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| 2. |
- Dogan, Emanuel M., 1984-, et al.
(author)
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Intra-aortic and Intra-caval Balloon Pump Devices in Experimental Non-traumatic Cardiac Arrest and Cardiopulmonary Resuscitation
- 2023
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In: Journal of Cardiovascular Translational Research. - : Springer-Verlag New York. - 1937-5387 .- 1937-5395. ; 16:4, s. 948-955
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Journal article (peer-reviewed)abstract
- Intra-aortic balloon pump (IABP) use during CPR has been scarcely studied. Intra-caval balloon pump (ICBP) may decrease backward venous flow during CPR. Mechanical chest compressions (MCC) were initiated after 10 min of cardiac arrest in anesthetized pigs. After 5 min of MCC, IABP (n = 6) or ICBP (n = 6) was initiated. The MCC device and the IABP/ICBP had slightly different frequencies, inducing a progressive peak pressure phase shift. IABP inflation 0.15 s before MCC significantly increased mean arterial pressure (MAP) and carotid blood flow (CBF) compared to inflation 0.10 s after MCC and to MCC only. Coronary perfusion pressure significantly increased with IABP inflation 0.25 s before MCC compared to inflation at MCC. ICBP inflation before MCC significantly increased MAP and CBF compared to inflation after MCC but not compared to MCC only. This shows the potential of IABP in CPR when optimally synchronized with MCC. The effect of timing of intra-aortic balloon pump (IABP) inflation during mechanical chest compressions (MCC) on hemodynamics. Data from12 anesthetized pigs.
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| 3. |
- Dogan, Emanuel M., 1984-, et al.
(author)
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Resuscitative endovascular balloon occlusion of the aorta in zone I versus zone III in a porcine model of non-traumatic cardiac arrest and cardiopulmonary resuscitation : A randomized study
- 2020
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In: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 151, s. 150-156
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) in zone I increases systemic blood pressure during cardiopulmonary resuscitation (CPR), while also obstructing the blood flow to distal organs. The aim of the study was to compare the effects on systemic blood pressure and visceral blood flow of REBOA-III (zone III, infrarenal) and REBOA-I (zone I, supraceliac) during non-traumatic cardiac arrest and CPR.METHODS: Cardiac arrest was induced in 61 anesthetized pigs. Thirty-two pigs were allocated to a hemodynamic study group where the primary outcomes were systemic arterial pressures and 29 pigs were allocated to a blood flow study group where the primary outcomes were superior mesenteric arterial (SMA) and internal carotid arterial (ICA) blood flow. After 7-8minutes of CPR with a mechanical compression device, REBOA-I, REBOA-III or no aortic occlusion (control group) were initiated after randomization.RESULTS: Systemic mean and diastolic arterial pressures were statistically higher during CPR with REBOA-I compared to REBOA-III (50mmHg and 16mmHg in REBOA-I vs 38mmHg and 1mmHg in REBOA-III). Systemic systolic, mean and diastolic arterial pressures were statistically elevated during CPR in the REBOA-I group compared to the controls. The SMA blood flow increased by 49% in REBOA-III but dropped to the levels of the controls within minutes. The ICA blood flow increased the most in REBOA-I compared to REBOA-III and the control group (54%, 19% and 0%, respectively).CONCLUSION: In experimental non-traumatic cardiac arrest and CPR, REBOA-I increased systemic blood pressures more than REBOA-III, and the potential enhancement of visceral organ blood flow by REBOA-III was short-lived.
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| 4. |
- Edström, Måns, 1984-
(author)
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Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsing-remitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4+ T cells have been shown to be of importance in disease pathology. A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS.The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4+ T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4+ T cells in vitro.We showed an imbalance in the mRNA expression of CD4+ T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated GATA3 and FOXP3 expression was decreased in RR-MS. Given the reciprocally inhibitory nature of TH subsets, this might imply not only diminished function of TH2 and TREG cells but also a permissive state of harmful TH1 and TH17 cells. The size of the peripheral TREG population was unaltered in RR-MS. When analysed in detail, activated and resting TREG were distinguished, showing clear differences in FOXP3 and CD39 expression. Furthermore, when investigating these subpopulations functionally, the ability of activated TREG to suppress proliferation of responder T cells was found to be decreased in RR-MS patients compared to controls. To further investigate this defect, the global gene expression of TREG was compared between patients and controls. Gene set enrichment analysis revealed an enrichment (over-expression) of chemokine receptor signalling genes in RR-MS TREG, possibly suggesting a role for chemokines in TREG function.A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. Furthermore, T cells from patients with MS displayed decreased responsiveness towards antigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells.The importance of CD4+ T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4+ T cell differentiation were enriched for many, not only immunerelated, diseases. Furthermore, global CD4+ T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4+ T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding.In conclusion, our results demonstrate an imbalance of peripheral CD4+ T cells in MS, along with a functional deficiency in the case of TREG. Taken together, these aberrations might result in differentiation and activation of harmful TH1 and TH17 cells, resulting in CNS tissue damage. The importance of CD4+ T cells was further demonstrated by the finding that genes associated with CD4+ T cell differentiation constitute a pleiotropic module common to a number of diseases. Investigation of natalizumab revealed drastic changes in the peripheral lymphocyte compartment caused by treatment. It also appears as treatment might influence the responsiveness of peripheral T cells to antigens. In addition, by using CD4+ T cell transcriptomics after in vitro drug exposure, prediction of treatment outcome may be possible.
