Table 1.
Criteria suggested to indicate mitochondrial dysfunction.
Fig 1.
Hierarchical identification of neurometabolic states using multimodality monitoring.
This protocol may be used for clinical identification of mitochondrial dysfunction if consistent LPR > 25 remains despite optimization of other multimodal parameters. We distinguish consistency from transience utilizing a novel algorithm described in Fig 2. *Mitochondrial dysfunction must be observed with consistency for identification. LPR, lactate/pyruvate ratio; ICP, intracranial pressure; PbtO2, brain tissue oxygenation; PRx, pressure reactivity index.
Fig 2.
A two-parametera algorithm for differentiating consistent from transient attributes.
The attribute may be unimodal (e.g., LPR > 25) or multimodal (e.g., LPR > 25 with ICP ≤ 20 mmHg, PbtO2 ≥ 15 mmHg, PRx ≤ 0.3, and cerebral glucose ≥ 1.0 mM, which our group proposes as suggesting mitochondrial dysfunction). ᵃTwo parameters: 1. maximum time gap (e.g., 6 hours) for Good Neighbor test. 2. minimum duration (e.g., 50 minutes) for Good Neighbor Chain duration test. LPR, lactate/pyruvate ratio; ICP, intracranial pressure; PbtO2, brain tissue oxygenation; PRx, pressure reactivity index.
Fig 3.
Distributions of patients’ percentage of observations meeting deranged CMD criteria regardless of consistency versus with consistency in the complete CMD data cohort (n = 592).
For each set of criteria, the statistical comparison between the two distributions (difference in medians, 95% CI, and p-value) is displayed in a box at the bottom right. Difference in medians were calculated by subtracting that of the ‘With Consistency’ cohort from that of the ‘Regardless of Consistency’ (i.e., All) cohort. Except for the LPR > 25 criterion from our multimodality-monitoring-based classification protocol (Fig 1), used here without multimodality monitoring integration, all other deranged CMD criteria variants, regardless of consistency, were suggested by other groups to indicate mitochondrial dysfunction (Table 1). LPR, lactate/pyruvate ratio; Med., Median; Cons., Consistent; Diff. Med., Difference in Medians; 95% CI, 95% confidence interval; Regardless, Regardless of Consistency; CMD, cerebral microdialysis.
Table 2.
Patterns of patients meeting deranged CMD criteriaa regardless of consistency or with consistencyb in the complete CMD data cohort (n = 592).
Table 3.
Patterns of patients meeting deranged CMD criteriaa regardless of consistency or with consistencyb in the complete MMM data cohort (n = 268).
Table 4.
Differencesa in central tendency of patients’ percentage of observations meeting deranged CMD criteriab regardless of consistency or with consistencyc in the complete CMD data cohort (n = 592) versus the complete MMM data cohort (n = 268).
Table 5.
Differencesa in central tendency of patients’ means of parameters coinciding with differing consistently met deranged CMD criteriab in the complete CMD data cohort (n = 592).
Fig 4.
Means of patients’ means of parameters coinciding with consistently met deranged CMD criteria in the complete CMD data cohort (n = 592).
Cell shading indicates favorability of the parameter value, from dark green being most favorable to dark red being least favorable observed in the column. The LPR > 25 criterion alone stems from our use of it as a trigger for our multimodality-monitoring-based classification protocol for identifying neurometabolic states and mitochondrial dysfunction (Fig 1), while other criteria were suggested by different groups to indicate mitochondrial dysfunction (Table 1). Results in this figure depend on the consistency of the CMD-based derangement, expanding on deranged CMD criteria suggested by other groups, which do not require consistency. CMD, cerebral microdialysis; LPR, lactate/pyruvate ratio; PRx, pressure reactivity index; CPP, cerebral perfusion pressure; ABP, arterial blood pressure; ICP, intracranial pressure; PbtO2, brain tissue oxygenation.
Table 6.
Differences in central tendency of patients’ percentage of observations demonstrating hierarchically identified mitochondrial dysfunction regardless of consistency versus with consistency in the complete MMM data cohort (n = 268).
Fig 5.
Select results from algorithmic differentiation of consistent from transient mitochondrial dysfunction identified using our hierarchical MMM-based classification protocol (with a trigger of LPR > 25) (Fig 1).
MMM, multimodality monitoring; LPR, lactate/pyruvate ratio.
Table 7.
Prevalence of neurometabolic states identified by hierarchical classification in the complete MMM data cohort (n = 268).
Fig 6.
Means of patients’ percentage of observations demonstrating consistent neurometabolic states in the complete MMM data cohort (n = 268).
Each bar displays the results corresponding to one of five variations in the CMD-based trigger for our hierarchical MMM-based classification protocol, originally using the trigger of LPR > 25 (Fig 1). MMM, multimodality monitoring; CMD, cerebral microdialysis; LPR, lactate/pyruvate ratio.
Fig 7.
Relative distribution of consistent neurometabolic states identified by hierarchical classification in the complete MMM data cohort (n = 268).
Each pie chart displays the 100%-normalized means of patients’ percentage of observations demonstrating a consistent neurometabolic state, corresponding to one of five variations in the CMD-based trigger for our MMM-based classification protocol that originally uses the trigger of LPR > 25 (Fig 1). Crucially, these neurometabolic states are mutually exclusive, as each observation is assigned only to the first derangement identified in the hierarchical protocol from intracranial hypertension through mitochondrial dysfunction. For example, observations with both high ICP and hypoxia are classified solely as intracranial hypertension. CMD, cerebral microdialysis; LPR, lactate/pyruvate ratio; MMM, multimodality monitoring.