Critical ICP thresholds in relation to outcome: Is 22 mmHg really the answer?

PURPOSE: Intensive care for patients with traumatic brain injury (TBI) aims, among other tasks, at avoiding high intracranial pressure (ICP), which is perceived to worsen motor and cognitive deficits and increase mortality. International recommendations for threshold values for ICP were increased from 20 to 22 mmHg in 2016 following the findings in a study by Sorrentino et al., which were based on an observational study of patients with TBI of averaged ICP values. We aimed to reproduce their approach and validate the findings in a separate cohort. METHODS: Three hundred thirty-one patients with TBI were included and categorised according to survival/death and favourable/unfavourable outcome at 6 months (based on Glasgow Outcome Score-Extended of 6-8 and 1-5, respectively). Repeated chi-square tests of survival and death (or favourable and unfavourable outcome) vs. high and low ICP were conducted with discrimination between high and low ICP sets at increasing values (integers) between 10 and 35 mmHg, using the average ICP for the entire monitoring period. The ICP limit returning the highest chi-square score was assumed to be the threshold with best discriminative ability. This approach was repeated after stratification by sex, age, and initial Glasgow Coma Score (GCS). RESULTS: An ICP limit of 18 mmHg was found for both mortality and unfavourable outcome for the entire cohort. The female and the low GCS subgroups both had threshold values of 18 mmHg; for all other subgroups, the threshold varied between 16 and 30 mmHg. According to a multiple logistic regression analysis, age, initial GCS, and average ICP are independently associated with mortality and outcome. CONCLUSIONS: Using identical methods and closely comparable cohorts, the critical thresholds for ICP found in the study by Sorrentino et al. could not be reproduced.

A randomized, double-blind trial comparing the effect of two blood pressure targets on global brain metabolism after out-of-hospital cardiac arrest.

PURPOSE: This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO2) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO2, plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category). RESULTS: We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16-31) vs. high MAP 23 (16-33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO2 during the first 48 h was 69.5% (62.0-75.0%) in the low MAP group and 69.0% (61.3-75.5%) in the high MAP group, p = 0.16. CONCLUSIONS: Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.

Bedside interpretation of cerebral energy metabolism utilizing microdialysis in neurosurgical and general intensive care.

The microdialysis technique was initially developed for monitoring neurotransmitters in animals. In 1995 the technique was adopted to clinical use and bedside enzymatic analysis of glucose, pyruvate, lactate, glutamate and glycerol. Under clinical conditions microdialysis has also been used for studying cytokines, protein biomarkers, multiplex proteomic and metabolomic analyses as well as for pharmacokinetic studies and evaluation of blood-brain barrier function. This review focuses on the variables directly related to cerebral energy metabolism and the possibilities and limitations of microdialysis during routine neurosurgical and general intensive care. Our knowledge of cerebral energy metabolism is to a large extent based on animal experiments performed more than 40 years ago. However, the different biochemical information obtained from various techniques should be recognized. The basic animal studies analyzed brain tissue homogenates while the microdialysis technique reflects the variables in a narrow zone of interstitial fluid surrounding the probe. Besides the difference of the volume investigated, the levels of the biochemical variables differ in different compartments. During bedside microdialysis cerebral energy metabolism is primarily reflected in measured levels of glucose, lactate and pyruvate and the lactate to pyruvate (LP) ratio. The LP ratio reflects cytoplasmatic redox-state which increases instantaneously during insufficient aerobic energy metabolism. Cerebral ischemia is characterized by a marked increase in intracerebral LP ratio at simultaneous decreases in intracerebral levels of pyruvate and glucose. Mitochondrial dysfunction is characterized by a moderate increase in LP ratio at a very marked increase in cerebral lactate and normal or elevated levels of pyruvate and glucose. The patterns are of importance in particular for interpretations in transient cerebral ischemia. A new technique for evaluating global cerebral energy metabolism by microdialysis of the draining cerebral venous blood is discussed. In experimental studies it has been shown that pronounced global cerebral ischemia is reflected in venous cerebral blood. Jugular bulb microdialysis has been investigated in patients suffering from subarachnoid hemorrhage, during cardiopulmonary bypass and resuscitation after out of hospital cardiac arrest. Preliminary results indicate that the new technique may give valuable information of cerebral energy metabolism in clinical conditions when insertion of an intracerebral catheter is contraindicated.

Endoscopic third ventriculostomy for adults with hydrocephalus: creating a prognostic model for success: protocol for a retrospective multicentre study (Nordic ETV).

