| 1. |
- Parenmark, Fredric, 1974-
(författare)
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Premature Discharge from Intensive Care with Special Reference to Night-Time Discharge and Capacity Transfers
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objectives Intensive care is an expensive and limited resource, and when a demand supply mismatch between available beds and influx of patients occurs, one temporary measure is to discharge a patient to make room for the new admission. Sometimes the patient is discharged sooner from its original ICU than ideal; i.e., a so-called ‘premature discharge’. This could be either to a different ward within the same hospital if the patient is deemed well enough to cope with a lower level of care, or to another intensive care unit if critical care is still to be provided. Data from the Swedish intensive care register (SIR) showed that there was a high incidence and increased mortality of patients discharged at night. There were also differences in mortalities between patients that were transferred from one ICU to another. I have analysed the mortality associated with different types of ICU-to-ICU transfers and control groups and examined a national quality improvement project regarding discharges at night to see if mortality, incidence, or discharge culture could change. Methods All three studies are conducted with data from the Swedish intensive care register and vital status was ascertained by linking SIR to the Swedish population register. Study I consisted of two parts: mortality, and incidence of night-time discharge. The quality improvement project in Study I was analysed in a before and after approach with local improvement projects at different ICUs. In Studies II and III, transfers were grouped by the attending intensivist according to SIR guidelines into one of three defined categories: capacity transfer, clinical transfer, or repatriation. The groups were compared to each other in Study II, and capacity transfers were matched to a control group that remained in the ICU in Study III. Multilevel logistic regression was used, and all studies contained some statistics using individual ICUs as a random factor. Life sustaining treatment limitations were included in Studies II and III. Results In Study I, there was a decrease in night-time discharges during the study period. The incidence fell from 7.0% in 2006 to 4.9% in 2015. Alongside this, the mortality associated with night-time discharge was reduced, the odds ratio fell from 1.20 to 1.06 with a loss of significance. All this coincided in time with the national improvement project. Study II showed that 14.8% of all discharges from a Swedish ICU ended with transfer to another ICU, and that an increased mortality rate was associated with ICU-to-ICU transfers during periods of demand–supply mismatch. Capacity transfers were 15.8% of all transfers accounting for roughly 2.0% of ICU survivors. One in four capacity transferred patient died within 30 days of discharge, compared to one in seven for transfers due to clinical reasons. The third study showed that capacity transfer was associated with an average risk increase in 30-day mortality of 4.7%, and a 180-day mortality of 4.9% compared to non-transferred patients when analysed using a potential outcomes framework. Conclusion The studies concludes that patients experiencing a capacity transfer are exposed to increased mortality risk, both when compared to other types of inter hospital ICU-to-ICU transfers as well as when compared to patients that were not transferred. The increased risk appeared to be unrelated to patient characteristics and illness severity as well as many additional factors measured in the referring ICU. The studies also suggest that a suboptimal outcome after premature discharge at night can be changed and that a national project to adjust outcome and incidence can be undertaken with positive results.
