| 1. |
- Basu, Samar, et al.
(författare)
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Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock
- 2000
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Ingår i: Expert Opinion on Investigational Drugs. - : Informa Healthcare. - 1354-3784 .- 1744-7658. ; 9:5, s. 1129-1137
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.
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| 2. |
- Basu, Samar, et al.
(författare)
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Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock
- 2001
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Ingår i: Resuscitation. - 0300-9572 .- 1873-1570. ; 50:3, s. 341-348
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia.METHODS: Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed.RESULTS: Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group.CONCLUSIONS: Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).
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| 3. |
- Chew, Michelle, et al.
(författare)
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National outcomes and characteristics of patients admitted to Swedish intensive care units for COVID-19 A registry-based cohort study
- 2021
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Ingår i: European Journal of Anaesthesiology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0265-0215 .- 1365-2346. ; 38:4, s. 335-343
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Mortality among patients admitted to intensive care units (ICUs) with COVID-19 is unclear due to variable follow-up periods. Few nationwide data are available to compare risk factors, treatment and outcomes of COVID-19 patients after ICU admission. OBJECTIVE To evaluate baseline characteristics, treatments and 30-day outcomes of patients admitted to Swedish ICUs with COVID-19. DESIGN Registry-based cohort study with prospective data collection. SETTING Admissions to Swedish ICUs from 6 March to 6 May 2020 with laboratory confirmed COVID-19 disease. PARTICIPANTS Adult patients admitted to Swedish ICUs. EXPOSURES Baseline characteristics, intensive care treatments and organ failures. MAIN OUTCOMES AND MEASURES The primary outcome was 30-day all-cause mortality. A multivariable model was used to determine the independent association between potential predictor variables and death. RESULTS We identified 1563 patients with complete 30-day follow-up. The 30-day all-cause mortality was 26.7%. Median age was 61 [52 to 69], Simplified Acute Physiology Score III (SAPS III) was 53 [46 to 59] and 62.5% had at least one comorbidity. Median PaO2/FiO(2) on admission was 97.5 [75.0 to 140.6] mmHg, 74.7% suffered from moderate-to-severe acute respiratory failure. Age, male sex [adjusted odds ratio (aOR) 1.5 (1.1 to 2.2)], SAPS III score [aOR 1.3 (1.2 to 1.4)], severe respiratory failure [aOR 3.0 (2.0 to 4.7)], specific COVID-19 pharmacotherapy [aOR 1.4 (1.0 to 1.9)] and continuous renal replacement therapy [aOR 2.1 (1.5 to 3.0)] were associated with increased mortality. Except for chronic lung disease, the presence of comorbidities was not independently associated with mortality. CONCLUSIONS Thirty-day mortality rate in COVID-19 patients admitted to Swedish ICUs is generally lower than previously reported despite a severe degree of hypoxaemia on admission. Mortality was driven by age, baseline disease severity, the presence and degree of organ failure, rather than pre-existing comorbidities.
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| 4. |
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| 5. |
- Gedeborg, Rolf, et al.
(författare)
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Susceptibility to SARS-Cov-2 infection and risk for severe COVID-19 in patients with prostate cancer on androgen deprivation therapy
- 2022
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 151:11, s. 1925-1934
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Tidskriftsartikel (refereegranskat)abstract
- Androgen deprivation therapy (ADT) has been hypothesized to protect against COVID-19, but previous observational studies of men with prostate cancer on ADT have been inconsistent regarding mortality risk from coronavirus disease 2019 (COVID-19). Using data from the Prostate Cancer data Base Sweden (PCBaSe), we identified a cohort of 114 547 men with prevalent prostate cancer on the start of follow-up in February 2020, and followed them until 16 December 2020 to evaluate the association between ADT and time to test positive for COVID-19. Among men testing positive for COVID-19, we used regression analyses to estimate the association between ADT and risk of COVID-19-related hospital admission/death from any cause within 30 days of the positive test. In total, 1695 men with prostate cancer tested positive for COVID-19. In crude analyses, exposure to ADT was associated with a 3-fold increased risk of both testing positive for COVID-19 infection and subsequent hospital admission/death. Adjustment for age, comorbidity and prostate cancer risk category substantially attenuated the associations: HR 1.3 (95% CI: 1.1-1.5) for testing positive for COVID-19, and OR 1.4 (95% CI: 1.0-1.9) for risk of subsequent hospital admission/death. In conclusion, although these results suggest increased risks of a positive COVID-19 test, and COVID-19-related hospital admission/death in men on ADT, these findings are likely explained by confounding by old age, cancer-associated morbidity and other comorbidities being more prevalent in men on ADT, rather than a direct effect of the therapy.
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| 6. |
- Kiiski, Ritva, et al.
