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BACKGROUND: In the absence of lung biopsy there are various algorithms for the diagnosis of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients that rely on clinical signs, underlying conditions, radiological features, and mycology. The aim of the present study was to compare four diagnostic algorithms in their ability to differentiate between probable IPA (i.e. requiring treatment) and colonization in critically ill patients. In addition, we determined their diagnostic accuracy to detect proven IPA.METHODS: For this diagnostic accuracy study, we included a mixed ICU population with a positive Aspergillus culture from respiratory secretions that were treated in a German quarternary care hospital between 2005 and 2020. Four different diagnostic algorithms were applied to all patients. We compared agreement among the four algorithms to discriminate probable IPA from colonization. In a subgroup of patients with lung tissue histopathology available we determined the sensitivity and specificity of the single algorithms to detect proven IPA. RESULTS: A total number of 684 critically ill patients were included. The mean age of the study population was 63 years (IQR 52-73). Sixty-nine percent (n=472) were medical and 31% (n=212) were surgical ICU patients. Overall, 79% (n=543) of patients fulfilled the criteria for probable IPA according to at least one diagnostic algorithm. Only 4% of patients (n=29) fulfilled the criteria for probable IPA according to all four algorithms. Agreement among the four diagnostic criteria was low (Cohen’s kappa 0.07-0.29). From 85 patients with histopathological examination of lung tissue 40% (n=34) had confirmed IPA. The new EORTC/MSGERC ICU working group criteria had high specificity (0.59 [0.41-0.75]) and sensitivity (0.73 [0.59-0.85]).CONCLUSIONS:In a cohort of mixed ICU patients, the agreement among four algorithms for the diagnosis of IPA was low. The 2021 EORTC/MSGERC ICU working group criteria achieved the highest specificity and sensitivity to detect proven IPA. Although improved by the latest diagnostic criteria, the discrimination of invasive fungal infection from Aspergillus colonization in critically ill patients remains challenging and may require further optimization.

Cerebral blood flow is tightly regulated by cerebrovascular autoregulation (CVA), and intraoperative impairment of CVA has been linked with perioperative neurocognitive disorders. We aim to assess whether impairment of CVA during major oncologic surgery is associated with delayed neurocognitive recovery (DNCR) postoperatively. We performed a secondary analysis of prospectively collected data. Patients were included if they had undergone complete pre- and postoperative neuropsychological assessments, continuous intraoperative measurement of CVA, and major oncologic surgery for visceral, urological, or gynecological cancer. Intraoperative CVA was measured using the time-correlation method based on near-infrared-spectroscopy, and DNCR was assessed with a neuropsychological test battery. A decline in cognitive function before hospital discharge compared with a preoperative baseline assessment was defined as DNCR. One hundred ninety-five patients were included in the analysis. The median age of the study population was 65 years (IQR: 60–68); 11 patients (5.6%) were female. Forty-one patients (21.0%) fulfilled the criteria for DNCR in the early postoperative period. We found a significant association between impaired intraoperative CVA and DNCR before hospital discharge (OR = 1.042 [95% CI: 1.005; 1.080], p = 0.028). The type of surgery (radical prostatectomy vs. other major oncologic surgery; OR = 0.269 [95% CI: 0.099; 0.728], p = 0.010) and premedication with midazolam (OR = 3.360 [95% CI: 1.039; 10.870], p = 0.043) were significantly associated with the occurrence of DNCR in the early postoperative period. Intraoperative impairment of CVA is associated with postoperative neurocognitive function early after oncologic surgery. Therefore, intraoperative monitoring of CVA may be a target for neuroprotective interventions. The initial studies were retrospectively registered with primary clinical trial registries recognized by the World Health Organization (ClinicalTrials.gov Identifiers: DRKS00010014, 21.03.2016 and NCT04101006, 24.07.2019).

BACKGROUND Diastolic dysfunction is a risk factor for postoperative major cardiovascular events. During anesthesia, patients with diastolic dysfunction might experience impaired hemodynamic function and worsening of diastolic function, which in turn, might be associated with a higher incidence of postoperative complications.We aimed to investigate whether patients with diastolic dysfunction require higher doses of norepinephrine during general anesthesia. Furthermore, we aimed to examine the association between the grade of diastolic dysfunction and the E/e' ratio during anesthesia. A high E/e' ratio corresponds to elevated filling pressures and is an important measure of impaired diastolic function. METHODS We conducted a prospective observational cohort study at a German university hospital from February 2017 to September 2018. Patients aged ≥60 years and undergoing general anesthesia (ie, propofol and sevoflurane) for elective noncardiac surgery were enrolled. Exclusion: mitral valve disease, atrial fibrillation, and implanted mechanical device.The primary outcome parameter was the administered dose of norepinephrine within 30 minutes after anesthesia induction (μg·kg-1 30 min-1). The secondary outcome parameter was the change of Doppler echocardiographic E/e' from ECHO1 (baseline) to ECHO2 (anesthesia). Linear models and linear mixed models were used for statistical evaluation. RESULTS A total of 247 patients were enrolled, and 200 patients (75 female) were included in the final analysis. Diastolic dysfunction at baseline was not associated with a higher dose of norepinephrine during anesthesia (P = .6953). The grade of diastolic dysfunction at baseline was associated with a decrease of the E/e' ratio during anesthesia (P < .001). CONCLUSIONS We did not find evidence for an association between diastolic dysfunction and impaired hemodynamic function, as expressed by high vasopressor support during anesthesia. Additionally, our findings suggest that diastolic function, as expressed by the E/e' ratio, does not worsen during anesthesia.

