Logo: to the web site of Uppsala University

Background: Although older traumatic brain injury (TBI) patients often exhibit cerebral autoregulatory impairment with high pressure reactivity index (PRx), the role of autoregulatory-guided management in these patients remains elusive. In this study, we aimed to explore if age affected the prognostic role of the autoregulatory variables, PRx and the PRx-derived optimal cerebral perfusion pressure (CPPopt), in a large TBI cohort.

Methods: In this observational study, 550 TBI patients who had been treated in the neurocritical care unit, Addenbrooke's Hospital, Cambridge, UK, between 2002 and 2022 with available data on age, intracranial pressure monitoring, and outcome (Glasgow Outcome Scale [GOS]) were included. The patients were classified into three age groups; youth and early adulthood (16-39 years), middle adulthood (40-59 years), and senior adulthood (60 years and above). Autoregulatory variables were studied in relation to outcome using heatmaps. Multivariate logistic regressions of mortality and favourable outcome (GOS 4 to 5) were performed with PRx and Delta CPPopt (CPP-CPPopt) in addition to baseline variables.

Results: TBI patients in the senior adulthood group exhibited higher PRx and lower ICP than younger patients. There was a transition towards worse outcome with higher PRx in heatmaps for all age groups. The combination of high PRx together with low CPP or negative Delta CPPopt was particularly associated with lower GOS. In multivariate logistic regressions, higher PRx remained independently associated with higher mortality and lower rate of favourable outcome in the senior adulthood cohort. There was a transition towards worse outcome for negative Delta CPPopt for all age groups, but it did not reach statistical significance for the senior adulthood group.

Conclusions: PRx was found to be an independent outcome predictor and influenced the safe and dangerous CPP and Delta CPPopt interval for all age groups. Thus, TBI patients older than 60 years may also benefit from autoregulatory-guided management and should not necessarily be excluded from future trials on such therapeutic strategies.

BackgroundTraumatic brain injury (TBI) triggers neuroinflammation both acutely and chronically, the latter which might be involved in neurodegenerative disorders. Resolvins are neuroinflammatory modulators, hypothesized to improve resolution of inflammation. This study sought to explore sustained immunological responses after delayed treatment with resolvins utilizing novel tools for automated cellular assessments.Materials and methodsTwenty-five rodents (Sprague-Dawley rats) were exposed to a penetrating TBI, following which delayed treatment with resolvin was initiated. Assessments of tissue loss, and persistent neuroinflammatory activation, was assessed at 6 weeks post-injury utilizing histological and immunohistochemical methods. We also developed a novel computational tool to count and automatically assess cell counts across treatment groups.ResultsThe TBI model elicited a substantial brain injury, as expected. The lesion cavity volume was not affected by resolvin or vehicle treatment. Notably, both microglial and macrophage responses were also similar between treatment groups, as deemed by state-of-the-art computational models.ConclusionResolvins administered in a delayed fashion following severe TBI did not affect the extent of chronic microglial or macrophage responses, but warrants future corroboration. Dosing and timing of resolvin treatment warrants further study.

Background: 

Severe cerebral venous thrombosis (CVT) patients often require neurointensive care with multimodal monitoring. However, optimal treatment targets for intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral autoregulation remain unclear. This study investigated the relationships between ICP, CPP, and autoregulation indices (PRx, optimal CPP [CPPopt]) with clinical outcomes in severe CVT.

Methods: 

This observational study included 15 patients with severe CVT with ICP-monitoring, treated in the neurointensive care (NIC) unit, Uppsala. The percentage of eligible monitoring time (EMT) outside certain thresholds was calculated for ICP, PRx, CPP, and ΔCPPopt (CPP-CPPopt) and analysed in relation to outcome (Glasgow Outcome at Discharge Scale [GODS]). Outcome heatmaps were generated to visualize transitions from better to worse outcomes for single variables and 2 variables (ICP, CPP, or ΔCPPopt in combination with PRx).

Results: 

Median %EMT for ICP>20 mm Hg and CPP<60 mm Hg was <5%. Higher %EMT for ICP>20 mm Hg (r=−0.60, P=0.02) correlated with worse outcome (lower GODS). The median %EMT of impaired cerebral pressure autoregulation was 34%. Outcome heatmaps indicated transitions toward worse outcome when PRx exceeded zero and ΔCPPopt became negative, but these correlations were not significant. Higher PRx reduced the safe ICP and CPP range, in 2-variable heatmaps.

