| 1. |
- Nord, Maria, et al.
(författare)
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Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
- 2017
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Ingår i: Advances in Parkinsons Disease. - : Scientific Research Publishing Inc. - 2169-9712 .- 2169-9720. ; 6:2, s. 52-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.
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| 2. |
- Nord, Maria, et al.
(författare)
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Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
- 2017
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Ingår i: Advances in Parkinsons Disease. - : Scientific Research Publishing. - 2169-9712 .- 2169-9720. ; 06:01
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Tidskriftsartikel (refereegranskat)abstract
- Levodopa uptake from the gastrointestinal tract in patients with Parkinson’s disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark® was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01). In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.
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| 3. |
- Nord, Maria
(författare)
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Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients.In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment.To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.
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| 4. |
- Israelsson, Johan, et al.
(författare)
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Health status and psychological distress among in-hospital cardiac arrest survivors in relation to gender
- 2017
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Ingår i: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 114, s. 27-33
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To describe health status and psychological distress among in-hospital cardiac arrest (IHCA) survivors in relation to gender.METHODS: This national register study consists of data from follow-up registration of IHCA survivors 3-6 months post cardiac arrest (CA) in Sweden. A questionnaire was sent to the survivors, including measurements of health status (EQ-5D-5L) and psychological distress (HADS).RESULTS: Between 2013 and 2015, 594 IHCA survivors were included in the study. The median values for EQ-5D-5L index and EQ VAS among survivors were 0.78 (q1-q3=0.67-0.86) and 70 (q1-q3=50-80) respectively. The values were significantly lower (p<0.001) in women compared to men. In addition, women reported more problems than men in all dimensions of EQ-5D-5L, except self-care. A majority of the respondents reported no problems with anxiety (85.4%) and/or symptoms of depression (87.0%). Women reported significantly more problems with anxiety (p<0.001) and symptoms of depression (p<0.001) compared to men. Gender was significantly associated with poorer health status and more psychological distress. No interaction effects for gender and age were found.CONCLUSIONS: Although the majority of survivors reported acceptable health status and no psychological distress, a substantial proportion reported severe problems. Women reported worse health status and more psychological distress compared to men. Therefore, a higher proportion of women may be in need of support. Health care professionals should make efforts to identify health problems among survivors and offer individualised support when needed.
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| 5. |
- Romlin, Birgitta S, et al.
(författare)
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Perioperative monitoring of platelet function in paediatric cardiac surgery by thromboelastometry, or platelet aggregometry?
- 2016
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Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 0007-0912 .- 1471-6771. ; 116:6, s. 822-828
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Tidskriftsartikel (refereegranskat)abstract
- Background Impaired platelet function increases the risk of bleeding complications in cardiac surgery. Reliable assessment of platelet function can improve treatment. We investigated whether thromboelastometry detects clinically significant preoperative, perioperative, and postoperative adenosine diphosphate (ADP)-dependent platelet dysfunction in paediatric cardiac surgery patients. Methods Fifty-seven children were included in a single-centre prospective observational study. Clot formation (modified rotational thromboelastometry with heparinase, HEPTEM) and platelet aggregation (multiple electrode aggregometry) were analysed at five time points before, during, and after surgery. The accuracy of thromboelastometric indices of platelet function [maximal clot firmness (MCF) and clot formation time (CFT)] to detect ADP-dependent platelet dysfunction (defined as ADP-induced aggregation ≤30 units) was calculated with receiver operating characteristics analysis, which also identified optimal cut-off levels. Positive and negative predictive values for the identified cut-off levels (CFT≥166 s; MCF≤43 mm) to detect platelet function were determined. Results The MCF and CFT were highly accurate in predicting platelet dysfunction during cardiopulmonary bypass [CPB; area under the aggregation curve 0.89 (95% confidence interval 0.80–0.97) and 0.86 (0.77–0.96), respectively] but not immediately after CPB [0.64 (0.48–0.79) and 0.67 (0.52–0.82), respectively] or on arrival at the intensive care unit [0.53 (0.37–0.69) and 0.60 (0.44–0.77), respectively]. The positive and negative predictive values were acceptable during CPB (87 and 67%, respectively, for MCF≤43 mm; 80 and 100% for CFT≥166 s) but markedly lower after surgery. Conclusion In paediatric cardiac surgery, thromboelastometry has acceptable ability to detect ADP-dependent platelet dysfunction during, but not after, CPB.
