Reproducibility of cerebral blood flow, oxygen metabolism, and lactate and N-acetyl-aspartate concentrations measured using magnetic resonance imaging and spectroscopy.

In humans, resting cerebral perfusion, oxygen consumption and energy metabolism demonstrate large intersubject variation regardless of methodology. Whether a similar large variation is also present longitudinally in individual subjects is much less studied, but knowing the time variance in reproducibility is important when designing and interpreting longitudinal follow-up studies examining brain physiology. Therefore, we examined the reproducibility of cerebral blood flow (CBF), global cerebral metabolic rate of oxygen (CMRO2), global arteriovenous oxygen saturation difference (A-V.O2), and cerebral lactate and N-acetyl-aspartate (NAA) concentrations measured using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques through repeated measurements at 6 h, 24 h, 7 days and several weeks after initial baseline measurements in young healthy adults (N = 26, 13 females, age range 18-35 years). Using this setup, we calculated the correlation, limit of agreement (LoA) and within-subject coefficient of variation (CoVWS) between baseline values and the subsequent repeated measurements to examine the longitudinal variation in individual cerebral physiology. CBF and CMRO2 correlated significantly between baseline and all subsequent measurements. The strength of the correlations (R2) and reproducibility metrics (LoA and CoVWS) demonstrated the best reproducibility for the within-day measurements and generally declined with longer time between measurements. Cerebral lactate and NAA concentrations also correlated significantly for all measurements, except between baseline and the 7-day measurement for lactate. Similar to CBF and CMRO2, lactate and NAA demonstrated the best reproducibility for within-day repeated measurements. The gradual decline in reproducibility over time should be considered when designing and interpreting studies on brain physiology, for example, in the evaluation of treatment efficacy.

Complement Profiles in Patients with Amyotrophic Lateral Sclerosis: A Prospective Observational Cohort Study.

BACKGROUND: The complement system has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease. In the present study, we compared levels of selected complement markers to clinical outcome in ALS patients. METHODS: This observational, explorative cohort study included 92 ALS patients, 61 neurological controls (NCs) admitted for suspected aneurysmal subarachnoid haemorrhage, and 96 neurologically healthy controls (NHCs). Peripheral blood and cerebrospinal fluid (CSF) were obtained for the measurement of ficolin-1, -2, and -3; collectin-11, MBL, MASP-3, MAP-1, C4, C3, PTX-3, and complement activation products C4c, C3bc, and sC5b-9. We recorded clinical outcomes of ALS patients for 24 to 48 months after inclusion in order to analyse the effects of the complement markers on survival time. RESULTS: Compared with both control groups, ALS patients exhibited increased collectin-11, C4 and sC5b-9 in plasma, as well as increased ficolin-3 in CSF. Ficolin-2 was significantly decreased in plasma of the ALS patients compared with NHCs, but not with NCs. The concentration of collectin-11, C3 and C3bc correlated negatively with the revised ALS functional rating scale (ALSFRS-R). No association was found between levels of complement markers and survival as estimated by hazard ratios. CONCLUSION: ALS patients exhibit aberrant expression of selected mediators of the lectin complement pathway as well as increased activation of the terminal complement pathway, corroborating the notion that the complement system might be involved in the pathophysiology of ALS.

Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials. OBJECTIVE: This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort. METHODS: The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS') was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS' was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis. RESULTS AND CONCLUSIONS: Both ΔFS' and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS', is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

Neuroplasticity induced by general anaesthesia: study protocol for a randomised cross-over clinical trial exploring the effects of sevoflurane and propofol on the brain - A 3-T magnetic resonance imaging study of healthy volunteers.

