Total TauProtein as Investigated by Cerebral Microdialysis Increases in Hypothermic Cardiac Arrest: A Pig Study.

The understanding and neurological prognostication of hypoxic ischemic encephalopathy (HIE) after hypothermic cardiac arrest (CA) is limited. Recent data suggest that the protein tau (total tau) might be a useful marker for outcome in patients with HIE. This translational porcine study aimed to analyze brain physiology in relation to total tau protein release during hypothermic CA. Eight domestic pigs were studied as part of a prospective porcine study using cerebral microdialysis (CMD). CMD samples for tau analysis were collected at baseline, after reaching the targeted core temperature of 28°C (hypothermia), after hypoxic hypercapnia (partial asphyxia), and finally 20 minutes after cardiopulmonary resuscitation. CMD-total tau-protein was analyzed using enzyme-linked immunosorbent essay. Cerebral tau protein was slightly elevated at baseline most likely due to an insertion trauma, remained stable during hypercapnic hypoxia, and significantly (p = 0.009) increased in 8/8 pigs during resuscitation to 1335 pg/mL (interquartile range: 705-2100). CMD-tau release was associated with lower levels of brain tissue oxygen tension (p = 0.011), higher CMD-lactate/pyruvate ratio, higher CMD-lactate, CMD-glutamate, and CMD-glycerol levels (p < 0.001, respectively), but not with cerebral perfusion pressure, intracranial pressure, or CMD-glucose levels. This study demonstrates an immediate tau protein release accompanied by deranged cerebral metabolism and decreased brain tissue oxygen tension during mechanical resuscitation in hypothermic CA. Understanding tau physiology and release kinetics is important for the design and interpretation of studies investigating tau as a biomarker of HIE.

Effects of head-up vs. supine CPR on cerebral oxygenation and cerebral metabolism - a prospective, randomized porcine study.

BACKGROUND: Recent studies have shown that during cardiopulmonary resuscitation (CPR) head-up position (HUP) as compared to standard supine position (SUP) decreases intracranial pressure (ICP) and increases cerebral perfusion pressure (CPP). The impact of this manoeuvre on brain oxygenation and metabolism is not clear. We therefore investigated HUP as compared to SUP during basic life support (BLS) CPR for their effect on brain oxygenation and metabolism. METHODS: Twenty pigs were anaesthetized and instrumented. After 8 min of cardiac arrest (CA) pigs were randomized to either HUP or SUP and resuscitated mechanically for 20 min. Mean arterial pressure (MAP), ICP, CPP, cerebral regional oxygen saturation (rSO2) and brain tissue oxygen tension (PbtO2) were measured at baseline, after CA and every 5 min during CPR. Cerebral venous oxygen saturation (ScvO2) was measured at baseline, after CA and after 20 min of CPR. Cerebral microdialysis parameters, e.g. lactate/pyruvate ratio (L/P ratio) were taken at baseline and the end of the experiment. RESULTS: ICP was significantly lower in HUP compared to SUP animals after 5 min (18.0 ±â€¯4.5 vs. 24.1 ±â€¯5.2 mmHg; p = 0.033) and 20 min (12.0 ±â€¯3.4 vs. 17.8 ±â€¯4.3 mmHg; p = 0.023) of CPR. Accordingly, CPP was significantly higher in the HUP group after 5 min (11.2 ±â€¯9.5 vs. 1.0 ±â€¯9.2 mmHg; p = 0.045) and 20 min (3.4 ±â€¯6.4 vs. -3.8 ±â€¯2.8 mmHg; p = 0.023) of CPR. However, no difference was found in rSO2, PbtO2, ScvO2 and L/P ratio between groups after 20 min of CPR. CONCLUSION: In this animal model of BLS CPR, HUP as compared to SUP did not improve cerebral oxygenation or metabolism.

Brain temperature but not core temperature increases during spreading depolarizations in patients with spontaneous intracerebral hemorrhage.

Spreading depolarizations (SDs) are highly active metabolic events, commonly occur in patients with intracerebral hemorrhage (ICH) and may be triggered by fever. We investigated the dynamics of brain-temperature (Tbrain) and core-temperature (Tcore) relative to the occurrence of SDs. Twenty consecutive comatose ICH patients with multimodal electrocorticograpy (ECoG) and Tbrain monitoring of the perihematomal area were prospectively enrolled. Clusters of SDs were defined as ≥2 SDs/h. Generalized estimating equations were used for statistical calculations. Data are presented as median and interquartile range. During 3097 h (173 h [81-223]/patient) of ECoG monitoring, 342 SDs were analyzed of which 51 (15%) occurred in clusters. Baseline Tcore and Tbrain was 37.3℃ (36.9-37.8) and 37.4℃ (36.7-37.9), respectively. Tbrain but not Tcore significantly increased 25 min preceding the onset of SDs by 0.2℃ (0.1-0.2; p < 0.001) and returned to baseline 35 min following SDs. During clusters, Tbrain increased to a higher level (+0.4℃ [0.1-0.4]; p = 0.006) when compared to single SDs. A higher probability (OR = 36.9; CI = 36.8-37.1; p < 0.001) of developing SDs was observed during episodes of Tbrain ≥ 38.0℃ (23% probability), than during Tbrain ≤ 36.6℃ (9% probability). Spreading depolarizations - and in particular clusters of SDs - may increase brain temperature following ICH.