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| 2. |
- Wickström, Anne, 1961-
(författare)
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Work ability in multiple sclerosis : the impact of immunomodulating treatments and adjusted working conditions
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease affecting the central nervous system (CNS) and is considered to be of autoimmune origin. The prevalence in Sweden is estimated to be about 1 in 500. The inflammation leads to demyelination as well as neurodegeneration and with time the patients often suffer from increasing neurological disability. The young age of onset makes MS one of the major causes of reduced ability to work in the Western society. Several factors in the disease affect the work ability. One important factor is ongoing inflammatory activity conferring risk to develop tissue damage and disability. Previous studies have indicated that fatigue, mobility and cognitive problems are the primary symptoms preventing individuals with MS to remain in employment. However, the possibility to adapt both tasks and the workplace, the possibility for sedentary work and flexible working hours also have great influence to keep the individual in employment.The purpose of the thesis was to investigate how factors in the disease, immunomodulating treatments and work requirements influence the ability to work and study in people with MS.Methods: A MS specific questionnaire was used in one retrospective and one prospective study to compare the work ability before and after start of the second-generation immunomodulating drug natalizumab. The number of working hours per week and the degree of sick leave before and after one year of treatment was calculated. The effect of disease-specific and workrelated factors on work ability was evaluated. The treatment effect on fatigue and walking ability was correlated to work ability. In addition, a healtheconomic calculation was performed to estimate the cost-benefit of the treatment. The degree of sickness absence was evaluated in a cross-sectional study of two MS-populations; one historical that never was exposed to immunomodulating drugs and the other consisted of individuals with MS that was diagnosed after the introduction of immunomodulating drugs. Furthermore, work ability was studied in two MS-populations, one southern and one northern cohort of Sweden, for the latter population more active immunomodulating treatment and work-promoting measures have been practiced. The data was collected using the instrument WAQ-MS. Results Paper I: After one year of treatment with natalizumab the average working hours per week had increased with 3.3 hours, corresponding to an economic value of 3216 euro per person per year. Paper II and III: After initiation of treatment with natalizumab, in an active phase of relapsing-remitting MS, the patients improved their working ability after one year from 31 % to 60 % (p<0.001) and reduced their sickness benefit correspondingly (p<0.001) in relation to their total employment rate. They also reported improved physical and cognitive ability in relation to their requirements. Short disease duration, younger age and lower Expanded Disability Status Scale (EDSS) grade at treatment onset predicted a positive effect on work ability and also improvement of walking ability correlated significantly with reduced sick leave. Paper IV: The proportion of individuals without any kind of sickness absence was higher in the MS population being exposed to disease modifying drugs compared to the unexposed population (66 % vs 38 %) (p<0.001). In addition, the proportion of patients with full-time sickness absence was higher in the unexposed compared to the exposed population (32 % vs 16 %) (p<0.001). The median EDSS was lower in the exposed compared to the unexposed MS population (p<0.001). Paper V: The proportion of MS patients who participated in the work force or studied was significantly higher in the northern cohort, where they had been exposed to more work promoting measures, compared with the southern cohort (p=0.022). MS patients in the northern cohort had significantly lower physical and cognitive requirements in their occupations, more adapted work conditions and could work more hours per week compared with the southern cohort. The EDSS level explained 12 % of the working ability in the northern cohort and 21 % in the southern cohort.Conclusion Our results indicate that patients in the inflammatory phase of the disease may retain their work ability several years after disease onset if they are subjected to effective anti-inflammatory treatment regimens from disease onset. Furthermore, work ability may be additionally improved by adjusted working conditions even in the progressive phase of the disease. It is obvious that these results have implications in a socioeconomic perspective as well as for the individual patients as improved quality of life due to retained work-life participation. Long-term follow-up of our data is required to determine whether these positive effects are durable over longer time-periods.