Purpose Surgery in the prolonged extreme Trendelenburg position may lead to elevated intracranial pressure and compromise cerebral hemodynamic regulation. We hypothesized that robot-assisted radical prostatectomy with head-down tilt causes impairment of cerebral autoregulation compared with open retropubic radical prostatectomy in the supine position. Methods Patients scheduled for elective radical prostatectomy were included at a tertiary care prostate cancer clinic. Continuous monitoring of the cerebral autoregulation was performed using the correlation method. Based on measurements of cerebral oxygenation with near-infrared spectroscopy and invasive mean arterial blood pressure (MAP), a moving correlation coefficient was calculated to obtain the cerebral oxygenation index as an indicator of cerebral autoregulation. Cerebral autoregulation was measured continuously from induction until recovery from anesthesia. Results There was no significant difference in cerebral autoregulation between robot-assisted and open retropubic radical prostatectomy during induction (p = 0.089), intraoperatively (p = 0.162), and during recovery from anesthesia (p = 0.620). Age (B = 0.311 [95% CI 0.039; 0.583], p = 0.025) and a higher difference between baseline MAP and intraoperative MAP (B = 0.200 [95% CI 0.073; 0.327], p = 0.002) were associated with impaired cerebral autoregulation, whereas surgical technique was not (B = 3.339 [95% CI 1.275; 7.952], p = 0.155). Conclusion Compared with open radical prostatectomy in the supine position, robot-assisted surgery in the extreme Trendelenburg position with capnoperitoneum did not lead to an impairment of cerebral autoregulation during the perioperative period in our study population. Trial registration number: DRKS00010014, date of registration: 21.03.2016, retrospectively registered.

OBJECTIVE To assess the effects of robot-assisted radical prostatectomy in the Trendelenburg position on postoperative neurocognitive outcomes this study compared cognitive function between patients who underwent robot-assisted radical prostatectomy and those who underwent open retropubic radical prostatectomy. METHODS Objective evaluations of pre- and postoperative cognitive function were performed upon admission and before hospital discharge, by using a neuropsychological test battery. We collected self-reported data on cognitive failures at 3 months postoperatively. Binary logistic regression analysis was used to assess the effects of surgical technique on postoperative cognitive performance. RESULTS The pre- and postoperative neuropsychological assessments were completed by 367 patients with a median age of 64 years (range 44-76). The incidence of postoperative cognitive dysfunction was 23.9% after robot-assisted (39/165) and 22.3% after open radical prostatectomy (45/202). There was no significant difference in postoperative cognitive function during the early postoperative period (P = 0.758) and self-reported cognitive failures at 3 months (P = 0.303) between robot-assisted and open surgery. Surgical technique was not associated with early postoperative cognitive dysfunction in multivariable analysis (OR 1.012, 95%CI: 0.608-1.685, P = 0.962). CONCLUSION Compared with open surgery in supine position postoperative neurocognitive disorders do not occur more frequently after robot-assisted radical prostatectomy in the extreme Trendelenburg position. Based on these findings potential adverse effects on cognitive function do not have to be considered in the choice of surgical approach for radical prostatectomy.

The current guidelines of the European Resuscitation Council recommend targeted temperature management to improve functional neurological outcome in comatose survivors after cardiac arrest. With the pathophysiological background of hypothermia-induced neuroprotection for prevention of hypoxic-ischemic encephalopathy, targeted temperature management is a key measure and represents a central aspect in postresuscitation care.In the 2021 guidelines the application of targeted temperature management in postresuscitation care has been recommended for all rhythms and irrespective of the location of cardiac arrest. Targeted temperature management is advocated for adult patients who remain unresponsive following return of spontaneous circulation (ROSC) after either out-of-hospital cardiac arrest or in-hospital cardiac arrest. The body temperature should be maintained at a constant value between 32 °C and 36 °C for at least 24 h. To avoid rebound hyperthermia, fever following targeted temperature management, defined as a temperature above 37.7 °C, should be prevented and treated for at least 72 h after ROSC in persistently comatose patients. The routine use of prehospital cooling by rapid infusion of large volumes of cold i.v. fluid immediately after ROSC is not recommended.Based on a systematic review of the current literature, this article summarizes the results of randomized trials and new findings on targeted temperature management in comatose adult patients after cardiac arrest. The review has a particular focus on the most recent evidence regarding the optimum range of target temperatures. Furthermore, recent data on preclinical management, different patient populations, the duration of targeted temperature management, cooling methods and rebound hyperthermia are discussed.The impact of targeted temperature management on neurological outcome after cardiac arrest has been a matter of controversy. Despite contradictory results and heterogeneity of study designs, the current evidence supports the relevance and the necessity of strict temperature control in postresuscitation care for neuroprotection and improvement in functional neurological outcomes.In den aktuellen Leitlinien des European Resuscitation Council wird das gezielte Temperaturmanagement zur Verbesserung des funktionell-neurologischen Outcome bei komatösen Patient:innen nach Wiedereinsetzten des Spontankreislaufs empfohlen. Mit dem pathophysiologischen Hintergrund der hypothermieinduzierten Neuroprotektion zur Prävention einer hypoxisch-ischämischen Enzephalopathie stellt das gezielte Temperaturmanagement einen zentralen Stellenwert in der Postreanimationsbehandlung dar.Basierend auf einer selektiven Literaturrecherche zeigt dieser Leitthemenbeitrag aktuelle Ergebnisse randomisierter Studien und Erkenntnisse bezüglich des optimalen Temperaturmanagements bei komatösen Patienten nach erfolgreicher Reanimation auf. Besonderer Fokus liegt auf neuer Evidenz hinsichtlich des angestrebten Temperaturzielbereichs. Weiterhin werden Entwicklungen und Änderungen hinsichtlich des präklinischen Managements, der Berücksichtigung unterschiedlicher Patient:innengruppen sowie der Dauer und Anwendung physikalischer Maßnahmen zur Temperaturregulation aufgeführt.In der Zusammenschau der Ergebnisse stellt der Einfluss des gezielten Temperaturmanagements auf das neurologische Outcome weiterhin eine viel diskutierte Kontroverse dar. Trotz der z. T. widersprüchlichen Ergebnisse der letzten Jahre und weiterhin offener Fragen hinsichtlich des optimalen Regimes unterstreichen die aktuellen Ergebnisse jedoch erneut die Relevanz und die Notwendigkeit einer strikten Temperaturkontrolle in den Postreanimationsabläufen.

