Predicting outcome after aneurysmal subarachnoid hemorrhage by exploitation of signal complexity: a prospective two-center cohort study

Abstract

Background: Signal complexity (i.e. entropy) describes the level of order within a system. Low physiological signal complexity predicts unfavorable outcome in a variety of diseases and is assumed to reflect increased rigidity of the cardio/cerebrovascular system leading to (or reflecting) autoregulation failure. Aneurysmal subarachnoid hemorrhage (aSAH) is followed by a cascade of complex systemic and cerebral sequelae. In aSAH, the value of entropy has not been established yet.

Methods: aSAH patients from 2 prospective cohorts (Zurich-derivation cohort, Aachen-validation cohort) were included. Multiscale Entropy (MSE) was estimated for arterial blood pressure, intracranial pressure, heart rate, and their derivatives, and compared to dichotomized (1-4 vs. 5-8) or ordinal outcome (GOSE-extended Glasgow Outcome Scale) at 12 months using uni- and multivariable (adjusted for age, World Federation of Neurological Surgeons grade, modified Fisher (mFisher) grade, delayed cerebral infarction), and ordinal methods (proportional odds logistic regression/sliding dichotomy). The multivariable logistic regression models were validated internally using bootstrapping and externally by assessing the calibration and discrimination.

Results: A total of 330 (derivation: 241, validation: 89) aSAH patients were analyzed. Decreasing MSE was associated with a higher likelihood of unfavorable outcome independent of covariates and analysis method. The multivariable adjusted logistic regression models were well calibrated and only showed a slight decrease in discrimination when assessed in the validation cohort. The ordinal analysis revealed its effect to be linear. MSE remained valid when adjusting the outcome definition against the initial severity.

Conclusions: MSE metrics and thereby complexity of physiological signals are independent, internally and externally valid predictors of 12-month outcome. Incorporating high-frequency physiological data as part of clinical outcome prediction may enable precise, individualized outcome prediction. The results of this study warrant further investigation into the cause of the resulting complexity as well as its association to important and potentially preventable complications including vasospasm and delayed cerebral ischemia.

Keywords: Complexity; Multiscale entropy; Outcome; Subarachnoid hemorrhage.

Fig. 1

Glasgow Outcome Scale Extended (GOSE) at 12 months (A—derivation cohort; B—validation cohort)

Fig. 2

MSE vs. Dichotomized Outcome. Panel A. The different MSE metrics are shown using boxplots comparing unfavourable (GOSE 1–4; pink) and favourable (5–8; green) outcome. An independent t-test was used for statistical analysis. Significant differences are shown using asterisks (*** = p < 0.001). The specific p-values were: MSE abo (9.15 e-16), MSE sbp (3.81 e-19), MSE dbp (7.17 e-13), MSE cpp (1.77 e-6), MSE hr (6.65 e-19) MSE icp (4.70 e-10), MSE amp (6.72 e-6). Panel B shows the corresponding ROC curves describing the predictive value of the different MSE scores

Fig. 3

MSE vs. Ordinal Outcome. The different MSE metrics are shown using boxplots grouped by ordinal outcome: Dead/Vegetative (GOSE 1–2), Severe Disability (GOSE 3–4), Moderate Disability (GOSE 5–6), and Good Recovery (GOSE 7–8). The color coding ranges from intense pink (dead/vegetative) to intense green (good recovery). The respective p-values of the performed ANOVA can be found in Table 3