263 results on '"Kirsten Møller"'
Search Results
2. Prompt closure versus gradual weaning of external ventricular drain for hydrocephalus following aneurysmal subarachnoid haemorrhage: a statistical analysis plan for the DRAIN randomised clinical trial
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Tenna Capion, Alexander Lilja-Cyron, Marianne Juhler, Kirsten Møller, Angelika Sorteberg, Pål André Rønning, Frantz Rom Poulsen, Joakim Wismann, Anders Emil Schack, Celina Ravlo, Jørgen Isaksen, Jane Lindschou, Christian Gluud, Tiit Mathiesen, and Markus Harboe Olsen
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Aneurysm ,Aneurysmal subarachnoid haemorrhage ,Hydrocephalus ,External ventricular drain ,Weaning ,Randomised clinical trial ,Medicine (General) ,R5-920 - Abstract
Abstract Background Insertion of an external ventricular drain (EVD) is a first-line treatment of acute hydrocephalus caused by aneurysmal subarachnoid haemorrhage (aSAH). Once the patient is clinically stable, the EVD is either removed or replaced by a permanent internal shunt. The optimal strategy for cessation of the EVD is unknown. Prompt closure carries a risk of acute hydrocephalus or redundant shunt implantations, whereas gradual weaning may increase the risk of EVD-related infections. Methods DRAIN (Danish RAndomised Trial of External Ventricular Drainage Cessation IN Aneurysmal Subarachnoid Haemorrhage) is an international multicentre randomised clinical trial comparing prompt closure versus gradual weaning of the EVD after aSAH. The primary outcome is a composite of VP-shunt implantation, all-cause mortality, or EVD-related infection. Secondary outcomes are serious adverse events excluding mortality and health-related quality of life (EQ-5D-5L). Exploratory outcomes are modified Rankin Scale, Fatigue Severity Scale, Glasgow Outcome Scale Extended, and length of stay in the neurointensive care unit and hospital. Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, alpha 5%, power 80%), 122 participants are required in each intervention group. Outcome assessment for the primary outcome, statistical analyses, and conclusion drawing will be blinded. Two independent statistical analyses and reports will be tracked using a version control system, and both will be published. Based on the final statistical report, the blinded steering group will formulate two abstracts. Conclusion We present a pre-defined statistical analysis plan for the randomised DRAIN trial, which limits bias, p-hacking, and data-driven interpretations. This statistical analysis plan is accompanied by tables with simulated data, which increases transparency and reproducibility. Trial registration ClinicalTrials.gov identifier: NCT03948256. Registered on May 13, 2019.
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- 2024
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3. Test–retest reliability of transfer function analysis metrics for assessing dynamic cerebral autoregulation to spontaneous blood pressure oscillations
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Markus Harboe Olsen, Christian Riberholt, Tenna Capion, Ronni R. Plovsing, Kirsten Møller, and Ronan M. G. Berg
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physiolometrics ,sepsis ,subarachnoid haemorrhage ,transcranial Doppler ultrasound ,Physiology ,QP1-981 - Abstract
Abstract Transfer function analysis (TFA) is a widely used method for assessing dynamic cerebral autoregulation in humans. In the present study, we assessed the test–retest reliability of established TFA metrics derived from spontaneous blood pressure oscillations and based on 5 min recordings. The TFA‐based gain, phase and coherence in the low‐frequency range (0.07–0.20 Hz) from 19 healthy volunteers, 37 patients with subarachnoid haemorrhage and 19 patients with sepsis were included. Reliability assessments included the smallest real difference (SRD) and the coefficient of variance for comparing consecutive 5 min recordings, temporally separated 5 min recordings and consecutive recordings with a minimal length of 10 min. In healthy volunteers, temporally separating the 5 min recordings led to a 0.38 (0.01–0.79) cm s−1 mmHg−1 higher SRD for gain (P = 0.032), and extending the duration of recordings did not affect the reliability. In subarachnoid haemorrhage, temporal separation led to a 0.85 (−0.13 to 1.93) cm s−1 mmHg−1 higher SRD (P = 0.047) and a 20 (−2 to 41)% higher coefficient of variance (P = 0.038) for gain, but neither metric was affected by extending the recording duration. In sepsis, temporal separation increased the SRD for phase by 94 (23–160)° (P = 0.006) but was unaffected by extending the recording. A recording duration of 8 min was required to achieve stable gain and normalized gain measures in healthy individuals, and even longer recordings were required in patients. In conclusion, a recording duration of 5 min appears insufficient for obtaining stable and reliable TFA metrics when based on spontaneous blood pressure oscillations, particularly in critically ill patients with subarachnoid haemorrhage and sepsis.
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- 2024
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4. Arterial to jugular‐bulb lactate difference in patients undergoing elective brain tumor craniotomy
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Alexandra Vassilieva, Markus Harboe Olsen, Jane Skjøth‐Rasmussen, Kirsten Møller, and Martin Kryspin Sørensen
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brain tumor ,cancer ,craniotomy ,hyperlactatemia ,lactate ,neurosurgery ,Physiology ,QP1-981 - Abstract
Abstract Hyperlactatemia is common during tumor craniotomy, but the underlying pathophysiology is unclear. This study measured simultaneous arterial and jugular‐bulb lactate concentrations in patients undergoing brain tumor craniotomy to investigate the hypothesis that hyperlactatemia was associated with a net cerebrovascular lactate input. In 20 patients, arterial and jugular‐bulb blood was collected hourly from the start of surgery to 6 h postoperatively for measurement of lactate, glucose, and oxygen concentration. For each marker, data were analyzed using a linear mixed‐effects model with jugular‐bulb concentration as dependent variable, arterial concentration as fixed effect, and patient as random effect. Furthermore, we generated regression lines between arterial and jugular‐bulb concentrations. The slope of the regression line between arterial and jugular‐bulb lactate was 0.95 (95% CI 0.93–0.97, R2 = 0.98), indicating that increasing arterial lactate levels were associated with an increasingly positive net cerebrovascular balance (net input). The line crossed the identity line at 2.86 (95% CI 0.57–5.16) mmol/L, indicating that lower levels of lactate were associated with a negative net cerebrovascular balance (net output). This suggests a switch from net lactate output during normolactatemia towards net input during hyperlactatemia. Hyperlactatemia in tumor‐craniotomy patients probably does not originate from the brain.
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- 2024
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5. Myths and methodologies: Assessment of dynamic cerebral autoregulation by the mean flow index
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Markus Harboe Olsen, Christian Gunge Riberholt, Ronan M. G. Berg, and Kirsten Møller
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cerebral haemodynamics ,physiolometrics ,reliability ,transcranial doppler ,validity ,Physiology ,QP1-981 - Abstract
Abstract The mean flow index—usually referred to as Mx—has been used for assessing dynamic cerebral autoregulation (dCA) for almost 30 years. However, concerns have arisen regarding methodological consistency, construct and criterion validity, and test–retest reliability. Methodological nuances, such as choice of input (cerebral perfusion pressure, invasive or non‐invasive arterial pressure), pre‐processing approach and artefact handling, significantly influence mean flow index values, and previous studies correlating mean flow index with other established dCA metrics are confounded by inherent methodological flaws like heteroscedasticity, while the mean flow index also fails to discriminate individuals with presumed intact versus impaired dCA (discriminatory validity), and its prognostic performance (predictive validity) across various conditions remains inconsistent. The test–retest reliability, both within and between days, is generally poor. At present, no single approach for data collection or pre‐processing has proven superior for obtaining the mean flow index, and caution is advised in the further use of mean flow index‐based measures for assessing dCA, as current evidence does not support their clinical application.
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- 2024
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6. Detecting signatures of consciousness in acute brain injury after stimulation with apomorphine and methylphenidate: protocol for a placebo-controlled, randomized, cross-over study
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Kirsten Møller, Daniel Kondziella, Jesper Kjærgaard, and Marwan H Othman
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Introduction Acute brain injury can lead to states of decreased consciousness, that is, disorder of consciousness (DoC). Detecting signs of consciousness early is vital for DoC management in the intensive care unit (ICU), neurorehabilitation and long-term prognosis. Our primary objective is to investigate the potential of pharmacological stimulant therapies in eliciting signs of consciousness among unresponsive or low-responsive acute DoC patients.Methods In a placebo-controlled, randomised, cross-over setting, we evaluate the effect of methylphenidate and apomorphine in 50 DoC patients with acute traumatic or non-traumatic brain injury admitted to the ICU. Patients are examined before and after administration of the trial drugs using (1) neurobehavioural scales to determine the clinical level of consciousness, (2) automated pupillometry to record pupillary responses as a signature for awareness and (3) near-infrared spectroscopy combined with electroencephalography to record neurovascular coupling as a measure for cortical activity. Primary outcomes include pupillary dilations and increase in cortical activity during passive and active paradigms.Ethics The study has been approved by the ethics committee (Journal-nr: H-21022096) and follows the principles of the Declaration of Helsinki. It is deemed to pose minimal risks and to hold a significant potential to improve treatment options for DoC patients. If the stimulants are shown to enhance cortical modulation of pupillary function and neurovascular coupling, this would warrant a large multicentre trial to evaluate their clinical impact.Dissemination Results will be available on EudraCT, clinicaltrialsregister.eu and published in an international peer-reviewed journal.Trial registration number EudraCT Number: 2021-001453-31.
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- 2024
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7. Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure
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Annette Buur Steffensen, Beatriche Louise Edelbo, Dagne Barbuskaite, Søren Norge Andreassen, Markus Harboe Olsen, Kirsten Møller, and Nanna MacAulay
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Cerebrospinal fluid ,Intracranial pressure ,Sleep ,Circadian rhythm ,Choroid plexus ,Na+,K+,2Cl− cotransporter ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background It is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance. Methods ICP was monitored continuously in patients who underwent placement of an external ventricular drain (EVD) and by telemetric monitoring in experimental rats. CSF was collected via the EVD in patients and the rodent CSF secretion rate determined by in vivo experimentation. Rodent choroid plexus transporter transcripts were quantified with RNAseq and transport activity with ex vivo isotope transport assays. Results We demonstrated that ICP increases by 30% in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients (12%) and CSF production rate in rats (20%), the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl- cotransporter (NKCC1), which is implicated in CSF secretion by this tissue. Conclusion CSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity in the rat. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.