Purpose The objective of this study was to determine the influence of postanesthesia care unit (PACU) delirium on self-reported cognitive function and perceived health status 3 months after surgery. Methods This prospective observational cohort study was performed in a PACU at a high-volume prostate cancer center. We used a convenience sample of patients > 60 years undergoing elective radical prostatectomy. Patients with a history of cerebrovascular or neurodegenerative disease were excluded. Fifteen, 30, 45, and 60 following extubation, patients were screened for signs of delirium with the Confusion Assessment Method for the Intensive Care Unit. Three months after surgery self-reported cognitive function was assessed with the Cognitive Failures Questionnaire, and health status was evaluated with the 36-item Short-Form Health Survey (SF-36). Results Signs of PACU delirium were present in 32.4% (n = 72/222) of patients, and 80.2% (n = 178/222) completed the 3-month follow-up. The presence of PACU delirium signs was not significantly associated with self-reported cognitive failures (B = 0.60, 95% CI: −1.72; 2.92, p = 0.61) or SF-36 physical component scores (B = 0.19, 95% CI: 0.02; 0.36, p = 0.03) or SF-36 mental component scores (B = −0.03, 95% CI: −0.18, 0.11, p = 0.66) 3 months after radical prostatectomy. Conclusions In a cohort of educated, highly functioning, elderly male patients who were assessed immediately after surgery and at a 3-month follow-up, we found no association between PACU delirium and self-reported cognitive failures or perceived health status, which implies that PACU delirium may be an event of limited duration and impact. Trial registration The study was registered at ClinicalTrials.gov (Identifier: NCT04168268, Date of registration: November 19, 2019).

About 20% of ICU patients with COVID-19 require renal replacement therapy (RRT). Mid-regional pro-adrenomedullin (MR-proADM) might be used for risk assessment. This study investigates MR-proADM for RRT prediction in ICU patients with COVID-19.We analysed data of consecutive patients with COVID-19, requiring ICU admission at a university hospital in Germany between March and September 2020. Clinical characteristics, details on AKI, and RRT were assessed. MR-proADM was measured on admission.64 patients were included (49 (77%) males). Median age was 62.5y (54-73). 47 (73%) patients were ventilated and 50 (78%) needed vasopressors. 25 (39%) patients had severe ARDS, and 10 patients needed veno-venous extracorporeal membrane oxygenation. 29 (45%) patients required RRT; median time from admission to RRT start was 2 (1-9) days. MR-proADM on admission was higher in the RRT group (2.491 vs. 1.23 nmol/l;AKI requiring RRT is frequent in ICU patients with COVID-19. MR-proADM on admission was able to predict RRT requirement, which may be of interest for risk stratification and management.

Background This RCT investigated the effect of opioid titration by three different nociception monitoring devices or clinical signs during general anaesthesia. Methods Ninety-six patients undergoing radical retropubic prostatectomy with propofol/remifentanil anaesthesia were randomised into one of four groups to receive remifentanil guided by one of three nociception monitoring devices (surgical pleth index [SPI], pupillary pain index [PPI], or nociception level [NOL]) or by clinical judgement (control). Intraoperative remifentanil requirement was the primary endpoint, whereas recovery parameters and stress hormone levels were secondary endpoints. Results The mean [95% confidence interval {CI}] remifentanil administration rate differed between the groups: control 0.34 (0.32–0.37), SPI 0.46 (0.38–0.55), PPI 0.07 (0.06–0.08), and NOL 0.16 (0.12–0.21) μg kg−1 min−1(P Conclusions The nociception monitoring devices and clinical signs reflect the extent of nociception differently, leading to dissimilar doses of remifentanil. Very low remifentanil doses were associated with an increase and higher remifentanil doses were accompanied by a decrease in serum cortisol concentrations. Use of nociception monitoring devices for guiding intra-operative opioid dosing needs further validation. Clinical trial registration NCT03380949.