INTRODUCTION: Endoscopic third ventriculostomy (ETV) is becoming an increasingly widespread treatment for hydrocephalus, but research is primarily based on paediatric populations. In 2009, Kulkarni et al created the ETV Success score to predict the outcome of ETV in children. The purpose of this study is to create a prognostic model to predict the success of ETV for adult patients with hydrocephalus. The ability to predict who will benefit from an ETV will allow better primary patient selection both for ETV and shunting. This would reduce additional second procedures due to primary treatment failure. A success score specific for adults could also be used as a communication tool to provide better information and guidance to patients. METHODS AND ANALYSIS: The study will adhere to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis reporting guidelines and conducted as a retrospective chart review of all patients≥18 years of age treated with ETV at the participating centres between 1 January 2010 and 31 December 2018. Data collection is conducted locally in a standardised database. Univariate analysis will be used to identify several strong predictors to be included in a multivariate logistic regression model. The model will be validated using K-fold cross validation. Discrimination will be assessed using area under the receiver operating characteristic curve (AUROC) and calibration with calibration belt plots. ETHICS AND DISSEMINATION: The study is approved by appropriate ethics or patient safety boards in all participating countries. TRIAL REGISTRATION NUMBER: NCT04773938; Pre-results.

Bedside microdialysis for detection of early brain injury after out-of-hospital cardiac arrest.

Bedside detection and early treatment of lasting cerebral ischemia may improve outcome after out-of-hospital cardiac arrest (OHCA). This feasibility study explores the possibilities to use microdialysis (MD) for continuous monitoring of cerebral energy metabolism by analyzing the draining cerebral venous blood. Eighteen comatose patients were continuously monitored with jugular bulb and radial artery (reference) MD following resuscitation. Median time from cardiac arrest to MD was 300 min (IQR 230-390) with median monitoring time 60 h (IQR 40-81). The lactate/pyruvate ratio in cerebral venous blood was increased during the first 20 h after OHCA, and significant differences in time-averaged mean MD metabolites between jugular venous and artery measurements, were documented (p < 0.02). In patients with unfavorable outcome (72%), cerebral venous lactate and pyruvate levels remained elevated during the study period. In conclusion, the study indicates that jugular bulb microdialysis (JBM) is feasible and safe. Biochemical signs of lasting ischemia and mitochondrial dysfunction are frequent and associated with unfavorable outcome. The technique may be used in comatose OHCA patients to monitor biochemical variables reflecting ongoing brain damage and support individualized treatment early after resuscitation.

Validation of the newly conceived Surgical Swedish ICH grading scale for surgically treated patients with intracerebral hemorrhage: patient series.

BACKGROUND: The authors sought to externally validate a newly developed clinical grading scale, the Surgical Swedish ICH (SwICH) score. Patients surgically treated for spontaneous supratentorial intracerebral hemorrhage (ICH) from 2009 to 2019 in a single center in Denmark were identified. Data were retrospectively collected from patient records and neuroimaging. Surgical SwICH and ICH scores were calculated for each patient, and the validity of the Surgical SwICH was assessed and compared. OBSERVATIONS: The 126 patients included had an overall 30-day mortality rate of 23%. All patients with a Surgical SwICH score of 0 survived past one year. No patient scored the maximum Surgical SwICH score of 6. The 30-day mortality rates for Surgical SwICH scores 1, 2, 3, and 4 were 0%, 20%, 53%, and 25%, respectively (p <0.0001 for trend). Mortality rates for ICH scores 1, 2, 3, and 4 were 0%, 11%, 33%, and 76%, respectively (p <0.001 for trend). Receiver operator characteristics showed an area under curve of 0.78 for the Surgical SwICH score and 0.80 for the ICH score (p = 0.21 difference). LESSONS: The Surgical SwICH score was a good predictor of 30-day mortality in patients surgically treated for spontaneous supratentorial ICH. However, the Surgical SwICH score did not outperform the previously established ICH score in predicting 30-day mortality.

Ethyl Pyruvate Increases Post-Ischemic Levels of Mitochondrial Energy Metabolites: A 13C-Labeled Cerebral Microdialysis Study.

