Our results show that neuroimaging combined with the neurological exam can improve prediction of clinical outcome for patients who survive more than 24 hours after cardiac arrest. Consistent with MRI studies that showed that global ADC reductions are predictive of poor outcome8, 9
, our study shows that changes in the brain due to cytotoxic edema resulting in decreases in median whole brain HU are also predictive. Not surprisingly, the initial rhythm of cardiac arrest (i.e. whether it was shockable or not) and GCS_Day3 were also found to be significant predictors.
Torbey et al showed that combining neuroimaging (ratio of CN/PLIC) with clinical parameters (reversed GCS and duration of arrest (DAR)) can improve patient prognostication31
in a cohort of 32 patients. Our study did not include DAR because it could not be determined accurately in the majority of our patients since it was not prospectively recorded. Our study also included only patients with a maximum admission GCS of 8, while the Torbey et al study included patients with GCS scores up to 15, suggesting our patients consisted of a more critically ill population. In addition, the CN HU in our study (27 [25–29]) was lower than that reported in previous studies13, 14
, again indicative of a more severely injured group. Our study strictly included only truly comatose patients, which may help to explain the high mortality rate in comparison to other studies which may have included post-cardiac arrest patients who, in distinction, had a depressed level of consciousness but who were not comatose. This led to the limited number of patients with good outcomes that in turn resulted in the large confidence intervals in our specificity for predicting poor outcome. Further studies are therefore necessary, involving greater number of patients to more accurately estimate the specificity of tools for prognosticating poor outcome in comatose cardiac arrest patients before they can be used for clinical decision-making. Such studies should be limited to those patients in whom the prognosis is truly in question, excluding those rapidly awakening (and therefore with higher GCS scores) or brain dead.
Regionally, we found that decreased HU's in the putamen and the PLIC were significant predictors of poor outcome, not surprising given their important roles in motor function and the emphasis of mRS on motor recovery32
. Further, the early selective sensitivity of the basal ganglia to global ischemia has been well documented12
. We found that the ratio of the putamen/PLIC was predictive of poor outcome, but not CN/PLIC, consistent with a previous study by Torbey et al13
. Another study14
by Choi et al found that CN/PLIC within 24 h in 28 patients was predictive of poor outcome. Differences in our findings are likely due to differences in outcome measures, patient cohorts and timing of CT. Subset analysis of patients imaged early or late showed that putamen/PLIC was significantly associated with poor recovery only for patients scanned >24 hours post-arrest. In comparison, the other regions no longer exhibited significant differences in the late group, despite being significantly different within 24 hours (), but this is likely due to limited number of patients with good recovery (N=3) in the late group. Of all the regions examined, only the putamen demonstrated a significant decline between early and late CT HU values.
Our regional results are consistent with our MRI study in comatose post-cardiac arrest patients8
. In the MR study, for 48 patients imaged within 72 h, ADC values tended to be higher in the patients who achieved good outcomes (N=6) compared to those with poor outcomes (N=42). These differences were not statistically significant for all regions, likely due to the limited sample size, which resulted in the MRI study being underpowered for regions that did not demonstrate severe ADC reduction. Further, there are temporal differences in the two studies. In the MRI study, 21% of the studies were performed on Day 0, while for this CT study 68% were performed on Day 0. We speculate that pseudonormalization in ADC as a result of reperfusion, as demonstrated in animal models of global ischemia33
, may diminish detectable differences in ADC values between patients with good and poor outcomes the later the MRI is obtained. To properly compare the strengths and weaknesses of the two imaging modalities, and to understand the physiological implications of differences in findings, one would need a prospective study in which both modalities were acquired at similar time points.
For patients for whom Day 3 neurological exam data was collected, our sensitivity and specificity results for the predictive performance of clinical signs for poor outcome were consistent with previously published findings7
. Discrepancies in predictive performance when using either M≤2 or AAN Practice Parameter recommendations were found for patients who underwent hypothermia therapy, suggesting caution is needed when using motor response for prognostication purposes given that hypothermia-treated patients may have poor motor responses on Day 3 despite eventual good outcome2, 34
. For patients for whom GCS_Day3 was obtained, combining neuroimaging data with neurological exam data improved prognostication of patient outcome over use of imaging or clinical data alone. For patients in whom prognostication is most difficult, i.e. those who are not rapidly deteriorating, imaging may therefore provide supplemental information regarding the severity of brain injury. Although sophisticated brain segmentation techniques can significantly increase prognostic performance of our models, inclusion of a single easily measured parameter, i.e. median whole brain HU, was able to offer significant improvements over the sole use of GCS measured 3-days post-arrest. Multivariate models involving regional changes, however, may be useful for providing insight into the pathophysiological processes following global hypoperfusion and resuscitation. Exclusion of hypothermia patients also improved prognostication for the multivariate models, although using GCS3 ≤8 provided 100% sensitivity at 100% specificity. This suggests that patients not treated with hypothermia who are still comatose at Day 3 will likely have a poor outcome. For patients treated with hypothermia, this may be inaccurate. In addition, not all hypothermia-treated patients had a good outcome. Of the 33 patients who received hypothermia, 79% had a poor outcome. The percentage of patients with good outcomes (21%) is much lower than what has previously been reported in two randomized studies of hypothermia treatment in survivors of cardiac arrest due to ventricular fibrillation, in which 43–55% of the patients treated had good outcomes35, 36
. We suspect this may be due to the fact that only 55% (N=18) of our treated patients had shockable rhythms, and of these only 33% (N=6) had good outcomes. The addition of imaging increased the specificity of the neurological exams and maintained high specificity even for patients treated with hypothermia. This is especially important as hypothermia increasingly becomes part of standard management in these patients.
The observational nature of this study introduces potential bias in terms of the decision to perform imaging and the timing of the scan. Ideally, imaging would be obtained at admission and at 3 days. Many patients died due to withdrawal of care, a common problem in these studies, resulting in a self-fulfilling prophecy of poor outcome in patients who may have otherwise recovered2
. Clinicians in this study were not blinded to the CT or any other data, and thus abnormal CTs might have swayed the treating team. However, the treating team did not do a quantitative evaluation of HUs, and thus any patient management decisions based on imaging findings would likely have been based purely on drastic gross changes, which were not common in our population. Prospective studies are clearly needed with pre-specified imaging and neurological examination times, as well as sufficient time to allow for recovery in patients for whom the outcome is in question.