 51%; specificity 100%) for predicting poor neurological outcomes. Moreover, the proportion of brain voxels with ADC values less than 650 × 10−6 mm2/s was 30.6%, which was higher than that in previous studies [20, 23]. There are several possible explanations for this discrepancy in the prognostic performance of the quantitative analysis of ADC between studies: differences in (1) the timing of scans after cardiac arrest, (2) the performance of the MRI machine (i.e. the strength of the magnet), and (3) a potential for confounding effects on brain image patterns emerging from neurological disorders other than HIBI after cardiac arrest.

The study by Wouters et al. [23] assumed that the reasons for the differences in results between studies included the differences in the timing of defining neurological outcomes after cardiac arrest, the timing of MRI scans, the MRI analysis method, and the definition of poor neurological outcomes. Furthermore, changes in the ADC can be apparent in the early post-arrest period. However, in many patients, changes in the ADC are not apparent until more than 24 h post-arrest [17]. In this study (within 6 h after ROSC), the DW-MRI was performed earlier compared to other studies (2–7 d after ROSC) [20,21,22,23]. Therefore, it is estimated that a higher proportion of brain voxels with an ADC value of less than 650 × 10−6 mm2/s is required to predict a poor neurological prognosis when the FPR is 0%, compared to previous studies, owing to the time-dependent occurrence of brain oedema (cytotoxic oedema) after HIBI [20,21,22,23]. In our previous study, ADC-PercentValue of 520 × 10−6 mm2/s obtained between 72 and 96 h after ROSC demonstrated a sensitivity of 73.3% (95% CI 44.9–92.2) at a cut-off value > 4.9% when the FPR was 0% [8]. However, in the present study, with the most similar ADC threshold at 500 × 10−6 mm2/s, the cut-off value exceeded 8% (sensitivity 41%; 95% CI 29–53). In addition to the DW-MRI, the GWR measured on brain CT also showed differential prognostic performance according to the timing of the scan in relation to cardiac arrest. Therefore, we suggest that it would be appropriate to adjust the cut-off threshold of FPR 0% at specific ADC thresholds based on the MRI scan time point.

Additionally, previous studies have compared images obtained from 1.5 T and 3 T MRI scanners by integrating them without distinguishing between them. However, we are concerned whether the 1.5 T and 3 T MRI scanners, due to their different imaging protocols, yield the same ADC thresholds to represent the size of restricted diffusion in HIBI. Furthermore, it is established that 3 T provides much better contrast, resolution and signal-to-noise ratio in DWI compared to 1.5 T MRI scanners [31, 32]. Although we were unable to find comparative data for HIBI, our concern is supported by the findings of Tang et al. who examined the use of DWI for the quantitative analysis of focal liver lesions and found that the ADC thresholds for both the largest solid area and the maximum diameter of the lesion differed between the 1.5 T and 3 T protocols [33].

To the best of our knowledge, none of the studies for the quantitative analysis of DW-MRI considered the confounding effects on the brain image patterns arising due to non-HIBI conditions after cardiac arrest, such as a metabolic crisis (e.g. hypoglycaemia, hyperammonaemia, or other conditions), seizures, or opioid intoxication [34]. In particular, seizures occur in 15–44% of the patients with HIBI after cardiac arrest [35, 36]. In view of the different manifestation in DW-MRI and the high prevalence of such medical conditions, the potential impact of non-HIBI conditions on the brain image patterns in DW-MRI needs to be considered in the future studies.

International guidelines for post-cardiac arrest care recommend a multimodal approach to predict prognosis [5]. However, it is not always possible to obtain all the predictive variables desired at the time of prognosis prediction [3]. Therefore, in this study, we used only a combination of easily available clinical variables, such as PLR and serum NSE levels within 6 h after ROSC, instead of identifying the optimal timing for each predictor to achieve the best predictive performance. Furthermore, considering that serum NSE levels and neuroimaging variables are minimally influenced by sedatives and neuromuscular blockers administered to patients, they are useful in this context [1,2,3, 5]. The predictive performance of the combination of the absence of PLR, serum NSE levels and mean whole brain ADC value was excellent (AUC 0.91), with a sensitivity of 51% at an FPR of 0%. Although the sensitivity was slightly lower than the 60% sensitivity at an FPR of 0% reported in an external validation study of the 2020 ERC/ESICM prognostic algorithm [35], it still holds considerable value when considering the prediction timing (within 6 h after ROSC vs. 72 to 96 h after ROSC). Additionally, in a recent study predicting a poor neurological outcome based on the presence or absence of HSI in DW-MRI within 6 h and up to 10 days after the ROSC, the sensitivity values at 0% FPR were 74.2% and 89.6%, respectively [7, 19]. Generally, these values are higher than those reported in previous studies using voxel-based quantitative ADC analysis [20,21,22,23]. Therefore, varying results obtained due to differences in analytical methods suggest the need for a prospective comparative study using MRI conducted at a more consistent time, considering inter-rater agreements and the applicability to clinical settings.

Limitations

This study has several limitations. First, it focused solely on patients who underwent DW-MRI within 6 h after the ROSC in a single centre, resulting in a small sample size. Most researchers are reluctant to obtain MRI scans from patients who are intubated and critically ill. No adverse events or complications related to early MRI were observed during the study period. Therefore, prospective multicentre studies are required to generalise these results. Second, due to the lack of universal consensus on the ideal technique for MRI analysis, the results can vary depending on the approach used. Third, when predicting outcomes in survivors of cardiac arrest at an early stage (i.e. within 6 h after the ROSC), it is preferable to focus on good neurological outcomes. However, in this study, our objective was to predict poor neurological outcomes. This is because there are many studies on the prediction of poor neurological outcomes in general and there are limitations in understanding values based on the results of single-centre studies with small sample sizes. However, Sandroni et al. reported in their study that the accuracy of predicting good neurological outcomes was inversely proportional to the accuracy of predicting poor neurological outcomes [3]. In other words, the specificity for predicting good neurological outcomes is equivalent to the sensitivity for predicting poor neurological outcomes and vice versa. Finally, MRI analysis using FSL software was performed blind to the clinical outcomes of the patients after their medical care was completed. However, the qualitative findings of early DW-MRI (presence or absence of HSI) were exposed to clinicians, potentially introducing a self-fulfilling prophecy bias. However, our institution did not allow WLST during TTM, unless the patient was diagnosed as brain dead; in this study, WLST during TTM did not occur, although some patients were pronounced dead according to circulatory or neurological criteria despite maximal support.



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