Mitochondrial dysfunction after transient cerebral ischemia can be monitored by cerebral microdialysis (CMD) using changes in the lactate and pyruvate concentrations and ratio. Other metabolites associated with mitochondrial (dys)function are, e.g., tricyclic acid (TCA) and purine metabolites. Ethyl pyruvate (EP) is a putative neuroprotectant, supposedly targeting mitochondrial energy metabolism, but its effect on cerebral energy metabolism has never been described using microdialysis. In this study we monitored the metabolic effects of EP in the endothelin-1 (ET-1) rat model using perfusion with 13C-succinate and analysis of endogenous and 13C-labeled metabolites in the dialysates by liquid chromatography-mass spectrometry (LC-MS). Adult Sprague Dawley rats (n = 27 of which n = 11 were included in the study) were subjected to the microdialysis experiments. Microdialysis probes were perfused with 13C-labeled succinate (1 mM), and striatal dialysates were collected at 30 min intervals before induction of the insult, during intracerebral application of ET-1, and during intravenous treatment with either EP (40 mg/kg) or placebo, which was administered immediately after the insult. The rats were subjected to transient cerebral ischemia by unilateral microinjection of ET-1 in the piriform cortex, causing vasoconstriction of the medial cerebral artery. Monitoring was continued for 5 h after reperfusion, and levels of endogenous and 13C-labeled energy metabolites before and after ischemia-reperfusion were compared in EP-treated and control groups. Infarct volumes were assessed after 24 h. In both the EP-treated and placebo groups, ET-1-induced vasoconstriction resulted in a transient depression of interstitial glucose and elevation of lactate in the ipsilateral striatum. In the reperfusion phase, the concentrations of labeled malate, isocitrate, and lactate as well as endogenous xanthine were significantly higher in the EP-group than in the placebo-group: (mean ± SEM) labeled malate: 39.5% ± 14.9, p = 0.008; labeled isocitrate: 134.8% ± 67.9, p = 0.047; labeled lactate: 61% ± 22.0, p = 0.007; and endogenous xanthine: 93.9% ± 28.3, p = 0.0009. In the placebo group, significantly elevated levels of uridine were observed (mean ± SEM) 32.5% ± 12.7, p = 0.01. Infarct volumes were not significantly different between EP-treated and placebo groups, p = 0.4679. CMD labeled with 13C-succinate enabled detection of ischemic induction and EP treatment effects in the ET-1 rat model of transient focal cerebral ischemia. EP administered as a single intravenous bolus in the reperfusion-phase after transient cerebral ischemia increased de novo synthesis of several key intermediate energy metabolites (13C-malate, 13C-isocitrate, and endogenous xanthine). In summary, mitochondria process 13C-succinate more effectively after EP treatment.

Discontinuation of External Ventricular Drainage in Patients with Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage - a Scandinavian Multi-institutional Survey.

BACKGROUND: Hydrocephalus requiring external ventricular drainage is common following aneurysmal subarachnoid hemorrhage (aSAH). Timing and strategy for the discontinuation of the external ventricular drain (EVD) are, however, controversial as guidelines are based on limited scientific evidence. A recent similar survey showed that guidelines and recommendations are not being followed. We conducted a questionnaire survey regarding the management of EVD treatment in patients with aSAH and investigated current treatment practice, consensus, and adherence to guidelines within the neurosurgical departments in Scandinavia. METHODS: A questionnaire concerning the management of EVD discontinuation in patients with hydrocephalus following aSAH was distributed to all 14 neurosurgical departments in Scandinavia (Norway, Sweden, and Denmark). Neurosurgeons and neurosurgical trainees at all levels were asked to complete the questionnaire individually. A total of 175 completed questionnaires were received between May 2018 and April 2019, resulting in a response rate of 64 %. RESULTS: Eighty-five percent of respondents reported no knowledge of international guidelines regarding EVD discontinuation in patients with hydrocephalus following aSAH. Within every department, respondents disagreed on whether a common discontinuation strategy was followed or not. Seventy-four percent decided upon the EVD discontinuation strategy mainly determined by patients' clinical condition and drainage volume. Forty-five percent considered Glasgow Coma Score (GCS) the most important clinical variable when assessing the timing of EVD discontinuation. There was general agreement towards the initiation of EVD discontinuation 4-7 days after ictus of aSAH in a stable patient with a drainage volume of < 150 ml/day and intracranial pressure (ICP) < 15 mmHg. CONCLUSION: Awareness of and adherence to international guidelines regarding EVD discontinuation in patients with hydrocephalus following aSAH were limited in Scandinavia. Internal consensus at department level was absent. Initiation of the discontinuation process appeared to be case dependent and mainly influenced by the patients' clinical condition and drainage volume. GCS was the clinical variable considered most important when deciding on the initiation of EVD discontinuation.

A Prospective Observational Feasibility Study of Jugular Bulb Microdialysis in Subarachnoid Hemorrhage.