BACKGROUND The aim of this study was to compare the incidence of early postoperative delirium in the postanesthesia care unit (PACU) between robot-assisted radical prostatectomy (RARP) in the extreme Trendelenburg position and open retropubic radical prostatectomy (ORP) in supine position. METHODS Patients were screened for delirium signs 15, 30, 45, and 60 minutes following extubation. RESULTS PACU delirium was present in 39.3% of RARP (64/163) patients and 41.8% of ORP (77/184) patients. Higher age (OR 1.072, 95%CI: 1.034-1.111, P

Neuroprotection through targeted temperature management is currently investigated in patients with severe brain injury in multiple trials. Feedback devices have been shown to precisely reach and maintain target temperature by constantly adjusting cooling activity. We analyzed the association between cooling activity expressed as cool bath temperatures and functional neurological outcome.Data were retrospectively analyzed from a prospective randomized trial on controlled prophylactic normothermia (i.e., 36.5 °C) in patients with severe cerebrovascular disease. Body core temperature of patients who had been randomized to the endovascular group, was controlled using an endovascular cooling device. Cool bath temperature was analyzed over a period of 168 h. Functional neurological outcome was evaluated at 180 days using the modified Rankin Scale.51 of 102 patients included were randomized to the endovascular group. Cool bath temperature data were available from 47/51 patients. Patients with lower cool bath temperatures reflecting high cooling activity had a more favorable neurological outcome at 180 days (mRS 0-2) than patients with low cooling activity (p0.05). We did not find a significant correlation between cool bath temperature and inflammatory markers.High cooling activity of an endovascular feedback device is associated with favorable outcome in patients with severe cerebrovascular disease.

Background Nosocomial infections are common in patients with spontaneous subarachnoid hemorrhage (SAH). The aim of this retrospective cohort study was to determine the incidence of infections during SAH and to evaluate the course of inflammation parameters and its implications for long term outcome. Objective Ninety-nine consecutive coiled SAH patients were included. Laboratory and clinical parameters as well as culture positive infections were followed over the disease course. Long-term outcome was assessed at 6-month by the Glasgow Outcome score (GOS) and dichotomized in favorable (GOSg3) and unfavorable outcome (GOS≤3). Results The most frequent infections were pulmonary (30.3%) urinary tract (25.3%), blood stream infections (20.2%) and ventriculitis (5.1%). The incidence of infections did not significantly differ between outcome groups. In contrast, patients with unfavorable outcome had a higher incidence of sepsis (46.7% versus 24.6%). C-reactive protein (CRP) and leukocytes were significantly higher in patients with unfavorable outcome. A CRP increase of 6 mg/dl or more in the first 3 days after SAH was independently associated with unfavorable outcome (OR 7.19 CI 1.7-30.52; p=0.008). Patients with an early CRP increase were more frequently treated with antimicrobial therapy in the first 3 days after admission which led to a significantly lower incidence of culture positive infections in the later course. Conclusion A sharp CRP-increase in the acute phase of SAH could potentially aid the intensivist in the early identification of patients at high risk for neurological morbidity. Early antimicrobial treatment reduces the rate of patients showing culture positive infections in the course of the disease.

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 high-grade (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). Conclusions: 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.

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.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.CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p0.001), glutamate (r=0.45, p0.001), pyruvate (r=0.26, p0.001), and the lactate-pyruvate ratio (r=0.26, p0.001), and were higher in episodes of hypoxic (PbtO220 mm Hg) brain extracellular lactate elevation (4 mmol/L) (p0.01). 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 (p0.01).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.

Alois J. Schiefecker *, Ronny Beer , Josef Steidl , Florian Sohm, Andrea Griesmacher , Alexander K. Brendel , Iris Unterberger , Marlene Fischer , Anelia Dietmann , Bettina Pfausler , Claudius Thome , Erich Schmutzhard , Raimund Helbok a Division of Neurocritical Care, Department of Neurology, Medical University Innsbruck, Austria Central Institute of Medical and Chemical Laboratory Diagnostics, Medical University Innsbruck, Austria Department of Neurosurgery, Medical University Innsbruck, Austria

Brain derived neurotrophic factor (BDNF) is associated with pain modulation and central sensitization. Recently, a role of BDNF in migraine and cluster headache pathophysiology has been suspected due to its known interaction with calcitonin gene-related peptide. Bi-center prospective study was done enrolling four diagnostic groups: episodic migraine with and without aura, episodic cluster headache, frequent episodic tension-type headache, and healthy individuals. In migraineurs, venous blood samples were collected twice: outside and during migraine attacks prior to pain medication. In cluster headache patients serum samples were collected in and outside cluster bout. Analysis of BDNF was performed using enzyme-linked immunosorbent assay technique. Migraine patients revealed significantly higher BDNF serum levels during migraine attacks (n = 25) compared with headachefree intervals (n = 53, P\0.01), patients with tensiontype headache (n = 6, P\0.05), and healthy controls (n = 22, P\0.001). There was no significant difference between patients with migraine with aura compared with those without aura, neither during migraine attacks nor during headache-free periods. Cluster headache patients showed significantly higher BDNF concentrations inside (n = 42) and outside cluster bouts (n = 24) compared with healthy controls (P\0.01, P\0.05). BDNF is increased during migraine attacks, and in cluster headache, further supporting the involvement of BDNF in the pathophysiology of these primary headaches. © The Author(s) 2012.

