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  • 1.
    Andersson, Kennet
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Assessment of cerebrospinal fluid system dynamics: novel infusion protocol, mathematical modelling and parameter estimation for hydrocephalus investigations2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with idiopathic normal pressure hydrocephalus (INPH) have a disturbance in the cerebrospinal fluid (CSF) system. The treatment is neurosurgical – a shunt is placed in the CSF system. The infusion test is used to assess CSF system dynamics and to aid in the selection of patients that will benefit from shunt surgery. The infusion test can be divided into three parts: a mathematical model, an infusion protocol and a parameter estimation method. A non-linear differential equation is used to mathematically describe the CSF system, where two important parameters are the outflow conductance (Cout) and the Pressure Volume Index (PVI). These are used both for clinical and research purposes. The analysis methods for the non-linear CSF system have limited the infusion protocols of presently used infusion investigations. They come with disadvantages such as long investigation time, no estimation of PVI and no measure of the reliability of the estimates.

    The aim of this dissertation was to develop and evaluate novel methods for infusion protocols, mathematical modelling and parameter estimation methods for assessment of CSF system dynamics.

    The infusion protocols and parameter estimation methods in current use, constant pressure infusion (CPI), constant infusion and bolus infusion, were investigated. The estimates of Cout were compared, both on an experimental set-up and on 20 INPH patients. The results showed that the bolus method produced a significantly higher Cout than the other methods. The study suggested a method with continuous infusion for estimating Cout and emphasized that standardization of Cout measurement is necessary.

    The non-linear model of the CSF system was further developed. The ability to model physiological variations that affect the CSF system was incorporated into the model and it was transformed into a linear time-invariant system. This enabled the use of methods developed for identification of such systems. The underlying model for CSF absorption was discussed and the effect of baseline resting pressure (Pr) in the analysis on the estimation of Cout was explored using two different analyses, with and without Pr.

    A novel infusion protocol with an oscillating pressure pattern was introduced. This protocol was theoretically better suited for the CSF system characteristics. Three new parameter estimation methods were developed. The adaptive observer was developed from the original non-linear model of the CSF system and estimated Cout in real time. The prediction error method (PEM) and the robust simulation error (RSE) method were based on the transformed linear system, and they estimated both Cout and PVI with confidence intervals in real time. Both the oscillating pressure pattern and the reference CPI protocol were performed on an experimental set-up of the CSF system and on 47 hydrocephalus patients. The parameter estimation methods were applied to the data, and the RSE method produced estimates of Cout that were in good agreement with the reference method and allowed for an individualized and considerably reduced investigation time.

    In summary, current methods have been investigated and a novel approach for assessment of CSF system dynamics has been presented. The Oscillating Pressure Infusion method, which includes a new infusion protocol, a further developed mathematical model and new parameter estimation methods has resulted in an improved way to perform infusion investigations and should be used when assessing CSF system dynamics. The advantages of the new approach are the pressure-regulated infusion protocol, simultaneous estimation of Cout and PVI and estimates of reliability that allow for an individualized investigation time.

  • 2.
    Andersson, Kennet
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Novel infusion method for measurement of CSF dynamicsManuscript (preprint) (Other academic)
  • 3.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Manchester, I. R.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Cesarini, K. Giuliana
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Measurement of CSF dynamics with oscillating pressure infusion2013In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 128, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Introduction Infusion tests are used to diagnose and select patients with idiopathic normal pressure hydrocephalus (INPH) for shunt surgery. The test characterizes cerebrospinal fluid dynamics and estimates parameters of the cerebrospinal fluid system, the pressure-volume index (PVI) and the outflow conductance (Cout). The Oscillating Pressure Infusion (OPI) method was developed to improve the test and reduce the investigation time. The aim of this study was to evaluate the new OPI method by comparing it with an established reference method. Methods Forty-seven patients (age 71.2 +/- 8.9years) with communicating hydrocephalus underwent a preoperative lumbar infusion investigation with two consecutive infusion protocols, reference (42min) and new (20min), that is, 94 infusion tests in total. The OPI method estimated Cout and PVI simultaneously. A real-time analysis of reliability was applied to investigate the possibility of infusion time reduction. Results The difference in Cout between the methods was 1.2 +/- 1.8l/s/kPa (Rout=-0.8 +/- 3.5mmHg/ml/min), P<0.05, n=47. With the reliability analysis, the preset 20min of active infusion could have been even further reduced for 19 patients to between 10 and 19min. PVI was estimated to 16.1 +/- 6.9ml, n=47. Conclusions The novel Oscillating Pressure Infusion method produced real-time estimates of Cout including estimates of reliability that was in good agreement with the reference method and allows for a reduced and individualized investigation time.