BACKGROUND: Although used extensively worldwide, the effects of general anaesthesia on the human brain remain largely elusive. Moreover, general anaesthesia may contribute to serious conditions or adverse events such as postoperative cognitive dysfunction and delirium. To understand the basic mechanisms of general anaesthesia, this project aims to study and compare possible de novo neuroplastic changes induced by two commonly used types of general anaesthesia, i.e. inhalation anaesthesia by sevoflurane and intravenously administered anaesthesia by propofol. In addition, we wish to to explore possible associations between neuroplastic changes, neuropsychological adverse effects and subjective changes in fatigue and well-being. METHODS: This is a randomised, participant- and assessor-blinded, cross-over clinical trial. Thirty healthy volunteers (male:female ratio 1:1) will be randomised to general anaesthesia by either sevoflurane or propofol. Multimodal magnetic resonance imaging (MRI) of the brain will be performed before and after general anaesthesia and repeated after 1 and 8 days. Each magnetic resonance imaging session will be accompanied by cognitive testing and questionnaires on fatigue and well-being. After a wash-out period of 4 weeks, the volunteers will receive the other type of anaesthetic (sevoflurane or propofol), followed by the same series of tests. Primary outcomes: changes in T1-weighted 3D anatomy and diffusion tensor imaging. SECONDARY OUTCOMES: changes in resting-state functional magnetic resonance imaging, fatigue, well-being, cognitive function, correlations between magnetic resonance imaging findings and the clinical outcomes (questionnaires and cognitive function). Exploratory outcomes: changes in cerebral perfusion and oxygen metabolism, lactate, and response to visual stimuli. DISCUSSION: To the best of our knowledge, this is the most extensive and advanced series of studies with head-to-head comparison of two widely used methods for general anaesthesia. Recruitment was initiated in September 2019. TRIAL REGISTRATION: Approved by the Research Ethics Committee in the Capital Region of Denmark, ref. H-18028925 (6 September 2018). EudraCT and Danish Medicines Agency: 2018-001252-35 (23 March 2018). www.clinicaltrials.gov , ID: NCT04125121 . Retrospectively registered on 10 October 2019.

Amyotrophic lateral sclerosis and the innate immune system: protocol for establishing a biobank and statistical analysis plan.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating, progressive disease that causes degeneration of the motor neurons leading to paresis of the bulbar and the skeletal musculature. The pathogenesis of ALS remains unknown. We will test the hypothesis that the complement system is involved in the pathophysiology of ALS. This protocol article describes our efforts to establish a national Danish ALS biobank. The primary aim is to obtain biological material from patients with ALS for the current study as well as for future studies. METHODS AND ANALYSIS: We intend to establish an observational ALS biobank; some of the material from this biobank will be used for a prospective, observational case-control study. The participants are patients with ALS, neurologically healthy controls and non-ALS neurological controls. Each participant consents to be interviewed and to donate blood and cerebrospinal fluid to the biobank. Analysis of the complement system will be carried out on the three groups of patients and compared. ETHICS AND DISSEMINATION: The project has been approved by the Committees on Health Research Ethics in the Capital Region of Denmark (Approval number H-16017145) and the Danish Data Protection Agency (file number 2012-58-0004). All results will be published in peer-reviewed, medical journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT02869048.

Amyotrophic lateral sclerosis: The complement and inflammatory hypothesis.

Amyotrophic lateral sclerosis (ALS) is a devastating, neurodegenerative motor neuron disease. The aetiology of ALS remains an enigma which hinders the design of an effective treatment to prevent, postpone, or reverse the pathophysiological changes occurring during the aggressive progression of this disease. During the last decade, basic research within the innate immune system, and in particular the complement system, has revealed new, important roles of the innate immune system during development, homeostasis, and ageing within as well as outside the central nervous system. Several lines of evidence indicate that aberrant activation of the complement system locally in the central nervous system as well as systemically may be involved in the pathophysiology of ALS. This exciting new knowledge could point towards the innate immune system as a potential target of medical intervention in ALS. Recently, the historic perception of ALS as a central neurodegenerative disease has been challenged due to the significant amount of evidence of a dying-back mechanism causing the selective destruction of the motor neurons, indicating that disease onset occurs outside the borders of the blood-brain-barrier. This review addresses the function of the innate immune system during ALS. We emphasize the role of the complement system and specifically suggest the involvement of ficolin-3 from the lectin pathway in the pathophysiology of ALS.

Carbon monoxide inhalation induces headache in a human headache model.

