scholarly journals Enrofloxacin Alters Fecal Microbiota and Resistome Irrespective of Its Dose in Calves

2021 ◽  
Vol 9 (10) ◽  
pp. 2162
Author(s):  
Ashenafi Feyisa Beyi ◽  
Debora Brito-Goulart ◽  
Tyler Hawbecker ◽  
Brandon Ruddell ◽  
Alan Hassall ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Clonal Expansion ◽  
Fecal Microbiota ◽  
High Dose ◽  
Low Doses ◽  
Complex Samples ◽  
Antimicrobial Resistance Genes ◽  
C 32 ◽  
And Control

Enrofloxacin is a fluoroquinolone drug used to prevent and control bovine respiratory disease (BRD) complex in multiple or single doses, ranging from 7.5 to 12.5 mg/kg body weight. Here, we examined the effects of high and low doses of a single subcutaneously injected enrofloxacin on gut microbiota and resistome in calves. Thirty-five calves sourced for this study were divided into five groups: control (n =7), two low dose groups (n = 14, 7.5 mg/kg), and two high dose groups (n = 14, 12.5 mg/kg). One group in the low and high dose groups was challenged with Mannheimia haemolytica to induce BRD. Both alpha and beta diversities were significantly different between pre- and post-treatment microbial communities (q < 0.05). The high dose caused a shift in a larger number of genera than the low dose. Using metagenomic ProxiMeta Hi-C, 32 unique antimicrobial resistance genes (ARGs) conferring resistance to six antibiotic classes were detected with their reservoirs, and the high dose favored clonal expansion of ARG-carrying bacterial hosts. In conclusion, enrofloxacin treatment can alter fecal microbiota and resistome irrespective of its dose. Hi-C sequencing provides significant benefits for unlocking new insights into the ARG ecology of complex samples; however, limitations in sample size and sequencing depth suggest that further work is required to validate the findings.

scholarly journals Enhanced intestinal 2-deoxy-2-[18F]fluoro-D-glucose uptake under metformin is not fully suppressed by loperamide

2018 ◽  
Vol 52 (4) ◽  
pp. 185-191
Author(s):  
Tomomi Nobashi ◽  
Tsuneo Saga ◽  
Yuji Nakamoto ◽  
Yoichi Shimizu ◽  
Sho Koyasu ◽  
...  
Keyword(s):  
Body Weight ◽  
Small Intestine ◽  
Low Dose ◽  
Control Group ◽  
High Dose ◽  
Fdg Uptake ◽  
Significant Difference ◽  
Mouse Small Intestine ◽  
Long Acting ◽  
And Control

AbstractObjective. This study investigated whether the metformin (Met)-induced enhanced intestinal uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is reduced by loperamide, a long-acting anti-diarrheal agent. Methods. Mean18F-FDG uptake in the mouse small intestine and colon with Met exposure was compared with that in control mice. In the Met group, high-dose (1.0 mg/kg body weight) and low-dose (0.1 mg/kg body weight) loperamide were introduced, and18F-FDG uptake in the small intestine and colon was compared with that of control mice administered high-dose loperamide. The percent injected dose of18F-FDG per gram of tissue (%ID/g) in the extracted tissues was then determined. Results.18F-FDG uptake increased significantly in the small intestine (0.64±0.06 vs. 1.01±0.15, p=0.040) and, especially, the colon (0.46±0.13 vs. 2.16±0.51, p<0.001) after Met exposure. Neither high-dose nor low-dose loperamide significantly reduced18F-FDG uptake in the small intestine (0.82±0.31 vs. 0.84±0.22, p=0.93 and 0.78±0.25 vs. 0.70±0.15, p=0.13, respectively) or colon (2.13±0.41 vs. 1.67±0.55, p=0.063 and 1.77±0.39 vs. 1.80±0.25, p=0.56, respectively). The colonic %ID/g was significantly higher in Met groups irrespective of loperamide introduction than in control group, whereas the significant difference in the small intestine was observed only between Met and control groups. Conclusion. Metformin increased18F-FDG uptake in intestines especially in colon. Loperamide administration partially, but not sufficiently, suppresses the Met-induced increased colonic uptake of18F-FDG.