BACKGROUND: Cerebral metabolic perturbations are common in aneurysmal subarachnoid hemorrhage (aSAH). Monitoring cerebral metabolism with intracerebral microdialysis (CMD) allows early detection of secondary injury and may guide decisions on neurocritical care interventions, affecting outcome. However, CMD is a regional measuring technique that is influenced by proximity to focal lesions. Continuous microdialysis of the cerebral venous drainage may provide information on global cerebral metabolism relevant for the care of aSAH patients. This observational study aimed to explore the feasibility of jugular bulb microdialysis (JBMD) in aSAH and describe the output characteristics in relation to conventional multimodal monitoring. METHODS: Patients with severe aSAH were included at admission or after in-house deterioration when local clinical guidelines prompted extended multimodal monitoring. Non-dominant frontal CMD, intracranial pressure (ICP), partial brain tissue oxygenation pressure (PbtO2), and cerebral perfusion pressure (CPP) were recorded every hour. The dominant jugular vein was accessed by retrograde insertion of a microdialysis catheter with the tip placed in the jugular bulb under ultrasound guidance. Glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol, and glutamate were studied for correlation to intracranial measurements. Modified Rankin scale was assessed at 6 months. RESULTS: Twelve adult aSAH patients were monitored during a mean 4.2 ± 2.6 days yielding 22,041 data points for analysis. No complications related to JBMD were observed. Moderate or strong significant monotonic CMD-to-JBMD correlations were observed most often for glucose (7 patients), followed by lactate (5 patients), and pyruvate, glycerol, and glutamate (3 patients). Moderate correlation for lactate/pyruvate ratio was only seen in one patient. Analysis of critical periods defined by ICP > 20, CPP < 65, or PbtO2 < 15 revealed a tendency toward stronger CMD-to-JBMD associations in patients with many or long critical periods. Possible time lags between CMD and JBMD measurements were only identified in 6 out of 60 patient variables. With the exception of pyruvate, a dichotomized outcome was associated with similar metabolite patterns in JBMD and CMD. A nonsignificant tendency toward greater differences between outcome groups was seen in JBMD. CONCLUSIONS: Continuous microdialysis monitoring of the cerebral drainage in the jugular bulb is feasible and safe. JBMD-to-CMD correlation is influenced by the type of metabolite measured, with glucose and lactate displaying the strongest associations. JBMD lactate correlated more often than CMD lactate to CPP, implying utility for detection of global cerebral metabolic perturbations. Studies comparing JBMD to other global measures of cerebral metabolism, e.g., PET CT or Xenon CT, are warranted.

In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia.

Cerebral micro-dialysis allows continuous sampling of extracellular metabolites, including glucose, lactate and pyruvate. Transient ischemic events cause a rapid drop in glucose and a rise in lactate levels. Following such events, the lactate/pyruvate (L/P) ratio may remain elevated for a prolonged period of time. In neurointensive care clinics, this ratio is considered a metabolic marker of ischemia and/or mitochondrial dysfunction. Here we propose a novel, sensitive microdialysis liquid chromatography-mass spectrometry (LC-MS) approach to monitor mitochondrial dysfunction in living brain using perfusion with 13C-labeled succinate and analysis of 13C-labeled tricarboxylic acid cycle (TCA) intermediates. This approach was evaluated in rat brain using malonate-perfusion (10-50 mM) and endothelin-1 (ET-1)-induced transient cerebral ischemia. In the malonate model, the expected changes upon inhibition of succinate dehydrogenase (SDH) were observed, i.e., an increase in endogenous succinate and decreases in fumaric acid and malic acid. The inhibition was further elaborated by incorporation of 13C into specific TCA intermediates from 13C-labeled succinate. In the ET-1 model, increases in non-labeled TCA metabolites (reflecting release of intracellular compounds) and decreases in 13C-labeled TCA metabolites (reflecting inhibition of de novo synthesis) were observed. The analysis of 13C incorporation provides further layers of information to identify metabolic disturbances in experimental models and neuro-intensive care patients.

The diagnostic value of continuous EEG for the detection of non-convulsive status epilepticus in neurosurgical patients - A prospective cohort study.

OBJECTIVE: To prospectively compare the diagnostic yields of standard EEG and continuous EEG (cEEG) monitoring for the diagnosis of non-convulsive status epilepticus (NCSE) in neurosurgical patients in the intensive care unit. METHODS: We included 50 consecutive patients with clinical suspicion of NCSE due to unexplained coma or subtle clinical phenomena such as discrete myoclonus. The initial 30-minute EEG recording and the following cEEG were analyzed separately for seizure activity. Data were collected on neurosurgical diagnosis, previous diagnosis of epilepsy, current medication, level of consciousness, and outcome at discharge from the neurosurgical department. RESULTS: Recurrent electrographic seizure activity was detected in five patients. This was within the first 30 mins for three patients and on the following cEEG for two patients. Antiepileptic treatment had been initiated in three of these patients. Most of the 50 patients had severe newly acquired neurological disability at discharge. CONCLUSIONS: The prospective finding of a 10% seizure incidence was lower than reports from retrospective studies. SIGNIFICANCE: Use of cEEG led to detection of seizure activity in 2 of 50 patients (4%) and was thus a low-yield method in neurosurgical patients with suspicion of NCSE. Specific markers for patient selection for cEEG are needed.