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| 6. |
- Singh, Sukhi, 1990, et al.
(författare)
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Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers
- 2019
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 119:5, s. 735-743
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Administration of agents that enhance platelet reactivity may reduce the perioperative bleeding risk in patients treated with the adenosine diphosphate (ADP)-receptor antagonist ticagrelor. Adrenaline potentiates ADP-induced aggregation and activation in blood samples from ticagrelor-treated patients, but it has not previously been evaluated in vivo.METHODS: Ten healthy male subjects were included in an interventional study. A loading dose of ticagrelor (180 mg) was administered, followed 2 hours later by a gradually increased intravenous adrenaline infusion (0.01, 0.05, 0.10 and 0.15 µg/kg/min; 15 minutes at each step). Blood pressure, heart rate, platelet aggregation (impedance aggregometry), platelet activation (flow cytometry), clot formation (rotational thromboelastometry) and adrenaline plasma concentration were determined before and after ticagrelor administration and at the end of each adrenaline step.RESULTS: = 0.007).CONCLUSION: Infusion of adrenaline at clinically relevant doses improves in vivo platelet reactivity and clot formation in ticagrelor-treated subjects. Adrenaline could thus potentially be used to prevent perioperative bleeding complications in ticagrelor-treated patients. Studies in patients are necessary to determine the clinical importance of our observations.TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT03441412.
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| 7. |
- Khoshnood, Ardavan
(författare)
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Prehospital Diagnosis and Oxygen Treatment in ST Elevation Myocardial Infarction
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionPaper I: An Artificial Neural Network (ANN) was constructed to identify ST Elevation Myocardial Infarction (STEMI) and predict the need for Percutaneous Coronary Intervention (PCI). Paper II, III and IV: Studies suggest that O2 therapy may be harmful in STEMI patients. We therefore conducted the SOCCER study to evaluate the effects of O2 therapy in STEMI patients.MethodsPaper I: 560 ambulance ECGs sent to the Cardiac Care Unit (CCU), was together with the CCU physicians interpretation and decision of conducting an acute PCI or not collected, and compared with the interpretation and PCI decision of the ANN. Paper II, III, IV: Normoxic (≥94%) STEMI patients accepted for acute PCI were in the ambulance randomized to standard care with 10 L/min O2 or room air. A subset of the patients underwent echocardiography for determination of the Left Ventricular Ejection Fraction (LVEF) and the Wall Motion Score Index (WMSI). All patients had a Cardiac Magnetic Resonance Imaging (CMRI) to evaluate Myocardial area at Risk (MaR), Infarct Size (IS) and Myocardial Salvage Index (MSI).ResultsPaper I: The area under the ANN’s receiver operating characteristics curve for STEMI detection as well as predicting the need of acute PCI were very good.Paper II, III, IV: No significant differences could be shown in discussing MaR, MSI or IS between the O2 group (n=46) and the air group (n=49). Neither could any differences be shown for LVEF and WMSI at the index visit as well after six months between the O2 group (n=46) and the air group (n=41)ConclusionsPaper I: The results indicate that the number of ECGs sent to the CCU could be reduced with 2/3 as the ANN would safely identify ECGs not being STEMI.Paper II, III, IV: The results suggest that it is safe to withhold O2 therapy in normoxic, stable STEMI patients.