  • 4.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Manchester, Ian R
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Andersson, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Shiriaev, Anton
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Assessment of cerebrospinal fluid outflow conductance using an adaptive observer-experimental and clinical evaluation2007In: Physiological Measurement, ISSN 0967-3334, E-ISSN 1361-6579, Vol. 28, no 11, p. 1355-1368Article in journal (Refereed)
    Abstract [en]

    Idiopathic normal pressure hydrocephalus (INPH) patients have a disturbance in the dynamics of the cerebrospinal fluid (CSF) system. The outflow conductance, C, of the CSF system has been suggested to be prognostic for positive outcome after treatment with a CSF shunt. All current methods for estimation of C have drawbacks; these include lack of information on the accuracy and relatively long investigation times. Thus, there is a need for improved methods. To accomplish this, the theoretical framework for a new adaptive observer (OBS) was developed which provides real-time estimation of C. The aim of this study was to evaluate the OBS method and to compare it with the constant pressure infusion (CPI) method. The OBS method was applied to data from infusion investigations performed with the CPI method. These consisted of repeated measurements on an experimental set-up and 30 patients with suspected INPH. There was no significant difference in C between the CPI and the OBS method for the experimental set-up. For the patients there was a significant difference, −0.84 ± 1.25 µl (s kPa)−1, mean ± SD (paired sample t-test, p < 0.05). However, such a difference is within clinically acceptable limits. This encourages further development of this new real-time approach for estimation of the outflow conductance.

  • 5.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Manchester, Ian R
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Real-time estimation of cerebrospinal fluid system parameters via oscillating pressure infusion2010In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 48, no 11, p. 1123-1131Article in journal (Refereed)
    Abstract [en]

    Hydrocephalus is related to a disturbed cerebrospinal fluid (CSF) system. For diagnosis, lumbar infusion test are performed to estimate outflow conductance, C (out), and pressure volume index, PVI, of the CSF system. Infusion patterns and analysis methods used in current clinical practice are not optimized. Minimizing the investigation time with sufficient accuracy is of major clinical relevance. The aim of this study was to propose and experimentally evaluate a new method, the oscillating pressure infusion (OPI). The non-linear model of the CSF system was transformed into a linear time invariant system. Using an oscillating pressure pattern and linear system identification methods, C (out) and PVI with confidence intervals, were estimated in real-time. Forty-two OPI and constant pressure infusion (CPI) investigations were performed on an experimental CSF system, designed with PVI = 25.5 ml and variable C (out). The ARX model robustly estimated C (out) (mean C (out,OPI) - C (out,CPI) = 0.08 μl/(s kPa), n = 42, P = 0.68). The Box-Jenkins model proved most reliable for PVI (23.7 ± 2.0 ml, n = 42). The OPI method, with its oscillating pressure pattern and new parameter estimation methods, efficiently estimated C (out) and PVI as well as their confidence intervals in real-time. The results from this experimental study show potential for the OPI method and supports further evaluation in a clinical setting.