(författare)
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An inhibitor of angiotensin converting enzyme (enalapril) augments endotoxin-induced hypotension in the pig
- 1999
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Ingår i: Upsala Journal of Medical Sciences. - 0300-9734. ; 104:2, s. 163-176
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Tidskriftsartikel (refereegranskat)abstract
- Septic shock causes an extensive inflammatory reaction including increased capillary leakage and a decrease in systemic blood pressure. Human septic shock can be replicated in the endotoxaemic pig. Angiotensin converting enzyme (ACE) is involved in the degradation of bradykinin, an inflammatory mediator, and in the regulation of blood pressure. Inhibition of ACE is a common approach to reduce hypertension as well as left ventricular insufficiency. Fifteen anaesthetised pigs received a continuous 3 h endotoxin infusion. The animals were randomly given an inhibitor of ACE (enalpril) [at a dose (0.5 mg x kg-1) that did not per se reduce mean arterial blood pressure (MAP); (n = 7)], or the corresponding volume of saline (n = 8). Another seven pigs were randomised for treatment with enalapril (0.5 mg x kg-1) + saline (n = 3). Four pigs were randomised to serve as untreated controls (saline + saline). Basic physiologic variables were registered. Endotoxaemia progressively reduced MAP. This decrease was significantly augmented by enalapril. Hypovolemia caused by increased permeability or salt/water excretion did not seem to explain this effect as neither blood haemoglobin nor plasma sodium differed between the two groups of endotoxaemic pigs. Inhibitors of ACE are known to potentiate the cardio-depressant effect of bradykinin. This may explain the reduction in MAP by enalapril during porcine endotoxaemia.
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| 7. |
- Mutschler, Diana K., et al.
(författare)
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Microdialysis-evaluated myocardial cyclooxygenase-mediated inflammation and early circulatory depression in porcine endotoxemia
- 2003
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 31:6, s. 1780-1785
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the early myocardial biochemical inflammatory response with the microdialysis technique during porcine endotoxemia and to simultaneously monitor systemic hemodynamics. DESIGN: Prospective, randomized, placebo-controlled trial with parallel groups. SETTING: Animal research laboratory at the University Hospital of Uppsala, Sweden. SUBJECTS: Thirteen piglets aged 12-14 wks receiving general anesthesia. INTERVENTIONS: After thoracotomy and the insertion of microdialysis probes in standardized locations in the left ventricle of the heart and in the quadriceps muscle, seven pigs received a continuous infusion of endotoxin, initiating a severe endotoxemic shock. Six pigs received saline instead of endotoxin. MEASUREMENTS AND MAIN RESULTS: Endotoxemia caused a rapid and pronounced elevation of a metabolite obtained from prostaglandin degradation, 15-keto-dihydro-PGF(2alpha), in myocardial microdialysate fluid being specific of cyclooxygenase (COX)-mediated inflammation (p <.001 vs. saline-infused controls). Simultaneously, we observed a decrease in left ventricular stroke work index in the endotoxemic pigs (p <.01 vs. saline-infused controls). Endotoxemia did not alter 15-keto-dihydro-PGF(2alpha) levels in quadriceps muscle. Endotoxemia caused increases in taurine, hypoxanthine, and magnesium in myocardial microdialysate (p <.05 vs. saline-infused controls), whereas the contents of pyruvate, lactate, inosine, adenosine, and calcium were not significantly changed. CONCLUSION: Endotoxemia induced a myocardial COX-mediated inflammation without signs of ischemia. In parallel, a depletion of myocardial energy substrates and a deterioration in myocardial performance were seen.
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| 8. |
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| 9. |
- Mutschler, Diana K., et al.
(författare)
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Riksstämman 2001
- 2001
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Annan publikation (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Mårtensson, Johan, et al.
(författare)
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COVID-19 critical illness in Sweden : characteristics and outcomes at a national population level
- 2020
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Ingår i: Critical Care and Resuscitation. - Strawberry Hills, NSW, Australia : AUSTRALASIAN MED PUBL CO LTD. - 1441-2772. ; 22:4, s. 312-320
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Tidskriftsartikel (refereegranskat)abstract
- Objective: During the coronavirus disease 2019 (COVID-19) pandemic, baseline demographics and comorbidities of patients with COVID-19 have been presented, but there are limited data on outcomes of severely ill patients. We aimed to examine the association between patient characteristics and 30-day mortality among patients with COVID-19 treated in the intensive care unit (ICU).Design: Population-based cohort study.Setting: ICUs in Sweden.Participants: All consecutive patients with COVID-19 admitted to Swedish ICUs from 6 March to 5 April 2020.Main outcome measures: The primary outcome was 30-day mortality after ICU admission. Patient demographics, comorbidities and clinical characteristics were also retrieved.Results: A total of 604 patients were included. The median age was 61 years (interquartile range [IQR], 52-70 years) and 458 patients (76%) were males. The most common comorbidities were hypertension (35.9%) and diabetes (25.7%), whereas 36.4% of patients had no comorbidities. Median Simplified Acute Physiology Score (SAPS) 3 was 53 (IQR, 46-60). Of 573 patients with available respiratory support data, 487 (85.0%) received invasive mechanical ventilation. Among 518 patients with available data, 117 (22.6%) received renal replacement therapy. Median length of stay was 13 days (IQR, 6-20 days). Mortality at 30 days was 32.6%. In the multivariable Cox regression model, age (hazard ratio [HR] 1.06; 95% CI, 1.04-1.07 per year), the presence of one or more comorbidities (HR, 1.80; 95% CI, 1.20-2.68), chronic obstructive pulmonary disease or asthma (HR, 1.68; 95% CI, 1.12-2.50), hypertension (HR, 1.41; 95% CI, 1.01-1.99), and acute illness severity (SAPS 3 excluding age and comorbidity) (HR, 1.06; 95% CI, 1.04-1.09) were associated with 30-day mortality.Conclusions: This population-based cohort study presents 30-day mortality of 604 ICU patients with COVID-19. The higher mortality was explained by older age, the presence chronic illness, and acute illness severity.
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