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| 3. |
- de Flon, Pierre, 1966-
(författare)
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Treatment with the monoclonal antibody rituximab in Multiple Sclerosis : a study based on an academic clinical trial
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple sclerosis (MS) is a chronic, inflammatory disease, affecting the central nervous system. A growing number of disease modifying treatment alternatives entails a need for an individualised risk-benefit- convenience analysis in the counselling of patients and methods to monitor the treatment effect, including markers for subclinical inflammation. Today, MRI and the biomarker neurofilament light chain (NFL) in cerebrospinal fluid (CSF- NFL) are commonly used. The development of new techniques for analysing NFL in very low concentrations in serum or plasma provides a promising opportunity for a less invasive method. Rituximab is a chimeric monoclonal antibody with B- cell depleting properties vastly used in rheumatological disease and certain haematological malignancies. Phase II studies have shown a beneficial effect on inflammation also in MS, the detailed mechanisms of action yet to be explained.Aims: The aims of this thesis were to evaluate rituximab as a treatment alternative in relapsing remitting MS (RRMS) by describing the clinical effect and patient related outcome measures after a switch of therapy from first-line injectables to rituximab and to explore possible immunological mechanisms of B cell depletion as well as to evaluate the use of neurofilament in plasma (p-NFL) as an end-point in a clinical trial setting.Methods: The thesis is based on the open-label phase II multicentre clinical trial Switch-To-RItuXimab in MS (STRIX-MS; EudraCT 2010-023021-38), in which 75 patients completed a therapy switch from first-line injectables to rituximab, and, to some part, the extended follow-up study, STRIX-MS extension (EudraCT 2013-002378-26). The disease modifying effect was evaluated by regular clinical evaluations, MRI and analyses of CSF-NFL. The clinical outcome was evaluated by the EDSS and SDMT scales. The questionnaires MSIS-29, FSMC and TSQM were used for the evaluation of patient related outcome measures. Immunological mechanisms of the B cell depletion were explored by the analysis of a broad panel of cyto- and chemokines in CSF by an electrochemiluminiscens method before and after therapy switch, and in comparison to healthy controls. The concentration of p-NFL was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit and explored for the use as a clinical trial end-point.Results: During the follow-up, signs of inflammatory activity decreased. Both the mean number of Gd enhancing lesions (0.03 vs 0.36, p=0.029) and the number of new or enlarged T2 lesions were reduced (0.01 vs 0.28, p=0.01). The mean concentration of CSF-NFL was reduced during the first year (491 vs 387, p=0.01). The corresponding reduction in plasma did not reach the level of statistical significance. The rating of overall treatment satisfaction improved significantly (6.3 vs 4.8, scale range 1-7, p<0.001). In the explorative immunological study, the immunological profile was altered after therapy switch with the most prominent reduction observed in the concentrations of IP-10 and IL-12/23p40.Conclusions: The results indicate a disease modifying effect of rituximab in line with other studies and provide support for a superior treatment satisfaction with rituximab as compared with injectable therapies. However, the lack of control group hampers the possibility to draw definite conclusions on the therapy effect. The immunological effects of B cell depletion need to be further explored.
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| 4. |
- Mellergård, Johan
(författare)
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Immunological Mechanisms and Natalizumab Treatment in Multiple Sclerosis : Studies on lymphocytes, inflammatory markers and magnetic resonance spectroscopy
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS), and a frequent cause of neurological disability among young adults. In addition to focal inflammatory demyelinated lesions, diffuse white matter pathology as well as a neurodegenerative component with accumulating axonal damage and gliosis have been demonstrated and contribute to MS disease characteristics. The inflammatory component is considered autoimmune and mediated by auto-reactive T lymphocytes together with other cell populations of the immune system and their respective products like cytokines and chemokines. Treatment with natalizumab, a monoclonal antibody directed against the α4β1-integrin (VLA-4), reduces migration of potential disease-promoting cells to the CNS. The efficacy of natalizumab in reducing relapses and MRI activity is evident, however associated effects on the immune response and the neurodegenerative component in MS are not clear.Methods: In total 72 MS patients were included, distributed among paper I-IV. We investigated effects associated with one-year natalizumab treatment in 31 MS patients regarding cytokine and chemokine levels in CSF and blood