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- 2023
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8. Reproducibility of cerebral blood flow, oxygen metabolism, and lactate and N-acetyl-aspartate concentrations measured using magnetic resonance imaging and spectroscopy
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Signe Sloth Madsen, Ulrich Lindberg, Sohail Asghar, Karsten Skovgaard Olsen, Kirsten Møller, Henrik Bo Wiberg Larsson, and Mark Bitsch Vestergaard
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cerebral blood flow ,cerebral metabolic rate of oxygen ,cerebral lactate ,phase contrast mapping ,arterial spin labelling ,reproducibility ,Physiology ,QP1-981 - Abstract
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.
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- 2023
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9. Autonomic response to early head‐up tilt in patients with severe traumatic brain injury: Analysis from a randomized feasibility trial
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Michala Dalsgaard Schultz, Morten Alstrup, Markus Harboe Olsen, Ronan M. G. Berg, Jesper Mehlsen, Kirsten Møller, and Christian Gunge Riberholt
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autonomic dysfunction ,heart rate variability ,mobilization ,orthostatic intolerance ,traumatic brain injury ,Physiology ,QP1-981 - Abstract
Abstract Patients with severe traumatic brain injury (TBI) may have autonomic dysfunction, one manifestation of which is orthostatic intolerance. This potentially impairs physical rehabilitation. However, the exact mechanisms remain elusive. In 30 patients participating in a trial of early tilt training versus standard care and 15 healthy volunteers, 5‐min electrocardiography was recorded in the supine position and during 70° head‐up tilt. Heart rate variability was analyzed by the low‐ and high‐frequency (LF and HF) power, the LF–HF ratio, the total power, the ratio of the standard deviation of normal‐to‐normal intervals (SDNN), the root mean square of successive differences (RMSSD), the detrended fluctuations, and sample entropy. In patients in the upright compared to the supine position, SDNN (p
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- 2023
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10. Critical ICP Thresholds in Relation to Outcome: Is 22 mmHg the Answer?
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Agnes Riparbelli, Tenna Bæk Capion, Kirsten Møller, Tiit Illimar Mathiesen, Markus Harboe Olsen, and Axel Forsse
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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11. Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study
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Anne-Lene Kjældgaard, Katrine Pilely, Karsten Skovgaard Olsen, Anders Hedegaard Jessen, Anne Øberg Lauritsen, Stephen Wørlich Pedersen, Kirsten Svenstrup, Merete Karlsborg, Helle Thagesen, Morten Blaabjerg, Ásta Theódórsdóttir, Elisabeth Gundtoft Elmo, Anette Torvin Møller, Lone Bonefeld, Mia Berg, Peter Garred, and Kirsten Møller
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ALSFRS-R slope ,Amyotrophic lateral sclerosis ,Median survival time ,Prognostic biomarker ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract 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.
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- 2021
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12. Effect of sevoflurane versus propofol on neutrophil-to-lymphocyte ratio in healthy individuals: a sub-study of a randomised crossover trial
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Rune Petring Hasselager, Signe Sloth Madsen, Kirsten Møller, Ismail Gögenur, and Mohammad Sohail Asghar
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lymphocytes ,neutrophil-to-lymphocyte ratio ,oncoanaesthesia ,propofol ,sevoflurane ,Anesthesiology ,RD78.3-87.3 - Abstract
Background: Sevoflurane and propofol are commonly used drugs in general anaesthesia. However, their effects on perioperative immune function are incompletely understood. We hypothesised that sevoflurane and propofol differentially affect immune function in healthy individuals. Therefore, we investigated the effect of sevoflurane and propofol on neutrophil-to-lymphocyte ratio before, during, and after general anaesthesia. Methods: In this randomised crossover study, 19 healthy individuals underwent 2 h of general anaesthesia with either propofol or sevoflurane. After 4 weeks, anaesthesia was repeated using the other drug. Blood samples were obtained before, during, 1 h after, and 1 day after anaesthesia. The primary outcome was whole-blood neutrophil-to-lymphocyte ratio, and secondary outcomes were specific white blood cell differential counts. A linear mixed-effects model was used to estimate effect sizes. Results: The neutrophil-to-lymphocyte ratio was higher in the propofol compared with the sevoflurane group during anaesthesia, 2.8 (confidence interval [CI]: 2.3–3.3) vs 1.6 (CI: 1.1–2.1), and 1 day after anaesthesia, 2.6 (CI: 2.1–3.1) vs 1.9 (CI: 1.4–2.4). In all patients, we observed transient lymphopaenia during propofol anaesthesia, 1.1 × 109 cells × L−1 (CI: 0.9–1.4), compared with sevoflurane anaesthesia, 1.9 × 109 cells × L−1 (CI: 1.7–2.1). In addition, neutrophil counts were higher 1 day after propofol anaesthesia, 4.4 × 109 cells × L−1 (CI: 4.0–4.9), compared with sevoflurane anaesthesia, 3.5 × 109 cells × L−1 (CI: 3.1–4.0). We observed no differences in the remaining white blood cell subgroups. Conclusions: In healthy individuals undergoing general anaesthesia without surgery, the neutrophil-to-lymphocyte ratio was affected by the type of hypnotic used. Transient lymphopaenia was observed in all participants during propofol anaesthesia.
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- 2022
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13. Lectin complement pathway initiators after subarachnoid hemorrhage — an observational study
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Jeppe Sillesen Matzen, Charlotte Loumann Krogh, Julie Lyng Forman, Peter Garred, Kirsten Møller, and Søren Bache
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Ficolin ,Lectin complement pathway ,Subarachnoid hemorrhage ,Delayed cerebral ischemia ,Functional outcome ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background This exploratory study investigated the time-course of lectin complement pathway (LCP) initiators in cerebrospinal fluid (CSF) and plasma in patients with subarachnoid hemorrhage (SAH), as well as their relationship to delayed cerebral ischemia (DCI) and functional outcome. Methods Concentrations of ficolin-1, ficolin-2, ficolin-3, and mannose-binding lectin (MBL) were analyzed in CSF and plasma from patients with SAH. Samples were collected daily from admission until day 9 (CSF; N_PATIENTS = 63, n_SAMPLES = 399) and day 8 (plasma; N_PATIENTS = 50, n_SAMPLES = 358), respectively. Twelve neurologically healthy patients undergoing spinal anesthesia and 12 healthy blood donors served as controls. The development of DCI during hospitalization and functional outcome at 3 months (modified Rankin Scale) were registered for patients. Results On admission, CSF levels of all LCP initiators were increased in SAH patients compared with healthy controls. Levels declined gradually over days in patients; however, a biphasic course was observed for ficolin-1. Increased CSF levels of all LCP initiators were associated with a poor functional outcome in univariate analyses. This relationship persisted for ficolin-1 and MBL in multivariate analysis after adjustments for confounders (age, sex, clinical severity, distribution and amount of blood on CT-imaging) and multiple testing (1.87 ng/mL higher in average, 95% CI, 1.17 to 2.99 and 1.69 ng/mL higher in average, 95% CI, 1.09 to 2.63, respectively). In patients who developed DCI compared with those without DCI, CSF levels of ficolin-1 and MBL tended to increase slightly more over time (p_interaction = 0.021 and 0.033, respectively); however, no association was found after adjustments for confounders and multiple testing (p-adj_interaction = 0.086 and 0.098, respectively). Plasma ficolin-1 and ficolin-3 were lower in SAH patients compared with healthy controls on all days. DCI and functional outcome were not associated with LCP initiator levels in plasma. Conclusion Patients with SAH displayed elevated CSF levels of ficolin-1, ficolin-2, ficolin-3, and MBL. Increased CSF levels of ficolin-1 and MBL were associated with a poor functional outcome. Trial registration This study was a retrospective analysis of samples, which had been prospectively sampled and stored in a biobank. Registered at clinicaltrials.gov ( NCT01791257 , February 13, 2013, and NCT02320539 , December 19, 2014).
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- 2020
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14. 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
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Signe Sloth Madsen, Kirsten Møller, Karsten Skovgaard Olsen, Mark Bitsch Vestergaard, Ulrich Lindberg, Henrik Bo Wiberg Larsson, Johan Mårtensson, Mads U. Werner, Sofia Alexandra Gaspar Santos, and Mohammad Sohail Asghar
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Neuroplasticity ,Neuroplastic changes ,General anaesthesia ,Magnetic resonance imaging ,Sevoflurane ,Propofol ,Medicine (General) ,R5-920 - Abstract
Abstract 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.
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- 2020
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15. Reliability of cerebral autoregulation using different measures of perfusion pressure in patients with subarachnoid hemorrhage
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Markus Harboe Olsen, Tenna Capion, Christian Gunge Riberholt, Søren Bache, Ronan M. G. Berg, and Kirsten Møller
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autoregulation ,mean flow index ,Mx ,reliability ,transfer function analysis ,Physiology ,QP1-981 - Abstract
Abstract Dynamic cerebral autoregulation to spontaneous fluctuations in cerebral perfusion pressure (CPP) is often assessed by transcranial Doppler (TCD) in the time domain, yielding primarily the mean flow index (Mx), or in the frequency domain using transfer function analysis (TFA), yielding gain and phase. For both domains, the measurement of blood pressure is critical. This study assessed the inter‐method reliability of dynamic cerebral autoregulation using three different methods of pressure measurement. In 39 patients with aneurysmal subarachnoid hemorrhage, non‐invasive arterial blood pressure (ABP), invasive ABP (measured in the radial artery) and CPP were recorded simultaneously with TCD. Intraclass correlation coefficient (ICC) was used to quantify reliability. Mx was higher when calculated using invasive ABP (0.39; 95% confidence interval [95% CI]: 0.33; 0.44) compared to non‐invasive ABP, and CPP. The overall ICC showed poor to good reliability (0.65; 95% CI: 0.11; 0.84; n = 69). In the low frequency domain, the comparison between invasively measured ABP and CPP showed good to excellent (normalized gain, ICC: 0.87, 95CI: 0.81; 0.91; n = 96; non‐normalized gain: 0.89, 95% CI: 0.84; 0.92; n = 96) and moderate to good reliability (phase, ICC: 0.69, 95% CI: 0.55; 0.79; n = 96), respectively. Different methods for pressure measurement in the assessment of dynamic cerebral autoregulation yield different results and cannot be used interchangeably.
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- 2022
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16. Hyperlactatemia associated with elective tumor craniotomy: Protocol for an observational study of pathophysiology and clinical implications.