Introduction Carbon monoxide (CO) is an endogenously produced signalling molecule that has a role in nociceptive processing and cerebral vasodilatation. We hypothesized that inhalation of CO would induce headache and vasodilation of cephalic and extracephalic arteries. Methods In a randomized, double-blind, placebo-controlled crossover design, 12 healthy volunteers were allocated to inhalation of CO (carboxyhemoglobin 22%) or placebo on two separate days. Headache was scored on a verbal rating scale from 0-10. We recorded mean blood velocity in the middle cerebral artery (VMCA) by transcranial Doppler, diameter of the superficial temporal artery (STA) and radial artery (RA) by high-resolution ultrasonography and facial skin blood flow by laser speckle contrast imaging. Results Ten volunteers developed headache after CO compared to six after placebo. The area under the curve for headache (0-12 hours) was increased after CO compared with placebo ( p = 0.021). CO increased VMCA ( p = 0.002) and facial skin blood flow ( p = 0.012), but did not change the diameter of the STA ( p = 0.060) and RA ( p = 0.433). Conclusion In conclusion, the study demonstrated that CO caused mild prolonged headache but no arterial dilatation in healthy volunteers. We suggest this may be caused by a combination of hypoxic and direct cellular effects of CO.

[An almost fatal airway obstruction caused by a secretion plug in an endotracheal tube].

Airway obstruction caused by a secretion plug in an endotracheal tube or a tracheostomy cannula can be a serious complication to mechanical ventilation. This case describes an event caused by a mucus plug localized to the distal part of a tracheostomy tube in a tetraplegic patient. The plug functioned as a check valve, allowing air to pass in - but not out - of the patient. A suction catheter could be passed through the airway without any resistance, and thus the airway was believed to be free. The event, which had an almost fatal outcome due to hyperinflation of the lungs, was relieved by replacement of the tracheostomy cannula.

Should patients walk from the postanesthesia care unit to the general ward after a lumbar discectomy? A randomized study.

PURPOSE: The aim of this pilot study was to investigate whether it was feasible and safe to mobilize patients shortly after lumbar disc surgery with the objective of reducing postoperative complications and allowing shorter hospitalization. DESIGN: Randomized controlled study. METHOD: The patients were randomized into two groups, intervention and control groups. Those in the intervention group used a walking frame to walk, with a porter and a nurse, from the postanesthesia care unit to the general ward. Patients in the control group were transported in their beds. The Bournemouth Questionnaire was used to define the various aspects of well-being of the patients. FINDINGS: A total of 22 patients were included, 11 in each group. Owing to the limited number of patients, statistical comparisons were not performed. However, patients in the walking group were mobilized earlier than the controls, and needed fewer painkillers and less oxygen supplement during the first postoperative day. The length of stay and the number of postoperative complications were similar in the two groups as tested during the three weeks after surgery. CONCLUSION: This pilot study suggests that it might be feasible and safe to mobilize patients shortly after lumbar disc surgery. There were no indications of an increased number of postoperative complications.

[Treatment of severe anaemia in patients who refuse blood transfusion].

In situations involving serious bleeding and anaemia, a refusal of blood transfusion puts the clinician in an ethical and medical dilemma, as standard treatment is not an option, and the patient risks dying of a potentially reversible cause. This status article describes methods of treatment under the concept of "bloodless medicine", where surgical and supportive techniques are used to manage and treat severe anaemia.

Effect of head rotation during surgery in the prone position on regional cerebral oxygen saturation: A prospective controlled study.

BACKGROUND: Near-infrared spectroscopy (NIRS) has been used to study regional cerebral blood oxygen saturation (rScO2) in patients in the prone position. OBJECTIVES: We aimed to test the hypothesis that head rotation more than 45° would affect the rScO2. DESIGN: A prospective, controlled, single cohort study. SETTING: University Hospital specialising in spinal surgery. PATIENTS: Fifty-two patients undergoing spinal surgery in prone position were enrolled and 48 completed the study. INTERVENTIONS: NIRS sensors were attached to each side of the forehead. Measurements were conducted during steady-state anaesthesia with the head in the neutral position, rotated left, rotated right and returned to the neutral position. Each series consisted of three measurements: resting on the head support, during head lift (to relieve pressure on the tissue at the sensors) and returned to rest on the head support. MAIN OUTCOME MEASURES: The differences in rScO2 between the neutral and the turned head positions. RESULTS: For both left and right sensors, the median differences in rScO2 between neutral and left or right positions were between 0 and -1 with the head up (P = 0.14 to 0.84). The median differences with the head down were between 3.8 and -0.8, with a significant difference for the left sensor when turned left (P < 0.01) and for the right sensor (P = 0.006) when turned right. Ten patients showed reductions of more than 10 in rScO2 in the rotated (and lifted) positions. When the head was lifted from the head support, the rScO2 was -0.5 to 3.75 units higher, but there was high variability between patients. CONCLUSION: We recommend the neutral head position for prone patients.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01760369.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the circulation after sumatriptan.