Cyclosporin A ameliorates cerebral oxidative metabolism and infarct size in the endothelin-1 rat model of transient cerebral ischaemia.

Cerebral microdialysis can be used to detect mitochondrial dysfunction, a potential target of neuroprotective treatment. Cyclosporin A (CsA) is a mitochondrial stabiliser that in a recent clinical stroke trial showed protective potential in patients with successful recanalisation. To investigate specific metabolic effects of CsA during reperfusion, and hypothesising that microdialysis values can be used as a proxy outcome measure, we assessed the temporal patterns of cerebral energy substrates related to oxidative metabolism in a model of transient focal ischaemia. Transient ischaemia was induced by intracerebral microinjection of endothelin-1 (150 pmol/15 µL) through stereotaxically implanted guide cannulas in awake, freely moving rats. This was immediately followed by an intravenous injection of CsA (NeuroSTAT; 15 mg/kg) or placebo solution during continuous microdialysis monitoring. After reperfusion, the lactate/pyruvate ratio (LPR) was significantly lower in the CsA group vs placebo (n = 17, 60.6 ± 24.3%, p = 0.013). Total and striatal infarct volumes (mm3) were reduced in the treatment group (n = 31, 61.8 ± 6.0 vs 80.6 ± 6.7, p = 0.047 and 29.9 ± 3.5 vs 41.5 ± 3.9, p = 0.033). CsA treatment thus ameliorated cerebral reperfusion metabolism and infarct size. Cerebral microdialysis may be useful in evaluating putative neuroprotectants in ischaemic stroke.

Scandinavian Multicenter Acute Subdural Hematoma (SMASH) Study: Study Protocol for a Multinational Population-Based Consecutive Cohort.

BACKGROUND: Traumatic acute subdural hematomas (ASDHs) are associated with high rate of morbidity and mortality, especially in elderly individuals. However, recent reports indicate that the morbidity and mortality rates might have improved. OBJECTIVE: To evaluate postoperative (30-d) mortality in younger vs elderly (≥70 yr) patients with ASDH. Comparing younger and elderly patients, the secondary objectives are morbidity patterns of care and 6 mo outcome according to Glasgow outcome scale (GOS). Finally, in patients with traumatic ASDH, we aim to provide prognostic variables. METHODS: This is a large-scale population-based Scandinavian study including all neurosurgical departments in Denmark and Sweden. All adult (≥18 yr) patients surgically treated between 2010 and 2014 for a traumatic ASDH in Denmark and Sweden will be included. Identification at clinicaltrials.gov is NCT03284190. EXPECTED OUTCOMES: We expect to provide data on potential differences between younger vs elderly patients in terms of mortality and morbidity. We hypothesize that elderly patients selected for surgery have a similar pattern of care as compared with younger patients. We will provide functional outcome in terms of GOS at 6 mo in younger vs elderly patients undergoing ASDH evacuation. Finally, clinical useful prognostic factors for favorable (GOS 4-5) vs unfavorable (GOS 1-3) will be identified. DISCUSSION: An improved understanding of the clinical outcome, treatment and resource allocation, clinical course, and the prognostic factors of traumatic ASDH will allow neurosurgeons to make better treatment decisions.

[Cerebral monitoring of neurocritical patients].

The neurointensive care field emerged as a separate medical speciality in the 1980s, driven by the development of new monitoring tools. The most important goal of neurointensive care is avoiding secondary brain injuries or detecting them in time to implement effective treatment. Understanding cerebral metabolism is key in the care of neurocritical patients, and continuous monitoring through intracerebral microdialysis allows for differentiation of different pathological mechanisms, in turn catalysing development of novel treatments.

[Bicycle helmet prevents brain damage]. / Cykelhjelm forebygger hjerneskade

The relatively small and declining incidence of traffic-related death accidents in Scandinavia is a result of targeted infra-structural measures and policies. Bicycle accidents represent a large fraction of the total traffic accident load and are often underreported in statistics. We argue that there is scientific evidence of bicycle helmet efficacy with a protective effect on serious brain injury of 63-88%. There is no consensus in favour of the effect of bicycle helmet legislation, although a Cochrane review from 2007 showed a significant reduction of injuries among children.