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Alexandra Vassilieva, Kirsten Møller, Jane Skjøth-Rasmussen, and Martin Kryspin Sørensen
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Medicine ,Science - Abstract
Hyperlactatemia occurs frequently after brain tumor surgery. Existing studies are scarce and predominantly retrospective, reporting inconsistent associations to new neurological deficits and prolonged hospital stay. Here we describe a protocol for a prospective observational study of hyperlactatemia during and after elective tumor craniotomy and the association with postoperative outcome, as well as selected pathophysiological aspects, and possible risk factors. We will include 450 brain tumor patients scheduled for elective craniotomy. Arterial blood samples for lactate and glucose measurement will be withdrawn hourly during surgery and until six hours postoperatively. To further explore the association of hyperlactatemia with perioperative insulin resistance, additional blood sampling measuring markers of insulin resistance will be done in 100 patients. Furthermore, in a subgroup of 20 patients, blood from a jugular bulb catheter will be drawn simultaneously with blood from the radial artery to measure the arterial to jugular venous concentration difference of lactate, in order to study the direction of cerebrovascular lactate flux. Functional clinical outcome will be determined by the modified Rankin Scale, length of stay and mortality at 30 days, 6 months, 1 year and 5 years. Clinical outcome will be compared between patients with and without hyperlactatemia. Multivariate logistic regression will be used to identify risk factors for hyperlactatemia. A statistical analysis plan will be publicized to support transparency and reproducibility. Results will be published in a peer-reviewed journal and presented at international conferences.
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- 2022
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17. Statistical analysis plan: Early mobilization by head-up tilt with stepping versus standard care after severe traumatic brain injury
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Christian Gunge Riberholt, Christian Gluud, Janus Christian Jakobsen, Christian Ovesen, Jesper Mehlsen, and Kirsten Møller
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Statistical analysis plan ,Early mobilization ,Trial sequential analysis ,Traumatic brain injury ,Medicine (General) ,R5-920 - Abstract
Background: Early mobilization on a tilt table with stepping versus standard care may be beneficial for patients with severe brain injury, but data from randomized clinical trials are lacking. This detailed statistical analysis plan describes the analyses of data collected in a randomized clinical feasibility trial for early mobilization by head-up tilt with stepping versus standard care after severe traumatic brain injury. Methods: Primary feasibility outcomes are the proportion of included participants who were randomized out of all screened patients; the proportion of participants allocated to the experimental intervention who received at least 60% of the planned exercise sessions; and safety outcomes such as adverse events and reactions and serious adverse events and reactions. Exploratory clinical outcomes are suspected unexpected serious adverse reactions; and functional outcomes as assessed by the Coma Recovery Scale-Revised at four weeks; Early Functional Ability Scale and Functional Independence Measure at three months. The description includes the statistical analysis plan, including the use of multiple imputations and Trial Sequential Analysis.
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- 2021
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18. Early Orthostatic Exercise by Head-Up Tilt With Stepping vs. Standard Care After Severe Traumatic Brain Injury Is Feasible
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Christian Gunge Riberholt, Markus Harboe Olsen, Christian Baastrup Søndergaard, Christian Gluud, Christian Ovesen, Janus Christian Jakobsen, Jesper Mehlsen, and Kirsten Møller
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early mobilization ,traumatic brain injury ,feasibility trial ,head-up tilt ,adverse events ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Intensive rehabilitation of patients after severe traumatic brain injury aims to improve functional outcome. The effect of initiating rehabilitation in the early phase, in the form of head-up mobilization, is unclear.Objective: To assess whether early mobilization is feasible and safe in patients with traumatic brain injury admitted to a neurointensive care unit.Methods: This was a randomized parallel-group clinical trial, including patients with severe traumatic brain injury (Glasgow coma scale
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- 2021
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19. Ketamine for critically ill patients with severe acute brain injury: Protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials
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Frederik Andreas Madsen, Trine Hjorslev Andreasen, Jane Lindschou, Christian Gluud, and Kirsten Møller
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Medicine ,Science - Abstract
Introduction Intensive care for patients with severe acute brain injury aims both to treat the immediate consequences of the injury and to prevent and treat secondary brain injury to ensure a good functional outcome. Sedation may be used to facilitate mechanical ventilation, for treating agitation, and for controlling intracranial pressure. Ketamine is an N-methyl-D-aspartate receptor antagonist with sedative, analgesic, and potentially neuroprotective properties. We describe a protocol for a systematic review of randomised clinical trials assessing the beneficial and harmful effects of ketamine for patients with severe acute brain injury. Methods and analysis We will systematically search international databases for randomised clinical trials, including CENTRAL, MEDLINE, Embase, and trial registries. Two authors will independently review and select trials for inclusion, and extract data. We will compare ketamine by any regimen versus placebo, no intervention, or other sedatives or analgesics for patients with severe acute brain injury. The primary outcomes will be functional outcome at maximal follow up, quality of life, and serious adverse events. We will also assess secondary and exploratory outcomes. The extracted data will be analysed using Review Manager and Trials Sequential Analysis. Evidence certainty will be graded using GRADE. Ethics and dissemination The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice. PROSPERO no CRD42021210447.
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- 2021
20. Amyotrophic lateral sclerosis and the innate immune system: protocol for establishing a biobank and statistical analysis plan
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Anne-Lene Kjældgaard, Katrine Pilely, Karsten Skovgaard Olsen, Anne Øberg Lauritsen, Stephen Wørlich Pedersen, Kirsten Møller, and Peter Garred
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Medicine - Abstract
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
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- 2020
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21. Early head-up mobilisation versus standard care for patients with severe acquired brain injury: A systematic review with meta-analysis and Trial Sequential Analysis.
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Christian Gunge Riberholt, Vibeke Wagner, Jane Lindschou, Christian Gluud, Jesper Mehlsen, and Kirsten Møller
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Medicine ,Science - Abstract
BACKGROUND:There is increasing focus on earlier rehabilitation in patients with traumatic or hypoxic brain injury or stroke. This systematic review evaluates the benefits and harms of early head-up mobilisation versus standard care in patients with severe acquired brain injury. METHODS:We searched Medline, CENTRAL, EMBASE, four other databases and 13 selected clinical trial registries until April 2020. Eligible randomised clinical trials compared early head-up mobilisation versus standard care in patients with severe acquired brain injury and were analysed conducting random- and fixed-effects meta-analyses and Trial Sequential Analysis (TSA). Certainty of evidence was assessed by GRADE. MAIN RESULTS:We identified four randomised clinical trials (total n = 385 patients) with severe acquired brain injury (stroke 86% and traumatic brain injury 13%). Two trials were at low risk and two at high risk of bias. We found no evidence of a difference between early mobilisation vs. standard care on mortality or poor functional outcome at end of the intervention (relative risk (RR) 1.19, 95% CI 0.93 to 1.53; I2 0%; very low certainty) or at maximal follow-up (RR 1.03, 95% CI 0.89 to 1.21; I2 0%; very low certainty). We found evidence against an effect on quality of life at maximal follow-up. The proportion of patients with at least one serious adverse event did not differ at end of intervention or at maximal follow-up. For most comparisons, TSA suggested that further trials are needed. CONCLUSIONS:We found no evidence of a difference between early mobilisation versus standard care for patients with severe acquired brain injury. Early mobilisation appeared not to exert a major impact on quality of life. This systematic review highlights the insufficient evidence in patients with severe brain injury, and no firm conclusions can be drawn from these data. TRIAL REGISTRATION:Protocol uploaded to PROSPERO: April 2018 (revised October 2018, CRD42018088790).
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- 2020
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22. Early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury – Protocol for a randomised clinical feasibility trial
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Christian Gunge Riberholt, Jane Lindschou, Christian Gluud, Jesper Mehlsen, and Kirsten Møller
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Brain injury ,Randomised feasibility trial ,Cerebral autoregulation of blood flow ,Rehabilitation ,Tilt-table therapy ,Medicine (General) ,R5-920 - Abstract
Abstract Background Intensive rehabilitation of patients with severe traumatic brain injury is generally applied in the subacute stages of the hospital stay. Few studies have assessed the association between early and intensive physical rehabilitation and functional outcomes. The aim of this trial is to assess the feasibility of an intensive physical rehabilitation intervention focusing on mobilisation to the upright position, starting as early as clinically possible versus standard care in the intensive care unit. The feasibility study is intended to inform a subsequent randomised clinical trial that will investigate benefits and harms of the intervention. Methods This randomised clinical feasibility trial with a follow-up period of 1 year will use blinded outcome assessors for the Coma Recovery Scale–Revised. A maximum of 60 patients admitted to the neurointensive care unit at Rigshospitalet, Denmark, with traumatic brain injury (age of at least 18 years), a low level of consciousness, and stable intracranial pressure will be included in the trial. Patients will be randomly assigned to experimental intervention versus standard care (1:1) stratified according to their Glasgow Coma Score. The intervention group will receive daily mobilisation in a tilt table with an integrated stepping device (ERIGO®). Feasibility is declared if more than 60% (the lower 95% confidence interval of the proportion) of eligible patients are included in the trial and more than 52% (the lower 95% confidence interval of the proportion) of patients in the intervention group receive more than 60% of the planned interventions. Safety is assessed by the occurrence of adverse events and adverse reactions. Exploratory clinical outcomes consist of cerebral haemodynamics (blood flow velocity and pressure autoregulation) and baroreceptor sensitivity in the early phase as well as functional outcomes (Coma Recovery Scale–Revised, Early Functional Ability scale, and Functional Independence Measure). Discussion Our findings will inform a future, larger-scale randomised clinical trial on early mobilisation using a tilt table early after severe traumatic brain injury. Trial registration ClinicalTrials.gov identifier: NCT02924649. Registered on 3 October 2016.
