In this study comprising more than 7,350 hourly samples of complete MD sets from 90 patients, we have performed an extensive search with several types of statistical and computer-based linear and nonlinear pattern recognition methods to explore the relationship between ICP, CPP and the commonly used MD markers in TBI monitoring. The main finding is that despite much of the data indicating highly perturbed metabolism, the relationships between MD and ICP and/or CPP are weak. This suggests that factors other than these pressure and/or surrogate flow variables may be dominant causes of perturbations in the clinical TBI setting. In contrast, intrasubject correlations (autocorrelation) of MD are high for all MD parameters and ratios, even up to 30 hours. In fact, these autocorrelations are so extended in time that subject identities alone explain 52% to 75% of MD variable variance. This indicates that the dominant patterns of MD seen in TBI (with the studied variables) are protracted, reflecting processes that change over days or longer. This leaves limited unexplained variance to be shared among other variables that have been shown to affect MD values during monitoring, such as hyperventilation , meningitis , temperature  and seizures . Importantly, this applies to catheters in both (CT-defined) pericontusional and nonpericontusional locations. In contrast to long-term associations of MD, short-term (differentiated) associations of MD, though significant for CPP in pericontusional tissue, explain only up to 0.2% of variance. These results may not be harmonious with the expectations of MD as a dynamic and interpretable online monitor of ischemia and/or hypoxia in TBI. In addition, a significant relation was found between CPP and/or ICP and GOS score, but this could not be confirmed for MD and GOS score.
MD is commonly sampled once per hour in the NICU. The objective is to monitor short-term changes and more long-term trends. Short-term changes have focused primarily on potentially ischemic and/or hypoxic interpretations of the data, where increased LP ratios and low glucose have often been implicated as being local ischemic and/or hypoxic metabolic responses . The traumatic border zone has been recognized as distinctly different from the ischemic penumbra as well as regionally heterogeneous [30–32]. The interpretation of more long-term patterns of metabolic perturbation have received less focus, but increased LP ratios have also been linked to different causes of altered oxygen utilization in TBI, as opposed to oxygen delivery. These include oxygen diffusion barriers , mitochondrial dysfunction [15, 33] and increased metabolism of glucose . In addition, irreversibly damaged (posthypoxic) but reperfused regions may also display extended periods with MD of ischemic and/or hypoxic character . Alternative interpretations of lactate, pyruvate and LP ratios in TBI have therefore been postulated , and more complex supply-and-demand relations of these parameters under nonischemic conditions have also been identified . Moreover, MD may also be influenced by static parameters such as catheter placement in gray or white matter , genetics  and patient sex . Our study strongly indicates that the dominant information content in MD of TBI patients are that of long-term patterns, which is reflected in the strong autocorrelations, and that MD can so highly be explained by subject identities. This includes the LP ratio, which is also seen to be highly autocorrelated. The significant but weak cross-correlations between MD and ICP and/or CPP are also seen to be predominantly caused by long-term perturbations, as the correlations are largely unaffected by how subject MD data hours are serially related to ICP and/or CPP hours. In addition, the MD response to CPP and/or ICP changes is variable even in ranges that are by consensus considered unsafe. This may lead clinicians to question the current value of hourly sampling of MD in clinical TBI monitoring in the absence of known cause-and-effect relationships and points to a need for more reliable interpretations of pathological values for clinical use. We suspect that to differentiate patterns displaying similar levels, and possibly with different etiologies, one needs also to better include temporal relations of MD patterns.
The effect of CPP and/or ICP on local and global blood flow in TBI is complex , and the effects on MD have been found to be variable. Extreme ranges of ICP and/or CPP have been shown to have predictable effects on regional MD , and Nordström et al.  identified MD changes related to CPP < 50 mmHg and > 70 mmHg. In contrast, CPP augmentation has been shown to increase cerebral blood flow with positron emission tomography (PET), but not to translate to predictable changes in regional chemistry as seen with MD . In addition, increased LP ratios in pericontusional tissue have been shown to be independent of CPP . Our study distinguishes long-term from short-term relationships between MD and ICP and/or CPP. We have used multiple analytical techniques to assess our data, and the findings are in basic congruence. Despite a weak correlation, CPP is found to be related to MD exclusively in pericontusional tissue, whereas ICP is related to MD in both peri- and nonpericontusional tissues. In contrast to long-term relations, differentiated short-term values were exclusively related to CPP in pericontusional locations, but with < 0.2% explained variance. Moreover, we cannot confirm the findings of Belli et al. , who found that increased LP ratios preceded increased ICP. Multivariate analyses in our study also suggest that the composite strongest association is found between MD and ICP in nonpericontusional data, which is reasonable as this catheter placement may represent a more global monitor. Glucose is identified as the most dynamic marker and is least autocorrelated. In the aggregate, we can identify several expected and previously known relations between CPP and/or ICP and MD, but we conclude that the explained variance is such that MD perturbations must have other main causes.
A few studies have related MD to GOS score. Patient outcome was earlier been found to be related to high MD potassium , increased lactate and low glucose , persistent low glucose [44, 45] and increased glutamate [46, 47] levels, but variable for glycerol [48, 49]. Recently, N-acetylaspartate sampled by MD has also been implicated as a marker of outcome . That MD is so highly subject-related motivates comparisons of mean (per subject) MD and GOS score. We found that GOS score was significantly related to CPP and ICP, but not to any separate MD marker level (glucose, lactate, pyruvate, or glycerol) or MD ratio. This indicates that the extremely local nature of this monitoring method may portray information that does not necessarily translate to a total patient situation.
Consequently, to our knowledge, there exists no current interpretation of absolute, relative or trend data of the current common MD variables that can be strongly and consistently related to explanatory variables, such that it lends evident support to clinical decision-making, a prerequisite for any monitoring system. In addition, although the distinction of peri- and nonpericontusional catheter locations appears to provide different information, possibly on the basis of different metabolic processes, the identification of pericontusional tissue may be uncertain on CT scans . Using MD as an alert signal (toward normality-good or away from normality-bad)  appears logical but must be accompanied by identifiable cause-and-effect relations on the basis of which to steer interventions. As yet, this information is, to our knowledge, lacking for MD.
A potential weakness of the study is that the caregivers were not blinded to the MD data. During periods when MD displayed possible true ICP and/or CPP dependencies, these have been identified and acted on. We do not believe this to be the case, as doctors' responses to pathological MD values vary greatly. Moreover, no standardized treatment algorithms were suggested during this study or in the literature. In addition, resistance governs the relation between CPP and flow. This is affected by autoregulation, which we have no measure of globally or locally. An additional weakness is that we have no direct measure of tissue hypoxia with which to validate the absence or presence of such in relation to MD values. A further weakness is that we have not related MD to interventions such as ventricular drainage of CSF, additional increase of CPP, Pentothal infusions or decompressive craniotomies. Therefore, we cannot exclude that such measures could have had an impact on MD in our study.