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| 8. |
- Hultkvist, Henrik, 1968-
(författare)
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Implications of myocardial dysfunction before and after aortic valve intervention
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUNDPostoperative heart failure in the setting of aortic valve surgery results in poor long-term survival. We hypothesized that there could be a myocardial factor that is not addressed by risk scores currently available. We speculated that this myocardial factor could be diastolic dysfunction. By evaluating postoperative heart failure, the EuroSCORE, the NT-proBNP level, and diastolic function, we might achieve a deeper understanding of the outcome for individuals with postoperative heart failure.METHODSThis research project was built upon four cohort studies. The first two studies (I and II) were retrospective in nature, and studies III and IV were prospective, observational, and longitudinal. All work was based on data from clinical and national databases. In Study I, we compared the outcome of patients with or without postoperative heart failure, evaluated according to the preoperative risk score. In Study II, we explored the effect of underlying heart disease on the preoperative level of NT-proBNP and the relationships between NT-proBNP and severe postoperative heart failure and short-term mortality. In Study III, we described the dynamicsof NT-proBNP, from a preoperative evaluation to a six-month follow-up, in patients that underwent one of two different procedures: a surgical aortic valve replacement and a transcatheter implantation. We related both pre- and postprocedural NT-proBNP levels to one-year mortality. In Study IV, we evaluated diastolic function in patients that underwent surgical aortic valve replacement and its influence on outcome. We also evaluated NT-proBNP levels and postoperative heart failure as predictors of long-term mortality.RESULTSStudy IThis study included 397 patients that underwent isolated surgical aortic valve replacements. Of these, 45 patients (11%) were treated for postoperative heart failure. With an average follow-up of 8.1 years (range 5.2-11.2), among patients at low risk (EuroSCORE≤7), the crude five-year survival rates were 58% in patients with postoperative heart failure and 89% in those without postoperative heart failure (p<0.001). Among patients with postoperative heart failure, those classified as low risk had the same poor long-term prognosis as those classified as high risk (EuroSCORE>7). In the high risk group, survival rates were similar between patients with or without postoperative heart failure (57% vs. 64%; p=0.60).Study IIThis study included a cohort of 2978 patients with coronary artery disease, aortic stenosis, and mitral regurgitation. Preoperative NTproBNP levels were found to be 1.7-fold higher in patients with aortic stenosis than in patients with coronary artery disease and 1.4-fold higher in patients with mitral regurgitation than in patients with coronary disease. The power of preoperative NT-proBNP for predicting severe postoperative heart conditions was good among patients with coronary heart disease and patients with mitral regurgitation, but not as good among patients with aortic stenosis. NT-proBNP also showed good discriminating power for short-term mortality among patients with coronary artery disease. Moreover, NT-proBNP was found to be an independent predictor for both severe postoperative heart failure and short-term mortality in patients with coronary artery disease.Study IIIThis study included 462 patients that underwent preoperative evaluations for aortic valve disease. Aortic valve interventions elicited a rise in NT-proBNP that was more pronounced in patients undergoing surgical aortic valve replacement compared to patients undergoing transcatheter valve implantation. No deterioration in NT-proBNP was observed during the waiting time before the intervention, despite a median duration of four months. At six months after the intervention, NT-proBNP levels had decreased to or below the preoperative levels in all groups. Among patients that received surgical aortic valve replacements, pre-and early postoperative NT-proBNP levels showed good discriminatory power for oneyear mortality. This discriminatory power was not observed among patients that had undergone a transcatheter procedure; those patients had higher levels of both pre- and postoperative NT-proBNP compared to patients that had undergone surgery.Study IVWe evaluated 273 patients that underwent aortic valve surgery. High left ventricular filling pressure was present in 22% (n=54) of patients at the time of surgery. At six months after surgery, diastolic function deteriorated in 24/193 (12%) patients and improved in 27/54 (50%) patients. Diastolic dysfunction was not found to be associated with long-term mortality. However, both postoperative heart failure and preoperative NTproBNP levels were associated with increases in long-term mortality. In a multivariable Cox analysis, NT-proBNP remained predictive of long-term mortality.CONCLUSIONPostoperative heart failure contributed to long-term mortality, even in patients considered to be at low risk preoperatively. Our results suggested that pressure overload, followed by a volume overload led to a NTproBNP response that was more pronounced than the ischemia response. Elevated levels of NT-proBNP were associated with both short- and long-term mortality. In these studies, we could not corroborate the notion that high left ventricular filling pressure was associated with long-term mortality.