Conclusions: 

A higher %EMT of ICP>20 mm Hg was unfavorable in severe CVT. Impaired cerebral autoregulation with high PRx was frequent and may reduce the safe ICP/CPP range. Larger, multi-centre studies are needed to validate these findings in this rare condition.

Patient-tailored treatment, also known as precision-medicine, has been emphasized as a prioritized area in traumatic brain injury research. In fact, pre-injury patient genetic factors alone account for almost 26% of outcome prediction variance following traumatic brain injury. Among implicated genetic variants single-nucleotide polymorphism in apolipoprotein E has been linked to worse prognosis following traumatic brain injury, but the underlying mechanism is still unknown. We hypothesized that apolipoprotein E genotype would affect the levels of pathophysiology-driving structural, or inflammatory, proteins in cerebral microdialysate following severe traumatic brain injury. We conducted a prospective observational study of patients with severe traumatic brain injury treated with invasive neuromonitoring including cerebral microdialysis at Uppsala University Hospital. All patients were characterized regarding apolipoprotein E genotype. Utilizing fluid- and plate-based antibody arrays, we quantified 101 proteins (of which 89 were eligible for analysis) in cerebral microdialysate at 1 day and 3 days following trauma. Statistical analysis included clustering techniques, as well as uni- and multi-variate linear mixed modelling. In total, 26 patients were included, and all relevant genotypes of apolipoprotein E were represented in the data. Among all proteins tested, 41 proteins showed a time-dependent expression level. There was a weak clustering tendency in the data, and not primarily to genotype, either depicted through t-distributed stochastic neighbour embedding or hierarchical clustering. Using linear mixed models, two proteins [the inflammatory protein CD300 molecule like family member f (CLM-1) and the neurotrophic protein glial-derived neurotrophic factor family receptor α1] were found to have protein levels concomitantly dependent upon time and genotype, albeit this effect was not seen following multiple testing corrections. Apart from amyloid-β-40 (Aβ) and Microtubule-associated protein tau, neither Aβ peptide levels nor the Aβ42/40 ratio were seen related to time from trauma or apolipoprotein E genotype. This is the first study in clinical severe traumatic brain injury examining the influence of apolipoprotein E genotype on microdialysate protein expression. Protein levels in cerebral microdialysate following trauma are seen to be strongly dependent on time from trauma, corroborating previous work on protein expression longitudinally following traumatic brain injury. We also identified protein expression level alterations dependent on apolipoprotein E genotype, which might indicate that apolipoprotein E affects ongoing pathophysiology in the injured brain at the proteomic level.

Objective

Malignant middle cerebral artery infarction (MMI) is a severe neurological condition. Decompressive craniectomy (DC) is an established lifesaving surgical treatment. However, the role of neurocritical care with monitoring and management of the intracranial pressure (ICP), pressure reactivity index (PRx), cerebral perfusion pressure (CPP), and optimal perfusion pressure (CPPopt) remain unclear. This study aims to examine the dynamics of these variables post-DC in relation to clinical outcome.

Methods

This retrospective study included 70 MMI patients who underwent DC with ICP monitoring of at least 12 hours and available data of clinical outcome (modified Rankin Scale [mRS] at 6 months). The associations between mRS and cerebral physiology (ICP, PRx, CPP, and ∆CPPopt) was analysed and presented in different outcome heatmaps over the first 7 days following DC.

Results

ICP above 15 mmHg was associated with unfavourable outcome, particularly for longer durations. As PRx exceeded zero, outcome worsened progressively, and values above 0.5 correlated to poor outcome regardless of duration. As CPP dropped below 80 mmHg, there was a transition from favourable to unfavourable outcome. Negative ∆CPPopt, particularly below -20 mmHg, corresponded to unfavourable outcome. In two-variable heatmaps, elevated PRx combined with high ICP, low CPP or negative ∆CPPopt correlated with worse outcome.

Conclusion

Invasive ICP-monitoring may provide prognostic information for long-term recovery in MMI patients post-DC. The study highlighted disease-specific optimal physiological intervals for ICP, PRx, CPP, and ΔCPPopt. Of particular interest, the autoregulatory variable, PRx, influenced the safe and dangerous ICP, CPP, and ∆CPPopt intervals.