  • 6.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Faes, Luca
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Directed coherence analysis in patients with severe autonomic dysfunction2014In: 2014 8th conference of the European Study Group on Cardiovascular Oscillations (ESGCO), IEEE conference proceedings, 2014, p. 167-168Conference paper (Refereed)
    Abstract [en]

    Many different approaches have been applied to analyse the coupling between cardiovascular signals. This study evaluated the use of directed coherence, based on multivariate autoregressive modelling, for analysis of cardiovascular signals in patients with transthyretin amyloidosis, a rare disease where severe autonomic dysfunction is common.

  • 7.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Sundström, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Effect of resting pressure on the estimate of cerebrospinal fluid outflow conductance2011In: Fluids and barriers of the CNS, ISSN 2045-8118, Vol. 8, no 1, p. 15-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A lumbar infusion test is commonly used as a predictive test for patients with normal pressure hydrocephalus and for evaluation of cerebrospinal fluid (CSF) shunt function. Different infusion protocols can be used to estimate the outflow conductance (Cout) or its reciprocal the outflow resistance, (Rout) with or without using the baseline resting pressure, Pr. Both from a basic physiological research and a clinical perspective, it is important to understand the limitations of the model on which infusion tests are based. By estimating Cout using two different analyses, with or without Pr, the limitations could be explored. The aim of this study was to compare the Cout estimates, and investigate what effect Pr had on the results.

    METHODS: Sixty-three patients that underwent a constant pressure infusion protocol as part of their preoperative evaluation for normal pressure hydrocephalus, were included (age 70.3+/-10.8 years (mean +/-SD). The analysis was performed without (Cexcl Pr) and with (Cincl Pr) Pr. The estimates were compared using Bland-Altman plots and paired sample t-tests (p<0.05 considered significant).

    RESULTS: Mean Cout for the 63 patients was: Cexcl Pr = 7.0+/-4.0 (mean +/-SD) ul/(s kPa) and Cincl Pr = 9.1+/-4.3 ul/(s kPa) and Rout was 19.0+/-9.2 and 17.7+/-11.3 mmHg/ml/min, respectively. There was a positive correlation between methods (r=0.79, n=63, p<0.01). The difference, DeltaCout, -2.1+/-2.7 ul/(s kPa) between methods was significant (p<0.01) and DeltaRout was 1.2 +/- 8.8 mmHg/ml/min). The Bland-Altman plot visualized that the variation around the mean difference was similar all through the range of measured values and there was no correlation between DeltaCout and Cout.

    CONCLUSIONS: The difference between Cout estimates, obtained from analyses with or without Pr, needs to be taken into consideration when comparing results from studies using different infusion test protocols. The study suggests variation in CSF formation rate, variation in venous pressure or a pressure dependent Cout as possible causes for the deviation from the CSF absorption model seen in some patients.

  • 8.
    Manchester, Ian
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Andersson, Kennet
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Shiriaev, Anton S
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    A nonlinear obsever for on-line estimation of the cerebrospinal fluid outflow restistance.2008In: Automatica, ISSN 0005-1098, E-ISSN 1873-2836, Vol. 44, no 5, p. 1426-1430Article in journal (Refereed)
    Abstract [en]

    Accurate estimates of the outflow resistance of the human cerebrospinal fluid system are important for the diagnosis of a medical condition known as hydrocephalus. In this paper we design a nonlinear observer which provides on-line estimates of the outflow resistance, to the best of our knowledge the first method to do so. The output of the observer is proven to globally converge to an unbiased estimate. Its performance is experimentally verified using the same apparatus used to perform actual patient diagnoses and a specially-designed physical model of the human cerebrospinal fluid system.

  • 9.
    Manchester, Ian R
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Andersson, Kennet
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Andersson, Nina
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Shiriaev, Anton S
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    A nonlinear observer for on-line estimation of the cerebrospinal fluid outflow resistance2008In: Automatica, ISSN 0005-1098, E-ISSN 1873-2836, Vol. 44, p. 1426-1430Article in journal (Refereed)
  • 10.
    Sundström, Nina
    et al.
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Kennet
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Marmarou, Anthony
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Comparison between 3 infusion methods to measure cerebrospinal fluid outflow conductance2010In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 113, no 6, p. 1294-1303Article in journal (Refereed)
    Abstract [en]

    Object There are several infusion methods available to estimate the outflow conductance (Cout) or outflow resistance (Rout = 1/Cout) of the CSF system. It has been stated that for unknown reasons, the bolus infusion method estimates a higher Cout than steady-state infusion methods. The aim of this study was to compare different infusion methods for estimation of Cout.