Little is known about endothelial activation under the influence of endovascular temperature management. This analysis was designed to measure the endothelial markers Angiopoietin-1 (Ang-1) and -2 (Ang-2) in endovascularly based prophylactic normothermia versus conventional temperature management.In this randomized controlled trial patients with spontaneous subarachnoid or spontaneous intracerebral hemorrhage were prospectively enrolled and randomized in two treatment arms: (a) prophylactic normothermia group with target core temperature 36.5°C using endovascular cooling, (b) active control group with conventional stepwise predefined fever management using antipyretic medication and surface cooling. Blood samples were obtained on days 1, 4, and 7. In a substudy Ang-1 and -2 were measured in 63 patients for whom samples on consecutive days were available.The median total fever burden during the course of treatment was 0.0°C and 5.9°C h in the endovascular and the conventional group, respectively (P 0.0001). Angiopoietin serum levels did not yield a statistical difference when comparing the two treatment arms. Ang-1 was significantly lowered, whereas Ang-2 levels were significantly elevated on day 4 compared to baseline levels irrespective of group allocation (P 0.0001). The application of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with significantly increased Ang-1 (P 0.05) and lower Ang-2 levels on day 7 (P 0.05).Endovascular long-term temperature management did not alter Ang-1 and -2 levels compared to the control group indicating that the endovascular cooling technique itself does not lead to additional endothelial impairment. However, application of NSAIDs led to lower Ang-2 serum concentrations in the endovascular group.

Background and Purpose— We analyzed the impact of long-term endovascularly based prophylactic normothermia versus conventional temperature management on inflammatory parameters in patients with severe cerebrovascular disease. Methods— This was a prospective, randomized, controlled trial comparing the course of inflammatory parameters between the 2 treatment arms: (1) prophylactically endovascular long-term normothermia; and (2) conventional, stepwise fever management with antiinflammatory drugs and surface cooling. Inclusion criteria were (1) spontaneous subarachnoid hemorrhage with Hunt–Hess grade between 3 and 5; (2) spontaneous intracerebral hemorrhage with a Glasgow Coma Scale score of ≤10; or (3) complicated cerebral infarction requiring intensive care unit treatment with a NIH Stroke Scale score of ≥15. Treatment period was 336 hours in subarachnoid hemorrhage patients and 168 hours in patients with complicated stroke or intracerebral hemorrhage patients. Results— A total of 102 patients (56 female) were enrolled during a 3.5-year period. Overall median total fever burden during the course of treatment was 0.0°C hour and 4.3°C hours in the catheter and conventional group, respectively ( P P P Conclusions— The proinflammatory cytokines C-reactive protein and interleukin-6 were significantly elevated in patients receiving prophylactic endovascularly based long-term normothermia. Nonsteroidal antiinflammatory drugs significantly affected the course of proinflammatory parameters; thus, future trials should investigate the role of nonsteroidal antiinflammatory drugs in severe cerebrovascular disease patients and their interaction with temperature management. Clinical Trial Registration— Trial not registered; enrollment began before July 2005.

Background and Purpose— Spontaneous subarachnoid hemorrhage (SAH) still has a high risk for poor outcome that is frequently attributable to symptomatic cerebral vasospasm (CVS). We hypothesize that cellular microparticles (MP) play a role in the pathogenesis of CVS and may serve as biomarkers for CVS. Methods— In 20 consecutive SAH patients, endothelial, leukocyte, platelet, and erythrocyte MP were measured during 15 days after ictus. CVS was detected by transcranial Doppler sonography. Twenty matched volunteers served as healthy controls. Results— Endothelial, leukocyte, and erythrocyte MP were elevated in SAH patients compared to healthy controls. CD105 + and CD62e + endothelial MP were significantly higher in SAH patients with Doppler sonographic CVS. CD105 + endothelial MP were especially increased on the days of Doppler sonographic CVS onset. In patients experiencing cerebral infarction attributable to vasospasm, CD41 + platelet MP were elevated in addition to endothelial MP. CD41 + platelet MP were significantly higher in patients with any level of disability (modified Rankin Scale score ≥1) compared to those who made a full recovery (modified Rankin Scale score=0) on discharge from hospital. Conclusion— Endothelial MP were elevated in patients with SAH. This elevation coincided with the occurrence of Doppler sonographic CVS and therefore could be a novel biomarker for CVS. Platelet MP might be involved in the pathogenesis of cerebral infarction attributable to vasospasm, resulting in neurological morbidity.

BACKGROUND Molecular mechanisms involved in the pathogenesis of severe Plasmodium falciparum malaria-specifically, cerebral malaria-are still unclear. Transforming growth factor beta (TGF-beta) family members are important regulators of inflammation that influence malaria pathogenesis. The soluble form of the auxiliary receptor endoglin (sEng) may play a role in malaria pathogenesis. METHODS Serum levels of sEng were measured using enzyme-linked immunosorbent-assay in Gabonese children with cerebral malaria (n = 7) severe malaria (n = 43), or uncomplicated malaria (n = 43) and were compared with levels in healthy control subjects (n = 25) and in another infectious disease group (n = 8). RESULTS Serum sEng levels were higher in patients with cerebral malaria and all patients with severe malaria when compared with levels in patients in the other infection group and the healthy control group. Furthermore, sEng correlated significantly with disease severity. Only 7% of patients with uncomplicated malaria and none of the control patients (patients in the other infection group or the healthy control group) had serum levels higher than 12 ng/mL, whereas this was found in 85.7% of patients with cerebral malaria and 46.5% of patients with severe malaria. CONCLUSIONS High sEng levels may attenuate anti-inflammatory response resulting in clinical deterioration of patients with P. falciparum malaria. Our results further corroborate the role of the vascular compartment, especially the endothelium, in severe malaria pathogenesis.