Background and purpose The origin of migraine pain is still elusive, but increasingly researchers focus on the neuropeptides in the perivascular space of cranial vessels as important mediators of nociceptive input during migraine attacks. The parasympathetic neurotransmitters, pituitary adenylate cyclase activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) may be released from parasympathetic fibres and activate sensory nerve fibres during migraine attacks. Triptans are effective and well tolerated in acute migraine management but the exact mechanism of action is still debated. Triptans might reduce circulating neuropeptides. To examine this question, we examined the effect of sumatriptan on VIP and PACAP levels in vivo, under conditions without trigeminovascular system activation. Methods In 16 healthy volunteers we measured VIP and PACAP levels before and after administration of subcutaneous sumatriptan. We simultaneously collected blood samples from the internal and external jugular, the cubital veins and the radial artery, thereby covering both the cerebral and systemic circulation. VIP and PACAP determinations were assayed blindly with respect to timing and vascular compartments, but with all samples of a patient in the same assay, to minimize the influence of interassay variation. Results We found no difference in VIP and PACAP concentrations between the internal and external jugular, the cubital veins and the radial artery, (P>0.05), and the circulating levels of VIP and PACAP did not change over time (P>0.05). We found excellent agreement between neuropeptide levels in the internal and the external jugular system. Conclusion Sumatriptan did not change the levels of circulating VIP and PACAP in the intra or extra cerebral circulation in healthy volunteers. Under baseline conditions, without trigeminovascular activation, sumatriptan does not affect the release of neuropeptides VIP and PACAP. Implications Our results indicate no effect of 5-HT1B/D receptor activation on circulating levels of VIP and PACAP in humans without trigeminovascular activation. Given that neuropeptides play an important role for migraine it would be interesting to conduct a similar study in a migraine population.

[Intoxication with gammahydroxybutyrate is still frequently seen]. / Forgiftning med gammahydroxybutyrat er fortsat hyppig.

Gammahydroxybutyrate (GHB) is also known as fantasy or liquid ecstasy. Its use as a recreational drug has been illegal in Denmark since 1999. However, the GHB pro-drug gammabutyrolactone (GBL) is available to everybody since it is the main ingredient in rim cleaners, which are often sold via the Internet. We describe two cases with patients, who were admitted to the intensive care unit at Glostrup Hospital within a six-month period. The symptoms of GHB intoxication are described, and the treatment is discussed.

Anaesthesia for awake craniotomy is safe and well-tolerated.

INTRODUCTION: Awake craniotomy for tumour resection has been performed at Glostrup Hospital since 2004. We describe and discuss the various anaesthetic approaches for such surgery and retrospectively analyse the 44 planned awake craniotomies performed at Glostrup Hospital. The surgery falls into four phases: craniotomy, mapping, tumour resection and closing. Three methods are being used: monitored anaesthetic care, asleep-awake-asleep and asleep-awake (AA). MATERIAL AND METHODS: Anaesthesia is induced and maintained with propofol and remifentanil. A laryngeal mask (LM) is used as an airway during the craniotomy phase. In the AA method, patients are mapped and the tumour is resected while the patient is awake. RESULTS: A total of 41 of 44 planned AA craniotomies were performed. Three had to be converted into general anaesthesia (GA) due to tight brain, leaking LM and tumour haemorrhage, respectively. The following complications were observed: bradycardia 10%, leaking LM 5%, nausea 10%, vomiting 5%, focal seizures 28%, generalized seizures 10%, hypoxia 2%, hypotension 5% and hypertension 2%. CONCLUSION: Our results comply well with the international literature in terms of complications related to haemodynamics, respiration, seizures, vomiting and nausea and in terms of patient satisfaction. Awake craniotomy is a well-tolerated procedure with potential benefits. More prospective randomized studies are required.

Sumatriptan does not change calcitonin gene-related peptide in the cephalic and extracephalic circulation in healthy volunteers.