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- 2018
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23. Intensive Care Antifungal Stewardship Programme Based on T2Candida PCR and Candida Mannan Antigen: A Prospective Study
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Jannik Helweg-Larsen, Morten Steensen, Finn Møller Pedersen, Pia Bredahl Jensen, Michael Perch, Kirsten Møller, Birthe Riis Olesen, Mathias Søderlund, and Maiken Cavling Arendrup
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antifungal stewardship ,invasive candidiasis ,T2Candida ,mannan antigen ,diagnostic test ,Biology (General) ,QH301-705.5 - Abstract
Non-culture-based biomarkers may improve diagnosis and antifungal treatment (AFT) of invasive candidiasis (IC). We evaluated an antifungal stewardship programme (AFSP) in a prospective intensive care unit (ICU) study, which included T2Candida and Candida mannan antigen (MAg) screening of patients with sepsis and a high risk of IC. Patients with non-neutropenic sepsis and a high risk of IC from two large tertiary ICUs were prospectively included, during a one-year period. IC was classified as proven, likely, possible or unlikely. The AFSP, diagnostic values of T2Candida and MAg, and the consumption of antifungals were evaluated. An amount of 219 patients with 504 T2Candida/MAg samples were included. IC was classified as proven in 29 (13.2%), likely in 7 (3.2%) and possible in 10 (5.5%) patients. Sensitivity/specificity/PPV/NPV values, comparing proven/likely versus unlikely IC, were 47%/100%/94%/90% for BC alone, 50%/97%/75%/90% for T2Candida alone, and 39%/96%/67%/88% for MAg alone. For the combination of T2Candida/MAg taken ≤3 days after AFT initiation, sensitivity/specificity/PPV/NPV was 70%/90%/63%/93%. T2Candida/MAg contributed to early (
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- 2021
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24. Microbiome Compositions and Resistome Levels after Antibiotic Treatment of Critically Ill Patients: An Observational Cohort Study
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Karen Leth Nielsen, Markus Harboe Olsen, Albert Pallejá, Søren Røddik Ebdrup, Nikolaj Sørensen, Oksana Lukjancenko, Rasmus L. Marvig, Kirsten Møller, Niels Frimodt-Møller, and Frederik Boëtius Hertz
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metagenomics ,microbiome ,microbiota ,antimicrobial resistance ,antimicrobial treatment ,Biology (General) ,QH301-705.5 - Abstract
Hospitalization and treatment with antibiotics increase the risk of acquiring multidrug-resistant bacteria due to antibiotic-mediated changes in patient microbiota. This study aimed to investigate how broad- and narrow-spectrum antibiotics affect the gut microbiome and the resistome in antibiotic naïve patients during neurointensive care. Patients admitted to the neurointensive care unit were treated with broad-spectrum (meropenem or piperacillin/tazobactam) or narrow-spectrum antibiotic treatment (including ciprofloxacin, cefuroxime, vancomycin and dicloxacillin) according to clinical indications. A rectal swab was collected from each patient before and after 5–7 days of antibiotic therapy (N = 34), respectively. Shotgun metagenomic sequencing was performed and the composition of metagenomic species (MGS) was determined. The resistome was characterized with CARD RGI software and the CARD database. As a measure for selection pressure in the patient, we used the sum of the number of days with each antibiotic (antibiotic days). We observed a significant increase in richness and a tendency for an increase in the Shannon index after narrow-spectrum treatment. For broad-spectrum treatment the effect was more diverse, with some patients increasing and some decreasing in richness and Shannon index. This was studied further by comparison of patients who had gained or lost >10 MGS, respectively. Selection pressure was significantly higher in patients with decreased richness and a decreased Shannon index who received the broad treatment. A decrease in MGS richness was significantly correlated to the number of drugs administered and the selection pressure in the patient. Bray–Curtis dissimilarities were significant between the pre- and post-treatment of samples in the narrow group, indicating that the longer the narrow-spectrum treatment, the higher the differences between the pre- and the post-treatment microbial composition. We did not find significant differences between pre- and post-treatment for both antibiotic spectrum treatments; however, we observed that most of the antibiotic class resistance genes were higher in abundance in post-treatment after broad-spectrum treatment.
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- 2021
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25. Consciousness in Neurocritical Care Cohort Study Using fMRI and EEG (CONNECT-ME): Protocol for a Longitudinal Prospective Study and a Tertiary Clinical Care Service
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Anine P. Skibsted, Moshgan Amiri, Patrick M. Fisher, Annette Sidaros, Melita Cacic Hribljan, Vibeke Andrée Larsen, Joan Lilja S. Højgaard, Miki Nikolic, John Hauerberg, Martin E. Fabricius, Gitte Moos Knudsen, Kirsten Møller, and Daniel Kondziella
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coma ,consciousness ,electroencephalography ,functional magnetic resonance imaging ,locked-in syndrome ,magnetic resonance imaging ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Aims and Objectives: To facilitate individualized assessment of unresponsive patients in the intensive care unit for signs of preserved consciousness after acute brain injury.Background: Physicians and neuroscientists are increasingly recognizing a disturbing dilemma: Brain-injured patients who appear entirely unresponsive at the bedside may show signs of covert consciousness when examined by functional MRI (fMRI) or electroencephalography (EEG). According to a recent meta-analysis, roughly 15% of behaviorally unresponsive brain-injured patients can participate in mental tasks by modifying their brain activity during EEG- or fMRI-based paradigms, suggesting that they are conscious and misdiagnosed. This has major ethical and practical implications, including prognosis, treatment, resource allocation, and end-of-life decisions. However, EEG- or fMRI-based paradigms have so far typically been tested in chronic brain injury. Hence, as a novel approach, CONNECT-ME will import the full range of consciousness paradigms into neurocritical care.Methods: We will assess intensive care patients with acute brain injury for preserved consciousness by serial and multimodal evaluation using active, passive and resting state fMRI and EEG paradigms, as well as state-of-the-art clinical techniques including pupillometry and sophisticated clinical rating scales such as the Coma Recovery Scale-Revised. In addition, we are establishing a biobank (blood, cerebrospinal fluid and brain tissue, where available) to facilitate future genomic and microbiomic research to search for signatures of consciousness recovery.Discussion: We anticipate that this multimodal approach will add vital clinical information, including detection of preserved consciousness in patients previously thought of as unconscious, and improved (i.e., personalized) prognostication of individual patients. Our aim is two-fold: We wish to establish a cutting-edge tertiary care clinical service for unresponsive patients in the intensive care unit and lay the foundation for a fruitful multidisciplinary research environment for the study of consciousness in acute brain injury. Of note, CONNECT-ME will not only enhance our understanding of consciousness disorders in acute brain injury but it will also raise awareness for these patients who, for obvious reasons, have lacked a voice so far.Trial registration: The study is registered with clinicaltrials.org (ClinicalTrials.gov Identifier: NCT02644265).
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- 2018
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26. Increased Intracranial Pressure during Hemodialysis in a Patient with Anoxic Brain Injury
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Anton Lund, Mette B. Damholt, Ditte G. Strange, Jesper Kelsen, Hasse Møller-Sørensen, and Kirsten Møller
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Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Dialysis disequilibrium syndrome (DDS) is a serious neurological complication of hemodialysis, and patients with acute brain injury are at increased risk. We report a case of DDS leading to intracranial hypertension in a patient with anoxic brain injury and discuss the subsequent dialysis strategy. A 13-year-old girl was admitted after prolonged resuscitation from cardiac arrest. Computed tomography (CT) revealed an inferior vena cava aneurysm and multiple pulmonary emboli as the likely cause. An intracranial pressure (ICP) monitor was inserted, and, on day 3, continuous renal replacement therapy (CRRT) was initiated due to acute kidney injury, during which the patient developed severe intracranial hypertension. CT of the brain showed diffuse cerebral edema. CRRT was discontinued, sedation was increased, and hypertonic saline was administered, upon which ICP normalized. Due to persistent hyperkalemia and overhydration, ultrafiltration and intermittent hemodialysis were performed separately on day 4 with a small dialyzer, low blood and dialysate flow, and high dialysate sodium content. During subsequent treatments, isolated ultrafiltration was well tolerated, whereas hemodialysis was associated with increased ICP necessitating frequent pauses or early cessation of dialysis. In patients at risk of DDS, hemodialysis should be performed with utmost care and continuous monitoring of ICP should be considered.
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- 2017
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27. Obesity and Low-Grade Inflammation Increase Plasma Follistatin-Like 3 in Humans
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Claus Brandt, Maria Pedersen, Anders Rinnov, Anne S. Andreasen, Kirsten Møller, Pernille Hojman, Bente K. Pedersen, and Peter Plomgaard
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Pathology ,RB1-214 - Abstract
Background. Rodent models suggest that follistatin-like 3 (fstl3) is associated with diabetes and obesity. In humans, plasma fstl3 is reduced with gestational diabetes. In vitro, TNF-α induces fstl3 secretion, which suggests a link to inflammation. Objective. To elucidate the association between plasma fstl3 and obesity, insulin resistance, and low-grade inflammation in humans. Study Design. Plasma fstl3 levels were determined in a cross-sectional study including three groups: patients with type 2 diabetes, impaired glucose tolerance, and healthy controls. In addition, lipopolysaccharide (LPS), TNF-α, or interleukin-6 (IL-6) as well as a hyperinsulinemic euglycemic clamp were used to examine if plasma fstl3 was acutely regulated in humans. Results. Plasma fstl3 was increased in obese subjects independent of glycemic state. Moreover, plasma fstl3 was positively correlated with fat mass, plasma leptin, fasting insulin, and HOMA B and negatively with HOMA S. Furthermore plasma fstl3 correlated positively with plasma TNF-α and IL-6 levels. Infusion of LPS and TNF-α, but not IL-6 and insulin, increased plasma fstl3 in humans. Conclusion. Plasma fstl3 is increased in obese subjects and associated with fat mass and low-grade inflammation. Furthermore, TNF-α increased plasma fstl3, suggesting that TNF-α is one of the inflammatory drivers of increased systemic levels of fstl3.
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- 2014
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28. Discrepant fibrinolytic response in plasma and whole blood during experimental endotoxemia in healthy volunteers.
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Sisse R Ostrowski, Ronan M G Berg, Nis A Windeløv, Martin A S Meyer, Ronni R Plovsing, Kirsten Møller, and Pär I Johansson
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Medicine ,Science - Abstract
Sepsis induces early activation of coagulation and fibrinolysis followed by late fibrinolytic shutdown and progressive endothelial damage. The aim of the present study was to investigate and compare the functional hemostatic response in whole blood and plasma during experimental human endotoxemia by the platelet function analyzer, Multiplate and by standard and modified thrombelastography (TEG).Prospective physiologic study of nine healthy male volunteers undergoing endotoxemia by means of a 4-hour infusion of E. coli lipopolysaccharide (LPS, 0.5 ng/kg/hour), with blood sampled at baseline and at 4 h and 6 h. Physiological and standard biochemical data and coagulation tests, TEG (whole blood: TEG, heparinase-TEG, Functional Fibrinogen; plasma: TEG±tissue-type plasminogen activator (tPA)) and Multiplate (TRAPtest, ADPtest, ASPItest, COLtest) were recorded. Mixed models with Tukey post hoc tests and correlations were applied.Endotoxemia induced acute SIRS with increased HR, temperature, WBC, CRP and procalcitonin and decreased blood pressure. It also induced a hemostatic response with platelet consumption and reduced APTT while INR increased (all p
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- 2013
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29. Type 2 diabetes is associated with altered NF-κB DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS.
