Alois Schiefecker

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Breath analysis for in vivo detection of pathogens related to ventilator-associated pneumonia in intensive care patients: a prospective pilot study

Existing methods for the early detection of infections in mechanically ventilated (MV) patients at intensive care units (ICUs) are unsatisfactory. Here we present an exploratory study assessing the feasibility of breath VOC analyses for the non-invasive detection of pathogens in the lower respiratory tract of ventilated patients. An open uncontrolled clinical pilot study was performed by enrolling 28 mechanically ventilated (MV) patients with severe intracranial disease, being at risk for the development of or already with confirmed ventilation-associated pneumonia (VAP). The recently developed sampling technique enabled the collection of breath gas with a maximized contribution of alveolar air directly from the respiratory circuit under continuous capnography control, adsorptive preconcentration and final analysis by means of gas chromatography-mass spectrometry (GC-MS).VAP was confirmed in 22/28 preselected patients (78%). The most common microorganisms were Staphylococcus aureus (5/22 VAP patients), Escherichia coli (5/22 VAP patients) and Candida spp. (5/22 VAP patients). 12/32 metabolites released by S. aureus in our previous in vitro studies were also detected in the end-tidal air of VAP patients infected with this pathogen. A similar overlap was seen in Candida albicans infections (8/29 VOCs). Moreover, the concentration profile of selected compounds correlated with the course of the infection.This prospective pilot study provides proof of the concept that the appearance and the concentration profile of pathogen-derived metabolites (elucidated from in vitro experiments) in the breath of ventilated patients during clinically confirmed VAP correlates with the presence of a particular pathogen.

Parenteral diclofenac infusion significantly decreases brain-tissue oxygen tension in patients with poor-grade aneurysmal subarachnoid hemorrhage

IntroductionDiclofenac, a nonsteroidal antiinflammatory drug, is commonly used as antipyretic therapy in intensive care. The purpose of this study was to investigate the effects of parenteral diclofenac infusion on brain homeostasis, including brain-tissue oxygen tension (PbtO2) and brain metabolism after aneurysmal subarachnoid hemorrhage (aSAH).MethodsWe conducted a prospective, observational study with retrospective analysis of 21 consecutive aSAH patients with multimodal neuromonitoring. Cerebral perfusion pressure (CPP), mean arterial pressure (MAP), intracranial pressure (ICP), body temperature, and PbtO2 were analyzed after parenteral diclofenac infusion administered over a 34-minute period (20 to 45 IQR). Data are given as mean ± standard error of mean and median with interquartile range (IQR), as appropriate. Time-series data were analyzed by using a general linear model extended by generalized estimation equations (GEEs).ResultsOne-hundred twenty-three interventions were analyzed. Body temperature decreased from 38.3°C ± 0.05°C by 0.8°C ± 0.06°C (P < 0.001). A 10% decrease in MAP and CPP (P < 0.001) necessitated an increase of vasopressors in 26% (n = 32), colloids in 33% (n = 41), and crystalloids in 5% (n = 7) of interventions. PbtO2 decreased by 13% from a baseline value of 28.1 ± 2.2 mm Hg, resulting in brain-tissue hypoxia (PbtO2 <20 mm Hg) in 38% (n = 8) of patients and 35% (n = 43) of interventions. PbtO2 <30 mm Hg before intervention was associated with brain-tissue hypoxia after parenteral diclofenac infusion (likelihood ratio, 40; AUC, 93%; 95% confidence interval (CI), 87% to 99%; P < 0.001). Cerebral metabolism showed no significant changes after parenteral diclofenac infusion.ConclusionsParenteral diclofenac infusion after aSAH effectively reduces body temperature, but may lead to CPP decrease and brain-tissue hypoxia, which were both associated with poor outcome after aSAH.