using multiplex bead assay analyses (paper I), as well as treatment effects on blood lymphocyte composition in 40 patients using flow cytometry, including functional assays of lymphocyte activation (paper II). Normal appearing white matter (NAWM) metabolite concentrations were assessed with proton magnetic resonance spectroscopy (1H-MRS) in 27 MS patients before and after one year of treatment (paper III). We also evaluated the balance between circulating T helper (Th) subsets in 33 MS patients using gene expression analyses of the CD4+ T cell related transcription factors in whole blood (paper IV).Results: One-year natalizumab treatment was associated with a marked decline in pro-inflammatory cytokines (IL-1β and IL-6) and chemokines (CXCL8, CXCL9, CXCL10 and CXCL11) intrathecally. Circulating plasma levels of some cytokines (GM-CSF, TNF, IL-6 and IL-10) also decreased after treatment. Natalizumab treatment was further associated with an increase in lymphocyte numbers of major populations in blood (total lymphocytes, T cells, T helper cells, cytotoxic T cells, NK cells and B cells). In addition, T cell responsiveness to recall antigens and mitogens was restored after treatment. As to 1H-MRS metabolite concentrations in NAWM, no change in levels were detected post-to pretreatment on a group level. However, correlation analyses between one-year change in metabolite levels (total creatine and total choline) and levels of pro-inflammatory IL-1β and CXCL8 showed a pattern of high magnitude correlation coefficients (r=0.43-0.67). Gene expression analyses demonstrated a systemically reduced expression of transcription factors related to immunoregulatory T cell populations (regulatory T cells and Th2) in relapsing MS compared with controls.Conclusions: Our findings support that an important mode of action of natalizumab is reducing lymphocyte extravasation, although cell-signalling effects through VLA-4 also may be operative. Correlation analyses between changes 1H-MRS metabolite concentrations and inflammatory markers possibly point towards an association between intrathecal inflammation and gliosis development in NAWM. Finally, gene expression analyses indicate a systemic defect at the mRNA level in relapsing MS, involving downregulation of beneficial CD4+ phenotypes.
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| 5. |
- Wilhelms, Susanne, 1985-
(författare)
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The epidemiology of severe sepsis in Sweden : Methodological aspects on the use of ICD coding in national registries
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Severe sepsis is characterized by acute organ dysfunction caused by an infection. Despite advanced treatment with antibiotics and organ support the mortality remains high. The epidemiological research on severe sepsis has expanded over the years but has led to conflicting results. In this thesis, we present evidence that some of these conflicting results may be explained by inappropriate methods used in epidemiological studies on severe sepsis. The definition of severe sepsis relies on consensus criteria including a number of clinical signs, parameters and laboratory findings. To facilitate large nation-wide studies on the incidence of severe sepsis in already existing administrative datasets, several investigators have attempted to mirror the clinical criteria by using combinations of the International Classification of Diseases (ICD) codes for infection and organ dysfunction. In paper I of this thesis, however, we found that three different ICD code abstraction strategies applied on the same dataset (the Swedish National Patient Register) generated three almost separate cohorts of patients. Furthermore, in paper II, where we followed intensive care unit (ICU)-treated patients with severe sepsis according to clinical consensus criteria to discharge, we observed that most patients did not meet any ICD code abstraction strategies for severe sepsis when reviewing their ICD codes registered at discharge from the hospital. In conclusion, the ICD code abstraction strategies previously used in the epidemiological research on sepsis seem to be inaccurate in the Swedish setting. Sepsis may also result in poor long-term outcomes, and contribute to an increased risk of late mortality. However, the actual causes of late mortality in sepsis remain unclear. In paper III, we investigated causes of death over 1 year after treatment of sepsis in the ICU. In this study, a matched control group consisting of ICU-treated patients without sepsis was included. The most common causes of late mortality in both the sepsis group and the control group were heart diseases and cancer. The sepsis group, however, had a significantly increased incidence of infectious-related deaths compared with the control group, even over 1 year after the initial ICU event.
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| 6. |
- Engerström, Lars
(författare)
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The significance of risk adjustment for the assessment of results in intensive care. : An analysis of risk adjustment models used in Swedish intensive care.