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Anne Sofie Andreasen, Meghan Kelly, Ronan Martin Griffin Berg, Kirsten Møller, and Bente Klarlund Pedersen
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Medicine ,Science - Abstract
Systemic inflammation is often associated with impaired glucose metabolism. We therefore studied the activation of inflammatory pathway intermediates that interfere with glucose uptake during systemic inflammation by applying a standardised inflammatory stimulus in vivo. After ethical approval, informed consent and a thorough physical examination, 10 patients with type 2 diabetes and 10 participants with normal glucose tolerance (NGT) were given an intravenous bolus of E. coli lipopolysaccharide (LPS) of 0.3 ng/kg. Skeletal muscle biopsies and plasma were obtained at baseline and two, four and six hours after LPS. Nuclear factor (NF)-κB p65 DNA binding activity measured by ELISA, tumor necrosis factor-α and interleukin-6 mRNA expression analysed by real time reverse transcription polymerase chain reaction, and abundance of inhibitor of NF-κB (IκB)α, phosphorylated c-Jun-N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase measured by Western blotting were detected in muscle biopsy samples. Relative to subjects with NGT, patients with type 2 diabetes exhibited a more pronounced increase in NF-κB binding activity and JNK phosphorylation after LPS, whereas skeletal muscle cytokine mRNA expression did not differ significantly between groups. AMPK phosphorylation increased in volunteers with NGT, but not in those with diabetes. The present findings indicate that pathways regulating glucose uptake in skeletal muscle may be involved in the development of inflammation-associated hyperglycemia. Patients with type 2 diabetes exhibit changes in these pathways, which may ultimately render such patients more prone to develop dysregulated glucose disposal in the context of systemic inflammation.ClinicalTrials.gov NCT00412906.
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- 2011
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30. Somatosensory Outcomes Following Re-Surgery in Persistent Severe Pain After Groin Hernia Repair: A Prospective Observational Study
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Elisabeth Kjær Jensen, Thomas K Ringsted, Joakim M Bischoff, Morten A Petersen, Kirsten Møller, Henrik Kehlet, and Mads U Werner
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Anesthesiology and Pain Medicine ,Journal of Pain Research - Abstract
Elisabeth Kjær Jensen,1,* Thomas K Ringsted,1,* Joakim M Bischoff,1 Morten A Petersen,2 Kirsten Møller,3,4 Henrik Kehlet,5 Mads U Werner1,6 1Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 2Statistical Research Unit, Department of Palliative Care, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Neuroanaesthesiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Section for Surgical Pathophysiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Sciences, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Elisabeth Kjær Jensen, Multidisciplinary Pain Center 7612, Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, Ole Maaløes Vej 26, Copenhagen N, 2200, Denmark, Tel +45 3545 7612, Email elisabeth.kjaer@live.dkPurpose: After groin hernia repair (globally more than 20 million/year) 2â 4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy.Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory âcomponentâ indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8â 11.5) months before and 4.0 (3.5â 4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed.Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of â 2.0, â 2.5, and â 2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (âdeafferentationâ). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001).Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep âpain generatorâ. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.Keywords: groin, hernia repair, chronic post-surgical pain, reoperation, sensory thresholds
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- 2023
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31. Understanding, detecting, and stimulating consciousness recovery in the ICU
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Daniel Kondziella, Moshgan Amiri, Marwan H. Othman, Elisabeth Waldemar Jakobsen, Tejs Jansen, and Kirsten Møller
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Surgery ,Neurology (clinical) - Abstract
Coma is a medical and socioeconomic emergency. Although underfunded, research on coma and disorders of consciousness has made impressive progress. Lesion-network-mapping studies have delineated the precise brainstem regions that consistently produce coma when damaged. Functional neuroimaging has revealed how mechanisms like "communication through coherence" and "inhibition by gating" work in synergy to enable cortico-cortical processing and how this information transfer is disrupted in brain injury. On the cellular level, break-down of intracellular communication between the layer 5 pyramidal cell soma and the apical dendritic part impairs dendritic information integration, with up-stream effects on microcircuits in local neuronal populations and on large-scale fronto-parietal networks, which correlates with loss of consciousness. A breakthrough in clinical concepts occurred when fMRI, and later EEG, studies revealed that 15% of clinically unresponsive patients in acute and chronic settings are in fact awake and aware, as shown by their command following abilities revealed by brain activation during motor and locomotion imagery tasks. This condition is now termed "cognitive motor dissociation." Furthermore, epidemiological data on coma were literally non-existent until recently because of difficulties related to case ascertainment with traditional methods, but crowdsourcing of family observations enabled the first estimates of how frequent coma is in the general population (pooled annual incidence of 201 coma cases per 100,000 population in the UK and the USA). Diagnostic guidelines on coma and disorders of consciousness by the American Academy of Neurology and the European Academy of Neurology provide ambitious clinical frameworks to accommodate these achievements. As for therapy, a broad range of medical and non-medical treatment options is now being tested in increasingly larger trials; in particular, amantadine and transcranial direct current stimulation appear promising in this regard. Major international initiatives like the Curing Coma Campaign aim to raise awareness for coma and disorders of consciousness in the public, with the ultimate goal to make more brain-injured patients recover consciousness after a coma. To highlight all these accomplishments, this paper provides a comprehensive overview of recent progress and future challenges related to understanding, detecting, and stimulating consciousness recovery in the ICU.
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- 2022
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32. Diagnostic and prognostic performance of Mxa and transfer function analysis-based dynamic cerebral autoregulation metrics
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Markus Harboe Olsen, Christian Riberholt, Ronni R Plovsing, Ronan MG Berg, and Kirsten Møller
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Neurology ,Ultrasonography, Doppler, Transcranial ,Homeostasis ,Humans ,Blood Pressure ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,Prognosis ,Blood Flow Velocity - Abstract
Dynamic cerebral autoregulation is often assessed by continuously recorded arterial blood pressure (ABP) and transcranial Doppler-derived mean cerebral blood flow velocity followed by analysis in the time and frequency domain, respectively. Sequential correlation (in the time domain, yielding e.g., the measure mean flow index, Mxa) and transfer function analysis (TFA) (in the frequency domain, yielding, e.g., normalised and non-normalised gain as well as phase in the low frequency domain) are commonly used approaches. This study investigated the diagnostic and prognostic performance of these metrics. We included recordings from 48 healthy volunteers, 19 patients with sepsis, 36 with traumatic brain injury (TBI), and 14 patients admitted to a neurorehabilitation unit. The diagnostic (between healthy volunteers and patients) and prognostic performance (to predict death or poor functional outcome) of Mxa and the TFA measures were assessed by area under the receiver-operating characteristic (AUROC) curves. AUROC curves generally indicated that the measures were ‘no better than chance’ (AUROC ∼0.5) both for distinguishing between healthy volunteers and patient groups, and for predicting outcomes in our cohort. No metric emerged as superior for distinguishing between healthy volunteers and different patient groups, for assessing the effect of interventions, or for predicting mortality or functional outcome.
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- 2023
33. Multimodal prediction of residual consciousness in the intensive care unit: the CONNECT-ME study
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Moshgan Amiri, Patrick M Fisher, Federico Raimondo, Annette Sidaros, Melita Cacic Hribljan, Marwan H Othman, Ivan Zibrandtsen, Simon S Albrechtsen, Ove Bergdal, Adam Espe Hansen, Christian Hassager, Joan Lilja S Højgaard, Elisabeth Waldemar Jakobsen, Helene Ravnholt Jensen, Jacob Møller, Vardan Nersesjan, Miki Nikolic, Markus Harboe Olsen, Sigurdur Thor Sigurdsson, Jacobo D Sitt, Christine Sølling, Karen Lise Welling, Lisette M Willumsen, John Hauerberg, Vibeke Andrée Larsen, Martin Fabricius, Gitte Moos Knudsen, Jesper Kjaergaard, Kirsten Møller, and Daniel Kondziella
- Subjects
ddc:610 ,Neurology (clinical) - Abstract
Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the objective of the prospective, observational, tertiary centre cohort, diagnostic phase IIb study ‘Consciousness in neurocritical care cohort study using EEG and fMRI’ (CONNECT-ME, NCT02644265) was to assess the accuracy of fMRI and EEG to identify residual consciousness in acute DoC in the ICU. Between April 2016 and November 2020, 87 acute DoC patients with traumatic or non-traumatic brain injury were examined with repeated clinical assessments, fMRI and EEG. Resting-state EEG and EEG with external stimulations were evaluated by visual analysis, spectral band analysis and a Support Vector Machine (SVM) consciousness classifier. In addition, within- and between-network resting-state connectivity for canonical resting-state fMRI networks was assessed. Next, we used EEG and fMRI data at study enrolment in two different machine-learning algorithms (Random Forest and SVM with a linear kernel) to distinguish patients in a minimally conscious state or better (≥MCS) from those in coma or unresponsive wakefulness state (≤UWS) at time of study enrolment and at ICU discharge (or before death). Prediction performances were assessed with area under the curve (AUC). Of 87 DoC patients (mean age, 50.0 ± 18 years, 43% female), 51 (59%) were ≤UWS and 36 (41%) were ≥ MCS at study enrolment. Thirty-one (36%) patients died in the ICU, including 28 who had life-sustaining therapy withdrawn. EEG and fMRI predicted consciousness levels at study enrolment and ICU discharge, with maximum AUCs of 0.79 (95% CI 0.77–0.80) and 0.71 (95% CI 0.77–0.80), respectively. Models based on combined EEG and fMRI features predicted consciousness levels at study enrolment and ICU discharge with maximum AUCs of 0.78 (95% CI 0.71–0.86) and 0.83 (95% CI 0.75–0.89), respectively, with improved positive predictive value and sensitivity. Overall, both machine-learning algorithms (SVM and Random Forest) performed equally well. In conclusion, we suggest that acute DoC prediction models in the ICU be based on a combination of fMRI and EEG features, regardless of the machine-learning algorithm used.
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- 2022
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34. Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury
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Elisabeth Waldemar Jakobsen, Vardan Nersesjan, Simon Sander Albrechtsen, Marwan H. Othman, Moshgan Amiri, Niels Vendelbo Knudsen, Merlin D. Larson, Christian Hassager, Kirsten Møller, Jesper Kjaergaard, and Daniel Kondziella
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Adult ,Disorders of consciousness ,Neurology & Neurosurgery ,Consciousness ,Clinical Sciences ,Neurosciences ,Miosis ,Middle Aged ,Cardiac arrest ,Prognosis ,Anisocoria ,Brain Disorders ,Automated pupillometry ,Traumatic brain injury ,Clinical Research ,Brain Injuries ,Brimonidine Tartrate ,Humans ,Surgery ,Female ,Neurology (clinical) ,Coma ,Ophthalmic Solutions ,Eye Disease and Disorders of Vision ,Aged - Abstract
Background There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner’s syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. Methods We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5–120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. Results We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: − 1.31 mm, 95% CI [− 1.51; − 1.11], p p p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. Conclusion In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the “intermediate zone” of disorders of consciousness in the ICU seems warranted.