Cerebral tau is elevated after aneurysmal subarachnoid haemorrhage and associated with brain metabolic distress and poor functional and cognitive long-term outcome

Background Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated. Methods Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12 months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject. Results CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20 mm Hg) brain extracellular lactate elevation (>4 mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12 months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1 year after aSAH (p<0.01). Conclusions These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques.

Clusters of Cortical Spreading Depolarizations in a Patient with Intracerebral Hemorrhage: A Multimodal Neuromonitoring Study

BackgroundSpontaneous intracerebral hemorrhage (ICH) is associated with high morbidity and mortality. Cortical spreading depolarizations (CSDs) increase brain matrix metalloproteinase (MMP)-9 activity leading to perihematomal edema expansion in experimental ICH.MethodsThe purpose of this report is to describe cerebral metabolic changes and brain extracellular MMP-9 levels in a patient with CSDs and perihematomal edema expansion after ICH.ResultsWe present a 66-year-old male patient with ICH who underwent craniotomy for hematoma evacuation. Multimodal neuromonitoring data of the perihematomal region revealed metabolic distress and increased MMP-9 levels in the brain extracellular fluid during perihematomal edema progression. At the same time, subdural electrocorticography showed clusters of CSDs, which disappeared after ketamine anesthesia on day six. Perihematomal edema regression was associated with decreasing cerebral MMP-9 levels.ConclusionsThis novel association between clusters of CSDs, brain metabolic distress, and increased MMP-9 levels expands our knowledge about secondary brain injury after ICH. The role of ketamine after this devastating disorder needs further studies.

Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression.

Pathophysiologic mechanisms of secondary brain injury after intracerebral hemorrhage and in particular mechanisms of perihematomal-edema progression remain incompletely understood. Recently, the role of spreading depolarizations in secondary brain injury was established in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury patients. Its role in intracerebral hemorrhage patients and in particular the association with perihematomal-edema is not known. A total of 27 comatose intracerebral hemorrhage patients in whom hematoma evacuation and subdural electrocorticography was performed were studied prospectively. Hematoma evacuation and subdural strip electrode placement was performed within the first 24 h in 18 patients (67%). Electrocorticography recordings started 3 h after surgery (IQR, 3–5 h) and lasted 157 h (median) per patient and 4876 h in all 27 patients. In 18 patients (67%), a total of 650 spreading depolarizations were observed. Spreading depolarizations were more common in the initial days with a peak incidence on day 2. Median electrocorticography depression time was longer than previously reported (14.7 min, IQR, 9–22 min). Postoperative perihematomal-edema progression (85% of patients) was significantly associated with occurrence of isolated and clustered spreading depolarizations. Monitoring of spreading depolarizations may help to better understand pathophysiologic mechanisms of secondary insults after intracerebral hemorrhage. Whether they may serve as target in the treatment of intracerebral hemorrhage deserves further research.

Targeted Temperature Management in Spontaneous Intracerebral Hemorrhage: A Systematic Review

BACKGROUND Fever is common in neurocritical care patients and is associated with poor outcome. Targeted temperature management (TTM), i.e. therapeutic hypothermia or controlled normothermia, after acute brain injury has been studied as a neuroprotectant for several decades. In contrast to pharmacological agents with specific targets TTM affects multiple pathophysiological mechanisms and is primarily thought to attenuate secondary brain injury. Most promising results have been obtained from experimental studies on cerebral ischemia or traumatic brain injury showing beneficial effects of hypothermia on structural and functional outcome. OBJECTIVE The aim of this systematic review of the literature is to provide an overview on preclinical and clinical data on the use of TTM for intracerebral hemorrhage (ICH). The impact of TTM on structural changes and functional outcome after induced and spontaneous ICH will be summarized. RESULTS AND DISCUSSION A positive influence of hypothermia has been observed in animal models of spontaneous ICH improving, among others, perihematomal edema, blood-brain barrier integrity, inflammation and thrombin-induced injury. However, results regarding functional outcome are conflicting. Little data is available on the effect of TTM after spontaneous ICH in humans. Single-center observational studies have shown reduced perihematomal edema under mild hypothermia and an association with favorable outcome. However, these beneficial effects on mortality and functional outcome have not been confirmed in randomized studies so far. Thus, results from ongoing, prospective randomized-controlled trials are highly anticipated.