Introduction There is a substantial amount of evidence from animal models that early brain injury (EBI) may play an important role for secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Cerebral microdialysis (CMD) allows online measurement of brain metabolites, including the pro-inflammatory cytokine interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9), which is indicative for disruption of the blood-brain barrier. Methods Twenty-six consecutive poor-grade aSAH patients with multimodal neuromonitoring were analyzed for brain hemodynamic and metabolic changes, including CMD-IL-6 and CMD-MMP-9 levels. Statistical analysis was performed by using a generalized estimating equation with an autoregressive function. Results The baseline cerebral metabolic profile revealed brain metabolic distress and an excitatory response which improved over the following 5 days (P P P P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P P ≤0.01). All models were adjusted for probe location, aneurysm securing procedure, and disease severity as appropriate. Conclusions Multimodal neuromonitoring techniques allow insight into pathophysiologic changes in the early phase after aSAH. The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

Background Triptans are recommended as first-line therapy in the acute phase of a migraine attack. We describe patterns of triptan use in a tertiary care headache outpatient clinic, particularly addressing factors that are associated with triptan discontinuation. Methods From December 2009 until August 2012, demographic and clinical data of consecutive patients with migraine were collected. The Headache Impact Test (HIT-6) was used to measure the adverse impact of headaches. Factors associated with triptan discontinuation were analyzed using binary logistic regression. Results Of 511 migraine patients included, 73.2% (n = 374) were triptan naive on first consultation. At follow-up, 57.1% of new triptan users (n = 72/126) reported pain-freedom or pain relief after 2 hours, 40.5% (n = 51/126) did not refill their triptan, another 15.1% (n = 19/126) switched to a different type of triptan. Negative response to triptan treatment and substantial or severe headache impact (HIT-6 score ≥56) at first follow-up were associated with triptan discontinuation (OR 0.39 [95% CI 0.20—0.78], P = .007; OR 3.33 [95% CI 1.10–10.03], P = .033). Conclusions Although triptans have been in clinical use for more than two decades, many migraine sufferers in our study population were found to be triptan naive on first consultation. The HIT-6 score may be used as an indicator of triptan adherence and help to identify patients at risk for triptan discontinuation.

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.

Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.

Short-term hematopoietic reconstituting cells have been identified in mice, nonhuman primates, and among human cells that engraft xenogeneic hosts. We now present clonal marking data demonstrating a rapid but unsustained contribution of cultured human autografts to the initial phase of hematologic recovery in myeloablated patients. Three patients received transplants of granulocyte colony-stimulating factor–mobilized autologous peripheral blood (PB) cells, of which a portion (8%-25% of the CD34+ cells) had been incubated in vitro with growth factors (5 days) and clinical grade LN retrovirus (3-5 days). More than 9% of the clonogenic and long-term culture-initiating cells harvested were transduced. Semiquantitative and linear amplification-mediated polymerase chain reaction analyses of serial PB samples showed that marked white blood cells appeared in all 3 patients within 11 days and transiently constituted up to 0.1% to 1% of those produced in the first month. However, within another 2 to 9 months, marked cells had permanently decreased to very low levels. Analysis of more than 50 vector insertion sites showed none of the clones detected in the first month were active later. Eighty percent of inserts were located within or near genes, 2 near CXCR4. These findings provide direct evidence of cells with rapid but transient repopulating activity in patients and demonstrate their efficient transduction in vitro.

Background Numerous studies suggest an increased vascular risk in patients with migraine, in particular in those with aura. A possible link between both conditions might be a dysfunction of the vascular endothelium. This observational study analyzed the endothelial markers angiopoietin-1, angiopoietin-2, Tie-2, sFlt-1 and NT-proBNP for the first time in migraineurs, patients with other primary headache disorders and healthy controls. Methods Patients with episodic migraine with and without aura, episodic cluster headache, tension-type headache and healthy controls were included. Blood samples were obtained during migraine attacks and headache-free periods in migraineurs, in and out of bout in cluster headache and during headache-free periods in tension-type headache and healthy individuals to analyze markers of endothelial function. Results No significant difference in endothelial markers between migraine, other headache disorders and healthy controls was detected. There was no significant difference between migraine attacks and headache-free intervals. Additionally, no distinction could be found between migraine with and without aura. Discussion The endothelial markers analyzed do not display a characteristic pattern in different headache disorders especially migraine compared to healthy controls. The novel findings of our study indicate that factors other than endothelial dysfunction seem to be responsible for the at least statistical association of migraine with vascular disease.