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- 2023
35. Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage
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Markus Harboe Olsen, Tenna Capion, Christian Gunge Riberholt, Søren Bache, Søren Røddik Ebdrup, Rune Rasmussen, Tiit Mathiesen, Ronan M. G. Berg, and Kirsten Møller
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Anesthesiology and Pain Medicine ,General Medicine - Published
- 2023
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36. Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus following aneurysmal subarachnoid haemorrhage: Protocol for the DRAIN randomised clinical trial
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Tenna Capion, Alexander Lilja‐Cyron, Markus Harboe Olsen, Marianne Juhler, Kirsten Møller, Angelika Sorteberg, Pål André Rønning, Frantz Rom Poulsen, Joakim Wismann, Celina Ravlo, Jørgen Isaksen, Jane Lindschou, Christian Gluud, and Tiit Mathiesen
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Anesthesiology and Pain Medicine ,General Medicine - Published
- 2023
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37. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36: Test-retest reproducibility and head-to-head comparison with the antagonist [18F]altanserin.
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Anders Ettrup, Claus Svarer, Brenda McMahon, Sofi da Cunha-Bang, Szabolcs Lehel, Kirsten Møller, Agnete Dyssegaard, Melanie Ganz, Vincent Beliveau, Louise Møller, Nic Gillings, and Gitte Moos Knudsen
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- 2016
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38. Diagnostic criteria of CNS infection in patients with external ventricular drainage after traumatic brain injury: a pilot study
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Rasmus Stanley Willer‐Hansen, Markus Harboe Olsen, John Hauerberg, Helle Krogh Johansen, Åse Bengaard Andersen, and Kirsten Møller
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Adult ,Blood Glucose ,External ventricular drainage ,Pilot Projects ,General Medicine ,Central Nervous System Infections ,Traumatic brain injury ,Anesthesiology and Pain Medicine ,Cerebrospinal fluid drains ,Brain Injuries, Traumatic ,Ventriculitis ,Drainage ,Humans ,Meningitis ,Biomarkers ,Cerebrospinal fluid shunts ,Retrospective Studies ,Central nervous system infections - Abstract
Background: Ventriculostomy-related infection (VRI) is a common complication in patients with traumatic brain injury (TBI) treated with an external ventricular drain (EVD). The aim of this study was to investigate incidence and characteristics of patients with VRI, and to explore diagnostic criteria to confidently rule out VRI in patients with TBI. Methods: This retrospective cohort pilot study included adults with severe TBI who were admitted to the ICU and received an EVD, during a 26-month period. Patients were categorized as having Culture-positive VRI, Culture-negative VRI, or No VRI. Variables that were potentially associated with Culture-positive VRI was analyzed, and predictive values were calculated. Results: 75 of 215 patients with severe TBI (35%) underwent EVD placement; nine of these (12%) were classified as Culture-negative VRI and eight (11%) as Culture-positive VRI. The CSF cell counts that led to VRI treatment were compared with 46 CSF cell counts from No VRI patients. A CSF/plasma glucose ratio below 0.6 had a negative predictive value (NPV) for culture-verified VRI of 0.97 (95% CI: 0.85–1), whereas a combination of three CSF-derived biomarkers within the reference limits (white/red blood cell ratio, CSF/plasma glucose ratio, and protein content) ruled out Culture-positive VRI in this cohort (PPV 0, 95% CI: 0–0.14). C-reactive protein did not reliably predict VRI. Conclusions: In this pilot study of patients after severe, a combination of biomarkers within reference limits ruled out VRI (PPV 0, CI: 0–0.14). Hypoglycorrhachia was a sensitive marker of VRI (NPV 0.97, CI: 0.85–1). Systemic signs and markers of infection did not predict VRI.
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- 2022
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39. Nocturnal increase in cerebrospinal fluid secretion as a regulator of intracranial pressure
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Annette Buur Steffensen, Beatriche Louise Edelbo, Dagne Barbuskaite, Søren Norge Andreassen, Markus Harboe Olsen, Kirsten Møller, and Nanna MacAulay
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It is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance. Through a combination of patient data andin vivotelemetric pressure measurements in adult male rats, we demonstrated that ICP increases in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients and CSF production rate in rats, the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl-cotransporter (NKCC1), which is implicated in CSF secretion by this tissue. In conclusion, CSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.
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- 2023
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40. Multimodal prediction of 3- and 12-month outcomes in ICU-patients with acute disorders of consciousness
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Moshgan Amiri, Federico Raimondo, Patrick M. Fisher, Annette Sidaros, Melita Cacic Hribljan, Marwan H. Othman, Ivan Zibrandtsen, Ove Bergdal, Maria Louise Fabritius, Adam Espe Hansen, Christian Hassager, Joan Lilja S Højgaard, Niels Vendelbo Knudsen, Emilie Lund Laursen, Vardan Nersesjan, Miki Nicolic, Karen Lise Welling, Helene Ravnholt Jensen, Sigurdur Thor Sigurdsson, Jacob E. Møller, Jacobo D. Sitt, Christine Sølling, Lisette M. Willumsen, John Hauerberg, Vibeke Andrée Larsen, Martin Ejler Fabricius, Gitte Moos Knudsen, Jesper Kjærgaard, Kirsten Møller, and Daniel Kondziella
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BackgroundIn intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC), outcome prediction is key to decision-making regarding prognostication, neurorehabilitation, and management of family expectations. Current prediction algorithms are largely based on chronic DoC, while multimodal data from acute DoC are scarce. Therefore, CONNECT-ME (Consciousness in neurocritical care cohort study using EEG and fMRI,NCT02644265) investigates ICU-patients with acute DoC due to traumatic and non-traumatic brain injuries, utilizing EEG (resting-state and passive paradigms), fMRI (resting-state) and systematic clinical examinations.MethodsWe previously presented results for a subset of patients (n=87) concerning prediction of consciousness levels at ICU discharge. Now, we report 3- and 12-month outcomes in an extended cohort (n=123). Favourable outcome was defined as modified Rankin Scale ≤3, Cerebral Performance Category ≤2, and Glasgow Outcome Scale-Extended ≥4. EEG-features included visual-grading, automated spectral categorization, and Support Vector Machine (SVM) consciousness classifier. fMRI-features included functional connectivity measures from six resting-state networks. Random-Forest and SVM machine learning were applied to EEG- and fMRI-features to predict outcomes. Here, Random-Forest results are presented as area under the curve (AUC) of receiver operating curves or accuracy. Cox proportional regression with in-hospital death as competing risk was used to assess independent clinical predictors of time to favourable outcome.ResultsBetween April-2016 and July-2021, we enrolled 123 patients (mean age 51 years, 42% women). Of 82 (66%) ICU-survivors, 3- and 12-month outcomes were available for 79 (96%) and 77 (94%), respectively. EEG-features predicted both 3-month (AUC 0.79[0.77-0.82] and 12-month (0.74[0.71-0.77]) outcomes. fMRI-features appeared to predict 3-month outcome (accuracy 0.69-0.78) both alone and when combined with some EEG-features (accuracies 0.73-0.84), but not 12-month outcome (larger sample sizes needed). Independent clinical predictors of time to favourable outcome were younger age (Hazards-Ratio 1.04[95% CI 1.02-1.06]), TBI (1.94[1.04-3.61]), command-following abilities at admission (2.70[1.40-5.23]), initial brain-imaging without severe pathology (2.42[1.12-5.22]), improving consciousness in the ICU (5.76[2.41-15.51]), and favourable visual-graded EEG (2.47[1.46-4.19]).ConclusionFor the first time, our results indicate that EEG- and fMRI-features and readily available clinical data reliably predict short-term outcome of patients with acute DoC, and EEG also predicts 12-month outcome after ICU discharge.
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- 2023
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41. Impact of hyperoxia and phenylephrine on cerebral oxygenation: An experimental clinical study
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Sofie S. Pedersen, Christian S. Meyhoff, Markus Harboe Olsen, Zara R. Stisen, Anton Lund, Kirsten Møller, Jane Skjøth‐Rasmussen, Finn B. Moltke, and Martin Kryspin Sørensen
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Adult ,Oxygen ,Phenylephrine ,Anesthesiology and Pain Medicine ,Brain Injuries ,Hypertension ,Humans ,Brain ,General Medicine ,Hyperoxia - Abstract
BackgroundOxygen supply to the brain is of special importance during intracranial surgery because it may be compromised by intracranial pathology. A high arterial blood pressure (mean arterial pressure above 80 mmHg) and a high arterial oxygen tension (PaO2 above 12 kPa) is therefore often targeted in these patients, when for example intracranial pressure is increased or when a mass effect on brain tissue from a tumour is present, and it is pursued by administering vasopressors such as phenylephrine and by increasing inspiratory oxygen fraction (FiO2). However, whether these interventions increase cerebral oxygenation remains uncertain. We aimed to investigate the effect of hyperoxia and phenylephrine on brain tissue oxygen tension (PbtO2) in patients undergoing craniotomy.MethodsIn this experimental study, we included 17 adult patients scheduled for elective craniotomy. After securing a stable baseline of the oxygen probe, PbtO2 was measured in white matter peripherally in the surgical field during general anaesthesia. Primary comparisons were PbtO2 before versus after an increase in FiO2 from 0.30 to 0.80 as well as before versus after a bolus dose of phenylephrine (0.1–0.2 mg depending on patient haemodynamics). Data were analysed with the Wilcoxon signed rank test.ResultsWe obtained complete data sets in 11 patients undergoing the FiO2 increase and six patients receiving the phenylephrine bolus. PbtO2 was 22 (median; 5%–95% range, 4.6–54) mmHg during 30% oxygen, 68 (8.4–99) mmHg during 80% oxygen (p = .004 compared to 30% oxygen), 21 (4.5–81) mmHg before phenylephrine, and 19 (4.2–56) mmHg after phenylephrine (p = .56 compared to before phenylephrine).ConclusionIn patients undergoing craniotomy under general anaesthesia, brain tissue oxygen tension increased with a high inspiratory oxygen fraction but remained unchanged after a bolus dose of phenylephrine.