Background

The effect of positive end-expiratory pressure (PEEP) on intracranial pressure (ICP) dynamics in patients with acute brain injury (ABI) remains controversial. PEEP can benefit oxygenation by promoting alveolar recruitment, but its influence on ICP is complex. The primary aims of this study were to investigate 1) how lung recruitability influences oxygenation and 2) how lung recruitability and regional gas distribution, measured via recruitment-to-inflation (RI) ratio and electrical impedance tomography (EIT), affect ICP in response to PEEP changes in critically ill patients in their early phase of ABI.

Methods

Ten mechanically ventilated ABI patients were included. Pressure reactivity index (PRx) was estimated. Using RI manoeuvre and EIT, lung recruitability and gas distribution were assessed in response to a standardised PEEP change (from high to low levels, with a delta of 10 cmH₂O). Changes in ICP (ΔICP) were calculated between high and low PEEP. Lung inhomogeneity indices (global inhomogeneity index [GI] and local inhomogeneity index [LI]) were derived from EIT. Correlations between ventilatory variables and ICP were analysed.

Results

Blood oxygenation significantly decreased, going from high (14 [IQR: 12–15] cmH₂O) to low (4 [IQR: 2–5] cmH₂O) PEEP. Reducing PEEP significantly increased ICP (from 9 [IQR: 5–13] to 12 [IQR: 8–16] mmHg, p < 0.01), while cerebral perfusion pressure (CPP) improved (from 71 [IQR:67–83] to 75 [IQR: 70–84] mmHg, p = 0.03) and mean arterial pressure (MAP) increased (from 79 [IQR: 69–95] to 84 [IQR: 76–99] mmHg, p < 0.01). The RI ratio correlated significantly with ΔICP (rho = 0.87, p < 0.01), as did Vrec% (proportion of recruited volume, rho = 0.65) and GI (rho = 0.5). LI did not correlate with ΔICP. PRx was 0.30 [IQR: 0.12–0.42], indicating a deranged cerebral autoregulation.

Conclusions

Patients with a higher potential for lung recruitability had a more beneficial effect of PEEP on oxygenation. These effects should be interpreted cautiously, given that lung recruitability and global inhomogeneity of gas distribution significantly influenced the intracranial response to PEEP in ABI patients. As indicated by MAP and CPP, PEEP may impact systemic haemodynamics and cerebral perfusion when cerebral autoregulation is deranged. These findings underscore the importance of multimodal (i.e. respiratory, cerebral and haemodynamics) monitoring for optimising ventilation strategies in ABI patients and provide a framework for future research.

Trial registration Registration number: NCT05363085, Date of registration: May 2022

Background: Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1-4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method.

Methods: Four pigs aged 2-3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2-3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels.

Results: In a linear mixed-effect model of standard CMD glucose (mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 (p < 0.001) for Loke MD glucose (mM), with an intercept at - 0.19 ± 0.15 (p = 0.20). The model showed a conditional R2 at 0.81 and a marginal R2 at 0.72. In a linear mixed-effect model of standard CMD lactate (mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 (p = 0.01) for Loke MD lactate (mM), with an intercept at 0.33 ± 0.21 (p = 0.25). The model showed a conditional R2 at 0.47 and marginal R2 at 0.17.

Conclusions: The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

Background

Sweden covers a large land area, but is sparsely populated. The country is divided into six heterogenous healthcare regions, each with different geographic conditions and referral patterns when it comes to traumatic brain injury (TBI). This study aimed to explore the variation in demography, injury patterns, care pathways, management, and mortality (30 d) for TBI patients within the country.

Methods

A nationwide, observational study, using data from the Swedish Trauma Registry (SweTrau) between 2018–2022, was performed. A total of 5036 TBI patients were included. Data on demography, admission status (through Glasgow Coma Scale [GCS] value at arrival at first managing hospital), injury-related variables, and mortality (30 d) were evaluated.

Results

The median age was 65 years (interquartile range 46–78), and the majority of patients were male, had sustained fall-related injuries, and were conscious upon admission. Slight, but significant differences (p < 0.05) existed among the regions in these variables. In multivariate logistic regression models, the healthcare region (p < 0.05) was independently associated with patient referral to a university hospital (as compared to care at a local hospital alone), craniotomy rate, and receiving an intracranial pressure-monitoring device, after adjustment for demographic and injury variables. In similar regressions regarding mortality, specific healthcare regions (p < 0.05) were independently associated with said outcome.