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To study the development of mortality in intensive care over time or compare different departments, you need some kind of risk adjustment to make analysis meaningful since patient survival varies with severity of the disease. With the aid of a risk adjustment model, expected mortality can be calculated. The actual mortality rate observed can then be compared to the expected mortality rate, giving a risk-adjusted mortality.In-hospital mortality is commonly used when calculating riskadjusted mortality following intensive care, but in-hospital mortality is affected by the duration of care and transfer between units. Time-fixed measurements such as 30-day mortality are less affected by this and are a more objective measure, but the intensive care models that are available are not adapted for this measure. Furthermore, how length of follow-up affects risk adjusted mortality has not been studied. The degree and pattern of loss of physiological data that exists and how this affects performance of the model has not been properly studied. General intensive care models perform poorly for cardiothoracic intensive care where admission is often planned, where cardiovascular physiology is more affected by extra corporeal circulation and where the reasons for admission are usually not the same.The model used in Sweden for adult general intensive care patients is the Simplified Acute Physiology Score 3 (SAPS3). SAPS3 recalibrations were made for in-hospital mortality and 30-, 90- and 180-day mortality. Missing data were simulated, and the resulting performance compared to performance in datasets with originally missing data.We conclude that SAPS3 works equally well using 30-day mortality as in-hospital mortality.The performance with both 90- and 180-day mortality as outcome was also good. It was found that the model was stable when validated in other patients than it was recalibrated with.We conclude that the amount of data missing in the SIR has a limited effect on model performance, probably because of active data selection based on the patient's status and reason for admission.A model for cardiothoracic intensive care based on variables available on arrival at Swedish cardiothoracic intensive care units was developed and found to perform well.
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| 7. |
- Larsen, Robert, 1980-
(författare)
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Risk-Adjustment for Swedish In-Hospital Trauma Mortality using International Classification of disease Injury Severity Score (ICISS) : issues with description and methods
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionDifferent methods have been used to describe the epidemiology of trauma with varying results. Crude mortality outcome data differ significantly from risk-adjusted information. A previous standard method for risk-adjustment in trauma was the Injury Severity Score (ISS), although it has several shortcomings. In this thesis I examine Swedish injury statistics from an epidemiological perspective using crude and risk-adjusted mortality, and to adjust for injury I used the International Classification of disease Injury Severity Score (ICISS). The groups of most lethal injuries (fall, traffic, and assault) were examined separately using an ICISS mortality prediction model that focused particularly on the effects on the prediction of mortality by adding coexisting conditions (comorbidity) to it. Differences in mortality between the sexes and changes over time were tested separately.Material and MethodsData from all patients with ICD-10 based diagnoses of injury (ICD-10: V01 to Y36) in the Swedish National Patient Registry and Cause of Death Registry were collected from 1999 to 2012 and used for assessment of mortality and comorbidity. A subgroup (patients in hospital) from 2001-2011 were selected as the study group. Their injuries were in the subgroups of falls, traffic, and assaults, and are the focus of this thesis. Mortality within 30 days of injury was used as the endpoint. The severity of injury was adjusted for using the ICISS, which was first described by Osler et al. The model was also adjusted for age, sex, and comorbidities.ResultsThe study group comprised 815 846 patients (of whom 17 721 died). There was a decrease over time in injuries caused by falls and traffic (coefficient -4.71, p=0.047 and coefficient -5.37, p<0.001), whereas there was no change in assault-related injuries/100 000 inhabitants. The risk-adjusted 30-day mortality showed a decrease in injuries related to traffic and assault (OR 0.95, p<0.001 and OR 0.93, p=0.022) whereas for falls it remained unchanged. There was also a risk-adjusted survival benefit for women, which increased with increasing age. Adjusting for comorbidities made the prediction of 30-day mortality by the ICISS model better (accuracy, calibration, and discrimination). However, most of this effect was found to be the result of the other characteristics of the fall related injury group (they were older, and had more coexisting conditions).ConclusionDuring a 10-year period, there has been a significant overall decrease in crude as well as risk-adjusted mortality for these three injury groups combined. Within these groups there is a clear, risk-adjusted, female survival advantage. The ICISS model for the prediction of mortality improves when comorbidities are added, but this effect is minor and seen mainly among the injuries caused by falls, where comorbidity is significant. The ICISS method was a valuable adjunct in the investigation of data on Swedish mortality after injury that has been gathered from health care registry data.
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