Background: Atrial natriuretic peptide (ANP) is a well-known prognostic marker of outcome and mortality in patients with cardiovascular disease. Midregional proatrial natriuretic peptide (MR-proANP) is a stable fragment of the ANP precursor hormone. As a prognostic marker after ischemic stroke, it reliably predicts poststroke mortality and functional outcome. This study aimed to analyze the prognostic value of MR-proANP in patients with hemorrhagic stroke, i.e. subarachnoid (SAH) and intracerebral hemorrhage (ICH). Methods: MR-proANP was analyzed in patients with spontaneous SAH or spontaneous ICH. All patients were prospectively randomized into two treatment arms: (1) a prophylactic normothermia group with a target core temperature 36.5°C using endovascular cooling, and (2) a control group with conventional stepwise predefined fever management using antipyretic medication and surface cooling. Blood samples were obtained on admission and on days 4 and 7. Measurement of MR-proANP was performed in serum using sandwich immunoassay. The primary endpoint was functional outcome [assessed by the Glasgow Outcome Score (GOS)] and the secondary endpoints were mortality within 180 days after hemorrhagic stroke and influence of temperature on MR-proANP. A favorable outcome was defined as GOS 4-5, and the patients were considered to have a poor outcome with a 180-day GOS score between 1 and 3. Results: Analysis of MR-proANP was performed in 24 patients with spontaneous SAH and 22 patients with spontaneous ICH. MR-proANP was elevated on days 4 and 7 as compared to baseline levels (p < 0.05 and p < 0.001, respectively). High MR-proANP levels (>120 pmol/l) were associated with increased mortality and poor outcome (after 180 days; p < 0.05, respectively). There was no significant difference regarding MR-proANP serum concentrations between the endovascular and the control groups. Conclusions: Increased levels of MR-proANP are independently associated with poor functional outcome and increased mortality after 180 days in patients with hemorrhagic stroke. Endovascular temperature control had no significant influence on MR-proANP levels.

Background Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS). Methods Blood samples were collected in 20 SAH patients on days 1 to 7, 9, 11, 13 and 15 and 20 healthy age and gender matched volunteers. Serum MMPs and TIMPs were analyzed using enzyme-linked immunosorbent assay. Doppler sonographic CVS was defined as a mean blood flow velocity above 120 cm/sec in the middle cerebral artery. When discharged from hospital and at 6 month follow-up neurological outcome was evaluated using the Glasgow Outcome Score and the modified Rankin Scale. Results MMP-9 was higher in SAH patients compared to healthy controls (p

Background Angiopoietin-1 (Ang-1) and -2 (Ang-2) are keyplayers in the regulation of endothelial homeostasis and vascular proliferation. Angiopoietins may play an important role in the pathophysiology of cerebral vasospasm (CVS). Ang-1 and Ang-2 have not been investigated in this regard so far. Methods 20 patients with subarachnoid hemorrhage (SAH) and 20 healthy controls (HC) were included in this prospective study. Blood samples were collected from days 1 to 7 and every other day thereafter. Ang-1 and Ang-2 were measured in serum samples using commercially available enzyme-linked immunosorbent assay. Transcranial Doppler sonography was performed to monitor the occurrence of cerebral vasospasm. Results SAH patients showed a significant drop of Ang-1 levels on day 2 and 3 post SAH compared to baseline and HC. Patients, who developed Doppler sonographic CVS, showed significantly lower levels of Ang-1 with a sustained decrease in contrast to patients without Doppler sonographic CVS, whose Ang-1 levels recovered in the later course of the disease. In patients developing cerebral ischemia attributable to vasospasm significantly lower Ang-1 levels have already been observed on the day of admission. Differences of Ang-2 between SAH patients and HC or patients with and without Doppler sonographic CVS were not statistically significant. Conclusions Ang-1, but not Ang-2, is significantly altered in patients suffering from SAH and especially in those experiencing CVS and cerebral ischemia. The loss of vascular integrity, regulated by Ang-1, might be in part responsible for the development of cerebral vasospasm and subsequent cerebral ischemia.

BACKGROUND: As brain temperature is reported to be extensively higher than core body temperature in traumatic brain injury (TBI) patients, posttraumatic hyperthermia is of particular relevance in the injured brain. OBJECTIVE: To study the influence of prophylactic normothermia on brain temperature and the temperature gradient between brain and core body in patients with severe TBI using an intravascular cooling system and to assess the relationship between brain temperature and intracranial pressure (ICP) under endovascular temperature control. METHODS: Prospective case series study conducted in the neurologic intensive care unit of a tertiary care university hospital. Seven patients with severeTBI with a Glasgow Coma Scale score of 8 or less were consecutively enrolled. Prophylactic normothermia, defined as a target temperature of 36.5� C, was maintained using an intravascular cooling system. Simultaneous measurements of brain and urinary bladder temperature and ICP were taken over a 72-hour period. RESULTS: The mean bladder temperature in normothermic patients was 36.3 6 0.4� C, and the mean brain temperature was determined as 36.4 6 0.5� C. The mean temperature difference between brain and bladder was 0.1� C. We found a significant direct correlation between brain and bladder temperature (r = 0.95). In 52.4% of all measurements, brain temperature was higher than core body temperature. The mean ICP was 18 6 8 mm Hg. CONCLUSION: Intravascular temperature management stabilizes both brain and body core temperature; prophylactic normothermia reduces the otherwise extreme increase of intracerebral temperature in patients with severe TBI. The intravascular cooling management proved to be an efficacious and feasible method to control brain temperature and to avoid hyperthermia in the injured brain. We could not find a statistically significant correlation between brain temperature and ICP.