Management of posterior inferior cerebellar artery aneurysms: What factors play the most important role in outcome?

BACKGROUND: Posterior inferior cerebellar artery (PICA) aneurysms are an uncommon, heterogeneous group of aneurysms with poorer clinical outcomes compared to other intracranial aneurysms. We performed a multicenter retrospective study to analyze the outcome in a large series of patients treated with modern microsurgical and endovascular techniques. METHODS: Records of 94 patients treated for PICA aneurysms between 2000 and 2015 at three large tertiary referral centers were retrospectively reviewed. RESULTS: Eighty-three patients met inclusion criteria and of these, two died before treatment, leaving 81 treated patients (43 underwent endovascular and 38 surgical treatment). Among patients treated endovascularly, procedure-related complications occurred in four cases (11.8%). Six patients (19.4%) suffered from complications directly associated with surgery. Recurrences occurred in 0% of surgical and in 16.3% of endovascularly treated patients, requiring treatment. Patients with unruptured asymptomatic aneurysms had good outcomes. In the group of 67 ruptured aneurysms, 16 endovascularly (47.1%) and 15 surgically (48.4%) treated patients had modified Rankin scale (mRS) scores of 3-6. Of patients in poor neurological condition (Hunt & Hess (H&H) IV-V at admission), 84.6% suffered a poor clinical outcome. Fifty percent of patients with distal and 31.9% patients with proximal ruptured PICA aneurysms suffered a poor neurological outcome. CONCLUSIONS: This study of PICA aneurysms demonstrates that results of both treatment modalities are comparable. However, endovascular treatment is associated with higher risks of recurrence, requiring additional treatment. Outcomes were mostly impacted by clinical state at admission.

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.

Monitoring of brain oxygenation during hypothermic CPR - A prospective porcine study.

BACKGROUND AND AIM: Limited data are available concerning the impact of CPR interventions on cerebral oxygenation during hypothermic cardiac arrest. We therefore studied cerebral perfusion pressure (CPP), brain tissue oxygen tension (PbtO2), cerebral venous oxygen saturation (ScvO2) and regional cerebral oxygen saturation (rSO2) in an animal model of hypothermic CPR. We also assessed the correlation between rSO2 and CPP, PbtO2 and ScvO2 to clarify whether near-infrared spectroscopy (NIRS) may be used to non-invasively monitor changes in cerebral oxygenation during hypothermic CPR. METHODS: Nine pigs were surface-cooled to a core temperature of 28°C and underwent a period of asphyxia before cardiac arrest was induced. After 2min of untreated cardiac arrest they were resuscitated for 45min. CPP, PbtO2, ScvO2 and rSO2 were monitored after periods of stable external chest compression, a short interruption of CPR and after epinephrine administration. RESULTS: During external chest-compressions before adrenalin administration CPP, PbtO2, ScvO2 and rSO2 increased in parallel and changes in rSO2 closely correlated with changes in CPP (r=.844; p<.001) and ScvO2 (r=.868; p<.001). After adrenaline administration CPP and PbtO2 increased, ScvO2 decreased and rSO2 values did not change and there was no significant correlation between rSO2 and CPP, PbtO2, or ScvO2. CONCLUSION: In this animal model of hypothermic cardiac arrest adrenaline was associated with an increase in global cerebral oxygen extraction despite an increase in CPP. Discrepancies in the time course of PbtO2 and ScvO2 suggest differences in regional oxygen metabolism after adrenalin. rSO2 values correlated closely with CPP and ScvO2 only during periods of external chest compression without adrenaline administration.

Remote ischemic preconditioning in the prevention of ischemic brain damage during intracranial aneurysm treatment (RIPAT): study protocol for a randomized controlled trial.

BACKGROUND: The treatment of intracranial aneurysms may be associated with cerebral ischemia. We hypothesize that pre-interventional remote ischemic preconditioning (RIPC) reduces ischemic cerebral tissue damage in patients undergoing elective intracranial aneurysm treatment. METHODS/DESIGN: This study is a single-center, prospective, randomized, double-blind explorative trial. Patients with an unruptured intracranial aneurysm admitted to Innsbruck Medical University Hospital for coiling or clipping will be consecutively randomized to either the intervention group (= RIPC by inflating an upper extremity blood-pressure cuff for 3 x 5 min to 200 mmHg) or the control group after induction of anesthesia. Participants will be randomized 1:1 to either the preconditioning group or the sham group using a random allocation sequence and block randomization. The precalculated sample size is n = 24 per group. The primary endpoint is the area-under-the-curve concentration of serum biomarkers (S100B, NSE, GFAP, MMP9, MBP, and cellular microparticles) in the first five days after treatment. Secondary endpoints are the number and volume of new ischemic lesions in magnetic resonance imaging and clinical outcome evaluated with the National Institutes of Health Stroke Scale, the modified Rankin Scale, and neuropsychological tests at six and twelve months. All outcome variables will be determined by observers blinded to group allocation. This study was approved by the local institutional Ethics Committee (UN5164), version 3.0 of the study protocol, dated 20 October 2013. DISCUSSION: This study uses the elective treatment of intracranial aneurysms as a paradigmatic situation to explore the neuroprotective effects of RIPC. If effects are demonstrable in this pilot trial, a larger, prospective phase III trial will be considered.