Neuroinflammation is Associated with Brain Extracellular TAU-Protein Release after Spontaneous Subarachnoid Hemorrhage

INTRODUCTION Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH. METHODS Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements. RESULTS Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt&Hess grade and age (P=0.01). CONCLUSION Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies.

Enteral nutrition increases interstitial brain glucose levels in poor-grade subarachnoid hemorrhage patients:

Low brain tissue glucose levels after acute brain injury are associated with poor outcome. Whether enteral nutrition (EN) reliably increases cerebral glucose levels remains unclear. In this retrospective analysis of prospectively collected observational data, we investigate the effect of EN on brain metabolism in 17 poor-grade subarachnoid hemorrhage (SAH) patients undergoing cerebral microdialysis (CMD) monitoring. CMD-values were obtained hourly. A nutritional intervention was defined as the clinical routine administration of EN without supplemental parenteral nutrition. Sixty-three interventions were analyzed. The mean amount of EN per intervention was 472.4 ± 10.7 kcal. CMD-glucose levels significantly increased from 1.59 ± 0.13 mmol/l at baseline to a maximum of 2.03 ± 0.2 mmol/l after 5 h (p < 0.001), independently of insulin-treatment, baseline serum glucose, baseline brain metabolic distress (CMD-lactate-to-pyruvate-ratio (LPR) > 40) and the microdialysis probe location. The increase in CMD-glucose was directly dependent on the magnitude of increase of serum glucose levels (p = 0.007). No change in CMD-lactate, CMD-pyruvate, CMD-LPR, or CMD-glutamate (p > 0.4) was observed. Routine EN also increased CMD-glucose even if baseline concentrations were critically low ( < 0.7 mmol/l, neuroglucopenia; p < 0.001). These results may have treatment implications regarding glucose management of poor-grade aneurysmal SAH patients.

Outcome prediction and temperature dependency of MR-proANP and Copeptin in comatose resuscitated patients.

OBJECTIVE To evaluate the prognostic potential of serum C-terminal provasopressin (CT-proAVP or Copeptin) and midregional pro-A-type natriuretic peptide (MR-proANP) to predict neurological outcome following resuscitation from cardiac arrest. METHODS In this prospective observational study, we employed novel ultra sensitive immunoassay technology to examine serial serum samples from 134 cardiac arrest patients. Patients were either allocated to mild therapeutic hypothermia using an endovascular device or normothermia. Serial blood samples were obtained from resuscitated cardiac arrest survivors during their first 7 days in an intensive care unit, and serum Copeptin and MR-proANP were measured. Cerebral function assessments were made using cerebral performance categorization (CPC) at discharge from hospital. Copeptin and MR-proANP data were analyzed using dichotomized CPC scores (1-2 versus 3-5). RESULTS Sixty-nine patients (51%) had a poor outcome (CPC 3-5) at hospital discharge. MR-proANP and Copeptin peaked on day 1 (i.e. 0-24h) with the medians being 249.3pmol/L and 77.2pmol/L, respectively. In the first 48h maximum levels of MR-proANP and Copeptin showed an AUC in the ROC of 0.743 (95% CI: 0.658-0.828) and 0.677 (95% CI: 0.583-0.771). Binary logistic regression revealed MR-proANP and Copeptin within 48h after ROSC being significantly associated with functional outcome (p<0.05). Copeptin within 48h was also associated with outcome in the hypothermia group (p<0.05). CONCLUSION Systemic levels of MR-proANP and Copeptin peak early in cardiac arrest patients in the 48h post-resuscitation period. MR-proANP and Copeptin were highly predictive for poor outcome in comatose resuscitated patients.