Background and Purpose— We sought to study the effectiveness and safety of endovascular cooling to maintain prophylactic normothermia in comparison with standardized, stepwise, escalating fever management to reduce fever burden in patients with severe cerebrovascular disease. Methods— This study was a prospective, randomized, controlled trial with a blinded neurologic outcome evaluation comparison between prophylactic, catheter-based normothermia (CoolGard; ie, body core temperature 36.5°C) and conventional, stepwise fever management with anti-inflammatory drugs and surface cooling. Patients admitted to 1 of the 2 neurointensive care units were eligible for study inclusion when they had a (1) spontaneous subarachnoid hemorrhage with Hunt & Hess grade between 3 and 5, (2) spontaneous intracerebral hemorrhage with a Glasgow Coma Scale score ≤10, or (3) complicated cerebral infarction requiring intensive care unit treatment with a National Institutes of Health Stroke Scale score ≥15. Results— A total of 102 patients (56 female) were enrolled during a 3.5-year period. Fifty percent had a spontaneous subarachnoid hemorrhage, 40% had a spontaneous intracerebral hemorrhage, and 10% had a complicated cerebral infarction. Overall median total fever burden during the course of treatment was 0.0°C hour and 4.3°C hours in the catheter and conventional groups, respectively ( P Conclusions— Long-term, catheter-based, prophylactic normothermia significantly reduces fever burden in neurointensive care unit patients with severe cerebrovascular disease and is not associated with increased major adverse events.

Clinical use of purified hematopoietic stem cells in myeloablated patients requires cotransplantation of short-term repopulating cells (STRCs) to ensure timely count recovery. Here, we investigated the flow fluorescence-based side population (SP) phenotype of mobilized human peripheral blood (mPB) cells that rapidly repopulate the highly permissive nonobese diabetic/severe combined immunodeficient (NOD/SCID)-beta2 microglobulin(-)/- mouse. No SP cells from this source regenerated detectable progeny in these mice before 8 weeks, although by 12 weeks human B-lymphoid cells were seen in some recipients of SP mPB cells. All myeloid reconstituting activity, including that seen within 3 weeks after transplantation, was associated with the non-SP fraction. Isolation of SP cells depletes human mPB of the rapid myeloid reconstitution capacity provided by myeloid-restricted STRCs which are vital for early hematologic recovery in clinical transplant recipients.

Objective Human mobilized peripheral blood (mPB) is known to contain high numbers of cells with rapid but short-term repopulating activity in NOD/SCID-β2microglobulin −/− mice. Here we assessed the effect of short-term culture on these cells and compared the levels of retained activity with the pace of hematologic recovery in myeloablated patients transplanted with similarly cultured autografts of the same cells. Patients and methods In a phase 1 clinical study, mPB cells were collected from 6 advanced cancer patients. CD34 + cells were then harvested, cultured for 3 days in the presence of early-acting growth factors, and transplanted, and posttransplant recovery of blood cell parameters monitored. Assays for primitive hematopoietic activity using both in vivo (in NOD/SCID-β2microglobulin −/− mice) and in vitro (CFC and LTC-IC) endpoints were also performed on the cells pre- and posttransplant. Results All patients showed event-free, timely leukocyte recoveries but slightly delayed platelet recoveries in some cases. During the 3-day period of culture, the CFCs doubled but the LTC-IC activity decreased (twofold), as did the short-term repopulating activity in NOD/SCID-β2microglobulin −/− mice. Conclusion Patients can be transplanted with 3-day cultured autografts with minimal effects on hematologic recovery. This is associated with a variable but, on average, modest loss of short-term repopulating activity detectable in NOD/SCID-β2microglobulin −/− mice.

Posterior reversible encephalopathy syndrome refers to a neurological disorder characterized by headache, disorders of consciousness, visual disturbances, epileptic seizures, and subcortical vasogenic edema. About two thirds of patients develop neurological symptoms, which are associated with blood pressure fluctuations. One hypothesis is that hypertensive episodes cause autoregulatory failure, and values above the upper limit of cerebral autoregulation result in a breakthrough followed by hyperperfusion and blood-brain barrier dysfunction. In another hypothesis, endothelial dysfunction triggered by numerous factors including preeclampsia, immunosuppressive agents, chemotherapeutics, sepsis, or autoimmune disorders is thought to be the key pathomechanism. Endo- or exogenic toxic agents including pharmacological substances, cytokines, or bacterial toxins are supposed to trigger endothelial activation and dysfunction resulting in the release of vasoconstrictors, pro-inflammatory mediators, and vascular leakage. Diagnosis is usually based on clinical and neuroimaging findings that frequently show a bilateral, symmetric, and parietooccipital pattern. However, the diagnosis can often only be confirmed during the course of disease after excluding important differential diagnoses. Currently, there is no specific treatment available. Lowering of arterial blood pressure and eliminating the underlying cause usually leads to an improvement of clinical and neuroradiological findings. Admission to a critical care unit is required in about 40 % of patients due to complicating conditions including status epilepticus, cerebral vasoconstriction, ischemia, or intracerebral hemorrhage. Prognosis is favorable; in the majority of patients neurological deficits and imaging findings resolve completely.

Introduction Elevated brain potassium levels ([K+]) are associated with neuronal damage in experimental models. The role of brain extracellular [K+] in patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) and its association with hemorrhage load, metabolic dysfunction and outcome has not been studied so far. Methods Cerebral microdialysis (CMD) samples from 28 poor grade aSAH patients were analyzed for CMD [K+] for 12 consecutive days after ictus, and time-matched to brain metabolic and hemodynamic parameters as well as corresponding plasma [K+]. Statistical analysis was performed using a generalized estimating equation with an autoregressive function to handle repeated observations of an individual patient. Results CMD [K+] did not correlate with plasma [K+] (Spearman’s ρ = 0.114, P = 0.109). Higher CMD [K+] was associated with the presence of intracerebral hematoma on admission head computed tomography, CMD lactate/pyruvate ratio >40 and CMD lactate >4 mmol/L (P