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- 2023
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42. Reliability and validity of the mean flow index (Mx) for assessing cerebral autoregulation in humans: A systematic review of the methodology
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Jesper Mehlsen, Kirsten Møller, Ronan M. G. Berg, Christian Gunge Riberholt, and Markus Harboe Olsen
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medicine.medical_specialty ,business.industry ,Cerebral autoregulation ,Neurology ,Cerebral blood flow ,Brain Injuries ,Cerebrovascular Circulation ,Internal medicine ,Cardiology ,medicine ,Homeostasis ,Humans ,Autoregulation ,Mean flow ,Neurology (clinical) ,Cerebral perfusion pressure ,Cardiology and Cardiovascular Medicine ,business ,Review Articles ,Blood Flow Velocity ,Reliability (statistics) - Abstract
Cerebral autoregulation is a complex mechanism that serves to keep cerebral blood flow relatively constant within a wide range of cerebral perfusion pressures. The mean flow index (Mx) is one of several methods to assess dynamic cerebral autoregulation, but its reliability and validity have never been assessed systematically. The purpose of the present systematic review was to evaluate the methodology, reliability and validity of Mx. Based on 128 studies, we found inconsistency in the pre-processing of the recordings and the methods for calculation of Mx. The reliability in terms of repeatability and reproducibility ranged from poor to excellent, with optimal repeatability when comparing overlapping recordings. The discriminatory ability varied depending on the patient populations; in general, those with acute brain injury exhibited a higher Mx than healthy volunteers. The prognostic ability in terms of functional outcome and mortality ranged from chance result to moderate accuracy. Since the methodology was inconsistent between studies, resulting in varying reliability and validity estimates, the results were difficult to compare. The optimal method for deriving Mx is currently unknown.
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- 2021
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43. Hypophosphataemia is common in patients with aneurysmal subarachnoid haemorrhage
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Mai Erritzøe-Jervild, Jesper Wesierski, Vagn Eskesen, Markus Harboe Olsen, Ruth Frikke-Schmidt, Stefano Romano, Matias Orre, and Kirsten Møller
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medicine.medical_specialty ,Hypophosphatemia ,Phosphate measurement ,hypophosphataemia ,Cohort Studies ,Danish ,aneurysmal subarachnoid haemorrhage ,Internal medicine ,Humans ,Medicine ,In patient ,Propensity Score ,Retrospective Studies ,business.industry ,Critically ill ,Retrospective cohort study ,General Medicine ,Odds ratio ,Subarachnoid Hemorrhage ,mortality ,language.human_language ,Anesthesiology and Pain Medicine ,SAH ,Cohort ,language ,Subarachnoid haemorrhage ,business - Abstract
Hypophosphataemia is common in critically ill patients, but neither its prevalence nor its association with outcome have been investigated specifically in patients with aneurysmal subarachnoid haemorrhage (aSAH). Methods Patients with aSAH and at least one phosphate measurement were included from two independent cohorts; An American cohort extracted from two open access databases (Medical Information Mart for Intensive Care-III and eICU Collaborative Research Database v. 2.0) and a Danish cohort consisting of patients with aSAH admitted to Rigshospitalet, Denmark over a four-year period. In each cohort, we calculated the prevalence of mild (0.32-0.80 mmol/L) and severe (textless0.32 mmol/L) hypophosphataemia and their association with in-hospital mortality before and after propensity-score matching. Results Hypophosphataemia occurred in 72.4 (95 68.1-76.3) n=471) and 54.9 (50.0-59.7) n=419). However, it was not associated with mortality in neither full (American: Mild, Odds ratio (OR) 0.99 (0.91-1.07), Severe OR 1.20 (0.95-1.51); Danish: Mild, OR 1.01 (0.95-1.08), Severe OR 1.20 (0.95-1.51)) nor propensity-score matched cohorts (American (n=168): Mild, OR 1.06 (0.88-1.28), Severe OR 1.46 (0.96-2.12); Danish (n=44): Mild, OR 1.16 (0.82-1.65), Severe OR 0.45 (0.13-1.55)). Conclusion In this retrospective study of patients with aSAH, hypophosphataemia was common. IntroductionHypophosphataemia is common in critically ill patients, but neither its prevalence nor its association with outcome have been investigated specifically in patients with aneurysmal subarachnoid haemorrhage (aSAH).MethodsPatients with aSAH and at least one phosphate measurement were included from two independent cohorts; an American cohort extracted from two open-access databases (Medical Information Mart for Intensive Care-III and eICU Collaborative Research Database v. 2.0) and a Danish cohort consisting of patients with aSAH admitted to Rigshospitalet, Denmark over a 4-year period. In each cohort, we calculated the prevalence of mild (0.32–0.80 mmol/L) and severe (ResultsHypophosphataemia occurred in 72.4% (95% CI: 68.1–76.3) of patients in the American cohort (n = 471) and 54.9% (50.0–59.7) in the Danish cohort (n = 419). However, it was not associated with mortality in neither full (American: Mild, Odds ratio (OR) 0.99 (0.91–1.07), Severe OR 1.20 (0.95–1.51); Danish: Mild, OR 1.01 (0.95–1.08), Severe OR 1.20 (0.95–1.51)) nor propensity-score matched cohorts (American (n = 168): Mild, OR 1.06 (0.88–1.28), Severe OR 1.46 (0.96–2.12); Danish (n = 44): Mild, OR 1.16 (0.82–1.65), Severe OR 0.45 (0.13–1.55)).ConclusionIn this retrospective study of patients with aSAH, hypophosphataemia was common.
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- 2021
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44. MicroRNA-9-3p:a novel predictor of neurological outcome after cardiac arrest
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Rasmus Paulin Beske, Søren Bache, Martin Abild Stengaard Meyer, Jesper Kjærgaard, John Bro-Jeppesen, Laust Obling, Markus Harboe Olsen, Maria Rossing, Finn Cilius Nielsen, Kirsten Møller, Niklas Nielsen, and Christian Hassager
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Hypothermia, Induced/methods ,General Medicine ,Critical Care and Intensive Care Medicine ,Prognosis ,Out-of-Hospital Cardiac Arrest/complications ,MicroRNAs ,MicroRNAs/genetics ,Hypothermia, Induced ,Coma/complications ,Humans ,Coma ,Cardiology and Cardiovascular Medicine ,Out-of-Hospital Cardiac Arrest ,Biomarkers - Abstract
Aims Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose after hospital arrival are at high risk of mortality due to anoxic brain injury. MicroRNA are small–non-coding RNA molecules ultimately involved in gene-silencing. They show promise as biomarkers, as they are stable in body fluids. The microRNA 9-3p (miR-9-3p) is associated with neurological injury in trauma and subarachnoid haemorrhage. Methods and results This post hoc analysis considered all 171 comatose OHCA patients from a single centre in the target temperature management (TTM) trial. Patients were randomized to TTM at either 33°C or 36°C for 24 h. MicroRNA-9-3p (miR-9-3p) was measured in plasma sampled at admission and at 28, 48, and 72 h. There were no significant differences in age, gender, and pre-hospital data, including lactate level at admission, between miR-9-3p level quartiles. miR-9-3p levels changed markedly following OHCA with a peak at 48 h. Median miR-9-3p levels between TTM 33°C vs. 36°C were not different at any of the four time points. Elevated miR-9-3p levels at 48 h were strongly associated with an unfavourable neurological outcome [OR: 2.21, 95% confidence interval (CI): 1.64–3.15, P Conclusion MiR-9-3p is strongly associated with neurological outcome following OHCA, and the levels of miR-9-3p are peaking 48 hours following cardiac arrest.
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- 2022
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45. Automated pupillometry to uncover signs of consciousness in acute brain injury: statistical analysis plan
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Marwan H. Othman, Markus Harboe Olsen, Kirsten Møller, Jesper Kjærgaard, and Daniel Kondziella
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Automated pupillometry, Disorder of consciousness, Acute brain injury, Intensive care unit, Statistical analysis plan - Abstract
Pre-specified statistical analysis plan (SAP) for Automated Pupillometry and Consciousness study with the aim of increasingtransparency and validity by stating the author's hypothesis, objective, and analysis approach before accessing the data.
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- 2022
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46. Reliability of the transcranial Doppler ultrasound-derived mean flow index for assessing dynamic cerebral autoregulation in healthy volunteers
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Jesper Mehlsen, Kirsten Møller, Lene Theil Skovgaard, Markus Harboe Olsen, Ronan M. G. Berg, and Christian Gunge Riberholt
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medicine.medical_specialty ,Supine position ,Correlation coefficient ,Ultrasonography, Doppler, Transcranial ,Intraclass correlation ,0206 medical engineering ,Biomedical Engineering ,Biophysics ,Blood Pressure ,02 engineering and technology ,Cerebral autoregulation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine.artery ,medicine ,Homeostasis ,Humans ,business.industry ,Reproducibility of Results ,Blood flow ,020601 biomedical engineering ,Healthy Volunteers ,Transcranial Doppler ,Standard error ,Cerebrovascular Circulation ,Middle cerebral artery ,Cardiology ,business ,Blood Flow Velocity ,030217 neurology & neurosurgery - Abstract
The transcranial Doppler ultrasound-derived mean flow index (Mxa) is widely used for assessing dynamic cerebral autoregulation (dCA) in different clinical populations. This study aimed at estimating the relative and absolute reliability of Mxa in healthy participants in the supine position and during head-up tilt (HUT). Fourteen healthy participants were examined on two separate occasions during which, mean middle cerebral artery blood flow velocity (MCAv), non-invasive blood pressure, and heart rate were continuously recorded in the supine position and during HUT. Mxa was calculated as the correlation coefficient between mean arterial blood pressure and MCAv using either 3-, 5-, or 10-second averages collected over a 300 second period. Intraclass correlation coefficient (ICC1.1) was calculated to assess relative reliability, while the standard error of measurement (SEM), and limits of agreement (LOA) were used to assess absolute reliability. Mxa-based 3-second averages yielded a similar relative and absolute reliability in both positions. When Mxa was calculated from 5-second averages, the most reliable values were obtained during HUT. The poorest reliability was achieved using 10-second averages, regardless of posture. The Mxa shows fair reliability with acceptable LOA in healthy volunteers when based on 3-second averages, both in the supine position and during HUT.