Conclusions

The study highlights, from a systems-level perspective, that there was a significant variation in care pathways and management among the six healthcare regions in Sweden, which might have impacted on clinical outcome. These findings call for more granular studies to understand which aspects of patient management that were particularly beneficial or detrimental for patient survival and recovery.

Background

The oxygen reactivity index (ORx) reflects the correlation between focal brain tissue oxygen (pbtO₂) and the cerebral perfusion pressure (CPP). Previous, small cohort studies were conflicting on whether ORx conveys cerebral autoregulatory information and if it is related to outcome in traumatic brain injury (TBI). Thus, we aimed to investigate these issues in a larger TBI cohort.

Methods

425 TBI patients with intracranial pressure (ICP)- and pbtO₂-monitoring for at least 12 h, who had been treated at Addenbrooke’s Hospital, Cambridge, UK, were included. Association between ORx and ICP, pressure reactivity index (PRx), CPP, ΔCPPopt (actual CPP-CPPopt [PRx based optimal CPP]), and pbtO₂ were evaluated with generalized additive models (GAMs). Association between ORx and outcome (Glasgow Outcome Scale [GOS]) was investigated with logistic regressions and heatmaps for those 239 patients with GOS data.

Results

GAMs showed that ORx increased with higher ICP, PRx above + 0.30, CPP below 60–70 mmHg, and negative ΔCPPopt. In contrast to PRx, ORx did not increase at higher CPP. In outcome heatmaps, there was a transition towards unfavourable outcome when ORx exceeded + 0.50, particularly for longer durations, and in combination with high ICP, high PRx, low CPP, negative ΔCPPopt, and low pbtO₂. In multivariable logistic regressions, higher ORx was associated with increased mortality.

Conclusions

ORx seemed to be sensitive to the lower, but not the upper, limit of autoregulation, in contrast to PRx which was sensitive to both. The combination of high values for both ORx and PRx was particularly associated with worse outcome and, thus, ORx may provide a complementary value to the global index PRx. ORx could also be useful to determine the safe and dangerous perfusion target intervals.

OBJECTIVE: There is a paucity of studies on the optimal thresholds for neurointensive care (NIC) targets such as intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in spontaneous intracerebral hemorrhage (sICH). There is also a need to clarify the role of cerebral pressure autoregulatory disturbances (pressure reactivity index [PRx]) and to determine if the autoregulatory CPP target (optimal CPP [CPPopt]) is superior to traditional fixed CPP targets in sICH. In this study, the authors aimed to explore the role of ICP, PRx, CPP, and CPPopt insults in sICH patients treated in the NIC unit.

METHODS: In this observational study, 184 adults with sICH with intracerebral hemorrhage (ICH) volume above 10 ml who received > 12 hours of ICP monitoring during the first 7 days at the authors' NIC unit, Uppsala University Hospital, Sweden, between 2010 and 2019 (10 years) were included. Demographic characteristics, admission status, radiological examination, and clinical outcome were evaluated. Favorable outcome was defined as conscious at discharge, while unfavorable outcome as unconscious or deceased. ICP, CPP, PRx, and CPPopt during the first 7 days were analyzed in relation to outcome.

RESULTS: In total, 138 (75%) patients recovered favorably at discharge. Lower percentage of good monitoring time with ICP above 25 mm Hg was independently associated with favorable outcome. CPP above 80 mm Hg was frequent and independently associated with favorable outcome. Median PRx did not differ between the outcome groups, but there was a trend toward worse outcome when PRx exceeded +0.5. Furthermore, when PRx was analyzed together with the concurrent ICP and CPP values, higher values increased the ICP and CPP interval associated with unfavorable outcome. Lastly, there was no independent correlation between CPP deviation from CPPopt and outcome.

CONCLUSIONS: Avoiding ICP elevations above 20 to 25 mm Hg and maintaining CPP above 80 mm Hg may be beneficial in sICH patients with large bleeding volume who require NIC. PRx was not independently associated with outcome, but higher values appeared to narrow the safe zones of ICP and CPP.