    Methods The following 3 different infusion methods were used: the bolus infusion method (Cout bol); the constant flow infusion method, both static (Cout stat) and dynamic (Cout dyn) analyses; and the constant pressure infusion method (Cout cpi). Repeated investigations were performed on an experimental model with well-known characteristics, with and without physiological pressure variations (B-waves, breathing, and so on). All 3 methods were also performed in a randomized order during the same investigation in 20 patients with probable or possible idiopathic normal-pressure hydrocephalus; 6 of these patients had a shunt and 14 did not.

    Results Without the presence of physiological pressure variations, the concordance in the experimental model was good between all methods. When they were added, the repeatability was better for the steady-state methods and a significantly higher Cout was found with the bolus method in the region of clinically relevant Cout (p < 0.05). The visual fit for the bolus infusion was dependent on subjective assessment by the operator. This experimental finding was confirmed by the clinical results, where significant differences were found in the investigations in patients without shunts between Cout of the visual bolus method and Cout stat, Cout dyn, and Cout cpi (4.58, 4.18, and 6.12 μl/[second × kPa], respectively).

    Conclusions This study emphasized the necessity for standardization of Cout measurements. An experienced operator could partly compensate for difficulties in correctly estimating the pressure parameters for the bolus infusion method, but for the general user this study suggests a steady-state method for estimating Cout.

  • 11.
    Wiklund, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Kadkhodaee, Amir
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Andersson, Kennet
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Cardiorespiratory Coherence Analysis of Abnormal Heart Rate Responses during Deep Breathing2013In: 2013 COMPUTING IN CARDIOLOGY CONFERENCE (CINC), 2013, Vol. 40, p. 109-112Conference paper (Refereed)
    Abstract [en]

    Although the heart rate variability (HRV) normally is highly synchronised with respiration during deep breathing, in patients with transthyretin amyloidosis we occasionally observe abnormal heart rate responses due to subtle arrhythmias, This study evaluates the use of cardiorespiratory coherence analysis for automatic detection of these abnormal patterns.

  • 12.
    Wiklund, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Kadkhodaee, Amir
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Andersson, Kennet
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Hörnsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Normal scores of deep breathing tests: beware of dysrhythmia in transthyretin amyloidosis2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 1, p. 54-61Article in journal (Refereed)
    Abstract [en]

    Background: The heart rate (HR) response to paced deep breathing (DB) is a common test of cardiac autonomic function, where high heart rate variability (HRV) is considered to reflect normal autonomic function. We evaluated the DB test in patients with hereditary transthyretin amyloid (ATTRm) amyloidosis, where autonomic dysregulation and atrial arrhythmias are common.Methods: Paced DB was performed during one minute (six breaths/min) in 165 recordings in adult ATTRm amyloidosis patients with the TTR Val30Met mutation, 42 hypertrophic cardiomyopathy (HCM) patients and 211 healthy subjects. HRV was scored by traditional DB indices and by a novel regularity index, estimating the fraction of the HRV that was coherent with the breathing pattern.Results: Twenty per cent of ATTRm amyloidosis patients presented with age-adjusted HRV scores within normal limits but poor regularity due to subtle atrial arrhythmias and cardiac conduction disturbances. Forty-seven per cent of ATTRm amyloidosis patients presented with HRV scores below normal limits, whereas HCM patients presented with higher HRV than ATTRm amyloidosis patients.Conclusions: Reduced HRV is common in ATTRm amyloidosis patients during DB, however, autonomic function cannot be evaluated in patients presenting with the combination of normal scores and low regularity, since their HR responses often reflects dysrhythmias.

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