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| 5. |
- Edström, Måns, PhD, 1984-, et al.
(author)
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Transcriptional characteristics of CD4+ T cells in multiple sclerosis: Relative lack of suppressive populations in blood
- 2011
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 17:1, s. 57-66
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Journal article (peer-reviewed)abstract
- Background: Multiple sclerosis (MS) is hypothetically caused by autoreactive Th1 and Th17 cells, whereas Th2 and regulatory T cells may confer protection. The development of Th subpopulations is dependant on the expression of lineage-specific transcription factors.Objective: The aim of this study was to assess the balance of CD4(+)T cell populations in relapsing-remitting MS.Methods: Blood mRNA expression of TBX21, GATA3, RORC, FOXP3 and EBI3 was assessed in 33 patients with relapsing-remitting MS and 20 healthy controls. In addition, flow cytometry was performed to assess T lymphocyte numbers.Results: In relapsing-remitting MS, diminished expression of FOXP3 (Treg) was found (p < 0.05), despite normal numbers of CD4(+)CD25(hi)Treg. Immunoregulatory EBI3 and Th2-associated GATA3 ([a-z]+) was also decreased in MS (p < 0.005 and p < 0.05, respectively). Expression of TBX21 (Th1) and RORC (Th17) did not differ between patients and controls. Similar changes were observed when analysing beta-interferon treated (n = 12) or untreated (n = 21) patients. Analysis of transcription factor ratios, comparing TBX21/GATA3 and RORC/FOXP3, revealed an increase in the RORC/FOXP3 ratio in patients with relapsing-remitting MS (p < 0.005).Conclusion: Our findings indicate systemic defects at the mRNA level, involving downregulation of beneficial CD4(+)phenotypes. This might play a role in disease development by permitting activation of harmful T cell populations.
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| 6. |
- Mellergård, Johan, et al.
(author)
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Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid
- 2010
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 16:2, s. 208-217
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Journal article (peer-reviewed)abstract
- Natalizumab exerts impressive therapeutic effects in patients with multiple sclerosis (MS). The proposed main mode of action is reducing transmigration of leukocytes into the CNS, but other immunological effects may also be operative. Cytokines and chemokines are involved in the regulation of inflammatory responses and may reflect the disease process in MS. The objective of this study was to evaluate the effects of natalizumab treatment on cytokine and chemokine profiles systemically and intrathecally in multiple sclerosis. We used luminex to analyse a panel of cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α, IFN-γ, GM-CSF) and chemokines (CXCL9, CXCL10, CXCL11, CCL17, CCL22) in blood and cerebrospinal fluid (CSF) from 31 patients with relapsing MS before and after one year of natalizumab treatment. There was a marked decline in CSF levels of cytokines and chemokines, thus including pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) as well as chemokines associated with both Th1 (CXCL9, CXCL10, CXCL11) and Th2 (CCL22). Circulating plasma levels of some cytokines (GM-CSF, TNF-α, IL-6 and IL-10) also decreased after one year of treatment. This is the first study to show that natalizumab treatment is associated with a global decline in cytokine and chemokine levels at a protein level. This finding was most pronounced in CSF, in line with the reduced transmigration of cells into CNS, whereas reduction in plasma levels indicates other possible mechanisms of natalizumab treatment.
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| 7. |
- Seilitz, Jenny, 1978-, et al.
(author)
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Early Onset of Postoperative Gastrointestinal Dysfunction Is Associated With Unfavorable Outcome in Cardiac Surgery : A Prospective Observational Study
- 2021
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In: Journal of Intensive Care Medicine. - : Sage Publications. - 0885-0666 .- 1525-1489. ; 36:11, s. 1264-1271
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The distribution of postoperative gastrointestinal (GI) dysfunction and its association with outcome were investigated in cardiac surgery patients. Gastrointestinal function was evaluated using the Acute Gastrointestinal Injury (AGI) grade proposed by the European Society of Intensive Care Medicine.DESIGN: Prospective observational study at a single center.SETTING: University hospital.PATIENTS: Consecutive patients presenting for elective cardiac surgery with extracorporeal circulation (ECC).INTERVENTIONS: None.RESULTS: Daily assessment using the AGI grade was performed on the first 3 postoperative days in addition to standard care. For analysis, 3 groups were formed based on the maximum AGI grade: AGI 0, AGI 1, and AGI ≥2. Five hundred and one patients completed the study; 32.7%, 65.1%, and 2.2% of the patients scored a maximum AGI 0, AGI 1, and AGI ≥2, respectively. Patients with AGI grade ≥2 had more frequently undergone thoracic aortic surgery and had longer surgery duration and time on ECC. Patients with AGI grade ≥2 had statistically significant higher frequency of GI complications within 30 days (63.6% vs 1.2% and 5.5% in patients with AGI 0 and AGI 1) and higher 30-day mortality (9.1% vs 0.0% and 1.8% in patients with AGI 0 and AGI 1).CONCLUSIONS: Early GI dysfunction following cardiac surgery was associated with an unfavorable outcome. Increased attention to GI dysfunction in cardiac surgery patients is warranted and the AGI grade could be a helpful adjunct to a structured approach.