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- 2021
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47. Lectin complement pathway initiators after subarachnoid hemorrhage — an observational study
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Julie Lyng Forman, Søren Bache, Peter Garred, Kirsten Møller, Charlotte Loumann Krogh, and Jeppe Sillesen Matzen
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Male ,0301 basic medicine ,medicine.medical_specialty ,Subarachnoid hemorrhage ,Neurology ,Immunology ,Ischemia ,Gastroenterology ,lcsh:RC346-429 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cerebrospinal fluid ,Modified Rankin Scale ,Internal medicine ,medicine ,Humans ,Longitudinal Studies ,Prospective Studies ,Delayed cerebral ischemia ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Retrospective Studies ,Univariate analysis ,Ficolin ,business.industry ,Research ,General Neuroscience ,Confounding ,Complement Pathway, Mannose-Binding Lectin ,Middle Aged ,Functional outcome ,medicine.disease ,030104 developmental biology ,Female ,business ,Biomarkers ,030217 neurology & neurosurgery ,Lectin complement pathway ,Follow-Up Studies - Abstract
Background This exploratory study investigated the time-course of lectin complement pathway (LCP) initiators in cerebrospinal fluid (CSF) and plasma in patients with subarachnoid hemorrhage (SAH), as well as their relationship to delayed cerebral ischemia (DCI) and functional outcome. Methods Concentrations of ficolin-1, ficolin-2, ficolin-3, and mannose-binding lectin (MBL) were analyzed in CSF and plasma from patients with SAH. Samples were collected daily from admission until day 9 (CSF; N_PATIENTS = 63, n_SAMPLES = 399) and day 8 (plasma; N_PATIENTS = 50, n_SAMPLES = 358), respectively. Twelve neurologically healthy patients undergoing spinal anesthesia and 12 healthy blood donors served as controls. The development of DCI during hospitalization and functional outcome at 3 months (modified Rankin Scale) were registered for patients. Results On admission, CSF levels of all LCP initiators were increased in SAH patients compared with healthy controls. Levels declined gradually over days in patients; however, a biphasic course was observed for ficolin-1. Increased CSF levels of all LCP initiators were associated with a poor functional outcome in univariate analyses. This relationship persisted for ficolin-1 and MBL in multivariate analysis after adjustments for confounders (age, sex, clinical severity, distribution and amount of blood on CT-imaging) and multiple testing (1.87 ng/mL higher in average, 95% CI, 1.17 to 2.99 and 1.69 ng/mL higher in average, 95% CI, 1.09 to 2.63, respectively). In patients who developed DCI compared with those without DCI, CSF levels of ficolin-1 and MBL tended to increase slightly more over time (p_interaction = 0.021 and 0.033, respectively); however, no association was found after adjustments for confounders and multiple testing (p-adj_interaction = 0.086 and 0.098, respectively). Plasma ficolin-1 and ficolin-3 were lower in SAH patients compared with healthy controls on all days. DCI and functional outcome were not associated with LCP initiator levels in plasma. Conclusion Patients with SAH displayed elevated CSF levels of ficolin-1, ficolin-2, ficolin-3, and MBL. Increased CSF levels of ficolin-1 and MBL were associated with a poor functional outcome. Trial registration This study was a retrospective analysis of samples, which had been prospectively sampled and stored in a biobank. Registered at clinicaltrials.gov (NCT01791257, February 13, 2013, and NCT02320539, December 19, 2014).
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- 2020
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48. Standardized distances for placement of REBOA in patients with aortic stenosis
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Kirsten Møller, Tasalak Thonghong, Lars Søndergaard, and Markus Harboe Olsen
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Male ,0301 basic medicine ,medicine.medical_specialty ,Resuscitation ,lcsh:Medicine ,Hemorrhage ,Femoral artery ,Balloon ,Severity of Illness Index ,Article ,Transcatheter Aortic Valve Replacement ,03 medical and health sciences ,0302 clinical medicine ,medicine.artery ,Humans ,Medicine ,lcsh:Science ,Retrospective Studies ,Cardiac device therapy ,Aorta ,Multidisciplinary ,business.industry ,Endovascular Procedures ,lcsh:R ,Retrospective cohort study ,Aortic Valve Stenosis ,Aortic bifurcation ,Balloon Occlusion ,medicine.disease ,Trunk ,Heart Arrest ,Femoral Artery ,Catheter ,Stenosis ,030104 developmental biology ,medicine.anatomical_structure ,Surgery, Computer-Assisted ,Female ,lcsh:Q ,Radiology ,Tomography, X-Ray Computed ,business ,Interventional cardiology ,030217 neurology & neurosurgery - Abstract
Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique where a balloon is advanced through the common femoral artery and temporarily inflated for treatment of cardiac arrest or non-compressible haemorrhage. The aim of this study was to measure intravascular distances relevant for correct placement of the REBOA catheter using computer tomographic (CT) scans. In a series of CT scans of the aorta from 100 patients diagnosed with severe aortic stenosis planned for transcatheter aortic valve implantation, we measured the intravascular distance from the insertion site in the common femoral artery to two potential zones for placement of the REBOA catheter; between the left subclavian artery and the celiac trunk (Zone 1), as well as between the aortic bifurcation and the distal take-off of the renal arteries (Zone 3). The mean (± SD) intravascular distance from the femoral artery to intra-aortic Zone 1 was 36 (± 2.5) cm for the lower border and 60 (± 4.1) cm for the upper border, respectively. For intra-aortic Zone 3, the mean (± SD) intravascular distance was 21 (± 2.1) cm to the lower border and 31 (± 2.3) cm to the upper border. Calculated potentially safe intervals for placement of the REBOA in Zone 1 was with 99.7% likelihood between 43 and 48 cm. No similar potentially safe interval could be calculated for Zone 3. According to this cohort study of patients with severe aortic stenosis, the balloon of the REBOA catheter should travel intraarterially between 43 (lower limit) and 48 cm (upper limit) from the site of insertion into the common femoral artery, which would lead to correct placement in intra-aortic Zone 1 in 99.7% of cases. In contrast, no potential safety interval could be similarly defined for insertion in Zone 3.
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- 2020
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49. Automated pupillometry and the FOUR score — what is the diagnostic benefit in neurointensive care?
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Søren Røddik Ebdrup, Daniel Kondziella, Nina Hvid Topp, Kirsten Møller, Helene Ravnholt Jensen, Ditte Strange, and Markus Harboe Olsen
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Adult ,Male ,medicine.medical_specialty ,Neurology ,Consciousness ,Critical Care ,Reflex, Pupillary ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Automation ,0302 clinical medicine ,Level of consciousness ,Automated pupillometry ,Prognostic marker ,medicine ,Humans ,Glasgow Coma Scale ,Pupillary light reflex ,FOUR ,Neuroradiology ,Monitoring, Physiologic ,business.industry ,Neurointensive care ,GCS ,Middle Aged ,Visual inspection ,Original Article - Neurosurgical intensive care ,Physical therapy ,Surgery ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Pupillometry - Abstract
Introduction The Glasgow Coma Scale (GCS) and visual inspection of pupillary function are routine measures to monitor patients with impaired consciousness and predict their outcome in the neurointensive care unit (neuro-ICU). Our aim was to compare more recent measures, i.e. FOUR score and automated pupillometry, to standard monitoring with the GCS and visual inspection of pupils. Methods Supervised trained nursing staff examined a consecutive sample of patients admitted to the neuro-ICU of a tertiary referral centre using GCS and FOUR score and assessing pupillary function first by visual inspection and then by automated pupillometry. Clinical outcome was evaluated 6 months after admission using the Glasgow Outcome Scale-Extended. Results Fifty-six consecutive patients (median age 63 years) were assessed a total of 234 times. Of the 36 patients with at least one GCS score of 3, 13 had a favourable outcome. All seven patients with at least one FOUR score of ≤ 3 had an unfavourable outcome, which was best predicted by a low “brainstem” sub-score. Compared to automated pupillometry, visual assessment underestimated pupillary diameters (median difference, 0.4 mm; P = 0.006). Automated pupillometry detected a preserved pupillary light reflex in 10 patients, in whom visual inspection had missed pupillary constriction. Discussion Training of nursing staff to implement frequent monitoring of patients in the neuro-ICU with FOUR score and automated pupillometry is feasible. Both measures provide additional clinical information compared to the GCS and visual assessment of pupillary function, most importantly a more granular classification of patients with low levels of consciousness by the FOUR score.
- Published
- 2020
50. Resting-State NIRS–EEG in Unresponsive Patients with Acute Brain Injury: A Proof-of-Concept Study
- Author
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Mahasweta Bhattacharya, Daniel Kondziella, Kirsten Møller, Marwan H. Othman, Jesper Kjaergaard, Anirban Dutta, Søren Kjeldsen, and Johannes Grand
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Coma ,medicine.medical_specialty ,Neurology ,Resting state fMRI ,medicine.diagnostic_test ,business.industry ,Traumatic brain injury ,030208 emergency & critical care medicine ,Electroencephalography ,Critical Care and Intensive Care Medicine ,Neurovascular bundle ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Level of consciousness ,Internal medicine ,medicine ,Cardiology ,Neurology (clinical) ,Neurosurgery ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Neurovascular-based imaging techniques such as functional MRI (fMRI) may reveal signs of consciousness in clinically unresponsive patients but are often subject to logistical challenges in the intensive care unit (ICU). Near-infrared spectroscopy (NIRS) is another neurovascular imaging technique but low cost, can be performed serially at the bedside, and may be combined with electroencephalography (EEG), which are important advantages compared to fMRI. Combined NIRS–EEG, however, has never been evaluated for the assessment of neurovascular coupling and consciousness in acute brain injury. We explored resting-state oscillations in eight-channel NIRS oxyhemoglobin and eight-channel EEG band-power signals to assess neurovascular coupling, the prerequisite for neurovascular-based imaging detection of consciousness, in patients with acute brain injury in the ICU (n = 9). Conscious neurological patients from step-down units and wards served as controls (n = 14). Unsupervised adaptive mixture-independent component analysis (AMICA) was used to correlate NIRS–EEG data with levels of consciousness and clinical outcome. Neurovascular coupling between NIRS oxyhemoglobin (0.07–0.13 Hz) and EEG band-power (1–12 Hz) signals at frontal areas was sensitive and prognostic to changing consciousness levels. AMICA revealed a mixture of five models from EEG data, with the relative probabilities of these models reflecting levels of consciousness over multiple days, although the accuracy was less than 85%. However, when combined with two channels of bilateral frontal neurovascular coupling, weighted k-nearest neighbor classification of AMICA probabilities distinguished unresponsive patients from conscious controls with > 90% accuracy (positive predictive value 93%, false discovery rate 7%) and, additionally, identified patients who subsequently failed to recover consciousness with > 99% accuracy. We suggest that NIRS–EEG for monitoring of acute brain injury in the ICU is worthy of further exploration. Normalization of neurovascular coupling may herald recovery of consciousness after acute brain injury.
- Published
- 2020
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