Triptans are effective and well tolerated in acute migraine management but their exact mechanism of action is still debated. Triptans might exert their antimigraine effect by reducing the levels of circulating calcitonin gene-related peptide (CGRP). To examine this question, we examined whether sumatriptan modulate the baseline CGRP levels in vivo, under conditions without trigeminovascular system activation. We sampled blood from the internal and external jugular, the cubital veins, and the radial artery before and after administration of subcutaneous sumatriptan in 16 healthy volunteers. Repeated-measure ANOVA showed no interaction between catheter and time of sampling and thus no significant difference in CGRP between the four catheters (P=0.75). CGRP did not change over time in the four compartments (P>0.05). The relative changes in CGRP between baseline and maximal sumatriptan concentration did not differ between the four vascular compartments (P=0.49). It was found that Sumatriptan did not change the levels of circulating CGRP in the intra or extracerebral circulation in healthy volunteers. This speaks against a direct CGRP-reducing effect of sumatriptan in vivo in humans when the trigemino vascular system is not activated.

Intracranial pressure and cerebral hemodynamic in patients with cerebral tumors: a randomized prospective study of patients subjected to craniotomy in propofol-fentanyl, isoflurane-fentanyl, or sevoflurane-fentanyl anesthesia.

BACKGROUND: A critical point during craniotomy is opening of dura, where a high intracranial pressure (ICP) results in swelling of cerebral tissue. Controlled studies concerning ICP, degree of dural tension, and degree of cerebral swelling are therefore warranted. METHODS: In an open-label study, 117 patients with supratentorial cerebral tumors were randomized to propofol-fentanyl (group 1), isoflurane-fentanyl (group 2), or sevoflurane-fentanyl anesthesia (group 3). Normo- to moderate hypocapnia was applied, with a target level of arterial carbon dioxid tension of 30-40 mmHg. Mean arterial blood pressure was stabilized with intravenous ephedrine (2.5-5 mg) if necessary. Subdural ICP, mean arterial blood pressure, cerebral perfusion pressure (CPP), arteriovenous oxygen difference (AVDo2), internal jugular vein oxygen saturation were monitored before and after a 10-min period of hyperventilation, and the carbon dioxide reactivity was calculated. Furthermore, the tension of dura before and during hyperventilation and the degree of cerebral swelling during hyperventilation and after opening of the dura were estimated by the neurosurgeon. RESULTS: No differences were found between groups with regard to demographics, neuroradiologic examination, positioning of the head, and time to ICP measurement. Before and during hyperventilation, ICP was significantly lower and mean arterial blood pressure and CPP significantly higher in group 1 compared with groups 2 and 3 (P < 0.05). The tension of dura before and during hyperventilation was significantly lower in group 1 compared with group2 (P < 0.05), but not significantly different from group 3. In group 1, cerebral swelling after opening of dura was significantly lower compared with groups 2 and 3 (P < 0.05). Furthermore, AVDo was significantly higher and jugular vein oxygen saturation and carbon dioxide reactivity were significantly lower in group 1 compared with groups 2 and 3 (P < 0.05). No significant differences with regard to ICP, CPP, AVDo, carbon dioxide reactivity, and jugular vein oxygen saturation were found between patients anesthetized with isoflurane and sevoflurane. CONCLUSIONS: The study indicates that before as well as during hyperventilation, subdural ICP and AVDo2 are lower and CPP higher in propofol-anesthetized patients compared with patients anesthetized with isoflurane or sevoflurane. These findings were associated with less tendency for cerebral swelling after opening of dura in the propofol group. The carbon dioxide reactivity in patients anesthetized with isoflurane and sevoflurane was significantly higher than in the propofol group. The differences in subdural ICP between the groups are presumed to be caused by differences in the degree of vasoconstriction elicited by the anesthetic agents, but autoregulatory mechanisms caused by differences in CPP cannot be excluded.

Epidural blood patch in the treatment of post-lumbar puncture headache.

Post-lumbar puncture headache is a common complication of dural puncture. Treatment of severe cases with an epidural 'blood patch'--injection of 10-20 ml autologous blood into the epidural space at the site of the dural puncture--is an effective and safe method with few and generally mild complications. The method has been used by anesthesiologists for many years with good results, but only rarely by radiologists, neurologists and other specialists who often perform lumbar punctures. The technique of 'blood patching,' its indications, effects, and complications and the epidural blood patch as post-lumbar puncture headache prophylaxis are discussed.