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| 8. |
- Seilitz, Jenny, 1978-, et al.
(author)
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Intestinal fatty acid-binding protein and acute gastrointestinal injury grade in postoperative cardiac surgery patients
- 2021
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In: Journal of cardiac surgery. - : Wiley-Blackwell Publishing Inc.. - 0886-0440 .- 1540-8191. ; 36:6, s. 1850-1857
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIM: Gastrointestinal complications post cardiac surgery are infrequent but difficult to diagnose and carry a high mortality. Plasma intestinal fatty acid-binding protein (I-FABP) concentrations and the relationship between I-FABP, gastrointestinal dysfunction, and postoperative outcomes were investigated in patients who developed gastrointestinal dysfunction (acute gastrointestinal injury [AGI] grade ≥2) and those with normal gastrointestinal function.METHODS: Patients with (AGI 2 group, n = 11) and without (matched controls, AGI 0 group, n = 22) early postoperative gastrointestinal dysfunction were extracted from a larger single-center prospective observational study, including adults undergoing elective cardiac surgery with extracorporeal circulation, and investigated in this nested case-control analysis.RESULTS: Both groups displayed variations in I-FABP concentrations with higher I-FABP on postoperative Day 1 compared to baseline and postoperative Days 2 and 3 (p < .001 and p = .005, respectively). The AGI 2 group had higher I-FABP concentrations on Day 2 compared to the AGI 0 group (p = .024). I-FABP on Day 2 correlated positively with AGI grade over the first 3 days (p = .036, p = .021 and p = .018, respectively). High I-FABP (defined as fourth quartile concentrations) on Day 1 was associated with more prolonged surgical procedures (p < .05). Furthermore, fourth quartile I-FABP on Day 1 and early gastrointestinal dysfunction were associated with higher frequencies of postoperative organ dysfunction (p < .05) and gastrointestinal complications (p < .05), and higher 365-day mortality.CONCLUSION: The present study indicates an association between intraoperative gastrointestinal injury, postoperative gastrointestinal dysfunction and gastrointestinal complications. A high-powered study is needed to further explore this relationship and the interpretation of I-FABP concentrations in individual cardiac surgery patients.
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| 9. |
- Seilitz, Jenny, 1978-
(author)
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The gastrointestinal tract in cardiac anaesthesia and intensive care : Clinical and experimental studies
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Gastrointestinal (GI) complications after cardiac surgery have a substantial impact on outcome. The aims were to investigate the frequency of, and methods for detecting, GI dysfunction after cardiac surgery and its relation to outcome, and the impact of vasoactive drugs on the GI tract in experimental cardiogenic shock. Paper I investigated the intraabdominal metabolism, using intraperitoneal microdialysis, during and after routine cardiac surgery in six patients. The results imply that, even during a normal perioperative course, the GI tract may be subjected to a subclinical anaerobic state. In Paper II the impact of stepwise reductions of cardiac output (CO) on the metabolism and circulation in the GI tract was studied in anaesthetised pigs using cardiac tamponade (n=6) or partial inflation of a caval vein balloon (n=6). The two models had similar haemodynamic effects and the intraabdominal metabolism became increasingly anaerobic when the CO was reduced by 50%. In Paper III the caval vein balloon model was utilised to examine the GI effects of two inodilators (levosimendan and milrinone) and two vasoconstrictors (vasopressin and norepinephrine) at 40% CO reduction (n=7/group). Negligible splanchnic vasodilation by the inodilators in fixed low CO, and possible GI specific side effects of high dose vasopressors, were demonstrated. Paper IV included 501 cardiac surgery patients assessed using the Acute Gastrointestinal Injury (AGI) grade. Only 32.7% were asymptomatic during the first three postoperative days. At least GI dysfunction, i.e. AGI grade ≥2, developed in 2.2% and was associated with more complex surgeries and higher postoperative frequencies of GI complications and mortality. In Paper V a biomarker for enterocyte damage, intestinal fatty acid-binding protein (IFABP), was investigated in relation to AGI grade. The group with AGI ≥2 (n=11) was compared to a matched group without GI symptoms (n=22). An I-FABP concentration in the fourth quartile on day one was associated with higher frequencies of organ dysfunction and 365-day mortality. In conclusion, this thesis provides evidence for an association between intraoperative GI injury, postoperative GI dysfunction and manifest complications, and that the effects of inodilators and vasoconstrictors must be considered.
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