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| 9. |
- Jiang, Huiqi, 1981-
(författare)
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NT-proBNP as a marker of postoperative heart failure in adult cardiac surgery
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Postoperative heart failure (PHF) remains the major cause of mortality after cardiac surgery. Unfortunately, generally accepted diagnostic criteria for PHF are lacking. This may explain why the evidence for the efficacy and safety of current treatment of PHF with inotropes is insufficient. In cardiology practice N-terminal pro-B-type natriuretic peptide (NT-proBNP) is an established biomarker for heart failure. However, the association between NT-proBNP and PHF after cardiac surgery needs further clarification. Glutamate is a key intermediate in myocardial metabolism, which may improve myocardial tolerance to ischemia and facilitate post-ischemic recovery. Glutamate was associated with a reduced risk of developing severe PHF in high-risk patients undergoing coronary artery bypass surgery (CABG). The aim of this thesis was to study the role of NT-proBNP for prediction and assessment of PHF in cardiac surgery (Paper I-III) and the impact of intravenous glutamate infusion on postoperative NTproBNP after CABG (Paper IV).Paper I: We retrospectively studied the role of underlying heart disease for preoperative NT-proBNP in patients admitted for first time CABG (n=2226), aortic valve surgery (AVR) for aortic stenosis (AS) (n=406) and mitral valve surgery for mitral valve regurgitation (MR) (n=346) by adjusting for non-cardiac confounders (age, gender, obesity and renal function). The level of NT-proBNP in AS or MR was 1.67 (p<0.0001) and 1.41 times (p<0.0001) higher respectively than in coronary artery disease (CAD) after adjusting for confounders. Preoperative NT-proBNP was predictive of severe PHF in CAD and MR patients but less so in AS patients. Preoperative NT-proBNP emerged as an independent risk factor for severe PHF and postoperative mortality in CAD patients.Paper II-III: We prospectively studied the association between postoperative NT-proBNP and PHF in two cohorts, patients undergoing AVR for AS (n=203) and patients undergoing isolated CABG for acute coronary syndrome (ACS) from the GLUTAMICS-trial (n=382). NT-proBNP was measured preoperatively, on the first (POD1) and third postoperative morning (POD3). An end-points committee blinded to NT-proBNP used prespecified criteria to diagnose PHF and its severity. After AVR for AS only NT-proBNP level on POD1 provided good discrimination of PHF. PHF with NT-proBNP POD1 ≥ 5290 ng•L-1 emerged as an independent risk factor for long-term mortality (Paper II). After isolated CABG for ACS both absolute postoperative levels on POD1 and POD3 and postoperative increases of NT-proBNP were associated with PHF and the levels reflected the severity of PHF (Paper III).Paper IV: We prospectively studied the impact of intravenous glutamate infusion on postoperative NT-proBNP in a randomized double-blind study on patients undergoing CABG for ACS from the GLUTAMICS-trial (n=399). Patients were randomly allocated to intravenous infusion of L-glutamate (n=200) or saline (n=199). No effect of glutamate on postoperative NT-proBNP levels was detected in the whole cohort. According to post-hoc analysis glutamate was associated with less increase of NT-proBNP from preoperative level to POD3 and significantly lower absolute levels on POD3 among high risk patients with EuroSCORE II ≥4.15 (upper quartile).Conclusion: Patients with AS or MR have higher preoperative NT-proBNP than CAD patients after adjusting for confounders. The predictive value of NT-proBNP with regard to severe PHF and postoperative mortality was confirmed in CAD patients. Postoperative NTproBNP may prove a useful tool for assessment of PHF after AVR for AS and isolated CABG. NT-proBNP POD1 identifies patients with PHF at risk of a poor long-term survival after AVR for AS. Intravenous infusion of glutamate may prevent or mitigate PHF in highrisk patients undergoing CABG but these results need to be confirmed.
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| 10. |
- Peters, Lynn, et al.
(författare)
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Multiple antibiotic resistance as a risk factor for mortality and prolonged hospital stay: A cohort study among neonatal intensive care patients with hospital-acquired infections caused by gram-negative bacteria in Vietnam
- 2019
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Antibiotic resistance (ABR) is an increasing burden for global health. The prevalence of ABR in Southeast Asia is among the highest worldwide, especially in relation to hospital acquired infections (HAI) in intensive care units (ICU). However, little is known about morbidity and mortality attributable to ABR in neonates. Aim This study aimed to assess mortality and the length of hospitalization attributable to ABR in gram-negative bacteria (GNB) causing HAI in a Vietnamese neonatal ICU (NICU). Methods We conducted a prospective cohort study (n = 296) in a NICU in Hanoi, Vietnam, from March 2016 to October 2017. Patients isolated with HAI caused by GNB were included. The exposure was resistance to multiple antibiotic classes, the two outcomes were mortality and length of hospital stay (LOS). Data were analysed using two regression models, controlling for confounders and effect modifiers such as co-morbidities, time at risk, severity of illness, sex, age, and birthweight. Results The overall case fatality rate was 44.3% and the 30 days mortality rate after infection was 31.8%. For every additional resistance to an antibiotic class, the odds of a fatal outcome increased by 27% and LOS increased by 2.1 days. These results were statistically significant (p amp;lt; 0.05). Conclusion ABR was identified as a significant risk factor for adverse outcomes in neonates with HAI. These findings are generally in line with previous research in children and adults. However, heterogeneous study designs, the neglect of important confounders and varying definitions of ABR impair the validity, reliability, and comparability of results.
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