scholarly journals The Effect of Ethanolic Extract of Cannabis sativa Leaves from Nigeria on the Antioxidants Markers in Albino Wistar Rats

2020 ◽  
pp. 58-65
Author(s):  
E. B. Umoren ◽  
I. Wopara ◽  
O. G. Adebayo ◽  
U. A. Ezike ◽  
A. O. Obembe
Keyword(s):  
Body Weight ◽  
Wistar Rats ◽  
Dose Group ◽  
Low Dose ◽  
Cannabis Sativa ◽  
Ethanolic Extract ◽  
High Dose Group ◽  
High Dose ◽  
Control Groups ◽  
And Control

Background: Cannabis sativa is an annual herbaceous plant in the Cannabis genus. The cannabis plant is widely regarded as a potent psychoactive, medicinal plant. Reportedly used for recreation and as intoxicant. The medical uses of the plant include effective control and management of chronic health problems such as HIV/AIDs, cancer, cachexia, nausea and vomiting, asthma and hypertension. C. sativa is known to possess antioxidative properties. This study therefore investigated the effects of C. sativa on antioxidant concentrations in albino Wistar rats. Materials and Methods: Thirty (30) rats used for this study were divided into three groups of 10 rats each. Group 1 received distilled water and served as control. Group 2 received C. sativa extract (100 ml/Kg body weight) by gavage and served as low dose group. Group 3 received C. sativa (250 ml/Kg body weight) by gavage and served as high dose group once daily for 28 days. Results: Catalase (CAT) concentration was significantly lower (P<0.05) in the low dose group as compared with control. In the high dose group, CAT concentration was significantly lower (P<0.05) when compared with the low and control groups respectively. Glutathione peroxidase (GPx) and Superoxide dismutase (SOD) concentrations were significantly higher (P<0.05) in the low dose group as compared with their respective control. GPx and SOD concentrations were significantly higher (P<0.05) in the high dose groups as compared to low dose and control groups respectively. Conclusion: CAT concentration decreased dose-dependently, while GPx and SOD concentrations increased dose-dependently among treated groups. Treatment with C. sativa revealed a paradoxical effect on CAT concentration with respect to GPx and SOD concentrations. Therefore, oral ingestion of ethanolic extract of C. sativa may not have significant effect on the body’s antioxidant stores due to the balance created for CAT deficiency by increased GPx and SOD concentrations.

scholarly journals Effect of Different Doses of Nitrate Supplements on hepatocellular Damage Markers in Male Sprague Dawley Rats Following One Session of Exercise

2020 ◽  
pp. 119-133
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Male Rats ◽  
Control Group ◽  
High Dose ◽  
Sprague Dawley ◽  
Hepatocellular Damage ◽  
Sprague Dawley Rats ◽  
And Control ◽  
Different Doses

Background: Hepatocellular damage caused by physical activity or the use of supplements is one of the serious problems facing athletes in various fields. This study aimed to evaluate the effect of different doses of nitric oxide supplements on AST and ALT liver enzymes and the ratio of AST to ALT following a session of eccentric exercise in Sprague Dawley male rats. Materials and Methods: In this study, 36 Sprague Dawley male rats (two months old) were divided into three groups of control, low dose (4.8 mg/kg body weight), and high dose of NO supplements (15.4 mg/kg body weight). Supplements were given to rats for seven days. Subsequently, all three groups of rats were forced to run on a treadmill for 45 min with a speed of 20 m/min, and a slope of -15 degrees. Blood samples were taken directly from cardiac puncture of rats 24 h after the running exercise. Blood serum variables of the study were measured afterward. Results: Low dose of nitrate supplements did not change AST and ALT indices, while the high dose of nitrate supplements increased ALT serum level and decreased AST to ALT ratio, compared to a low dose of NO supplements and control group. Conclusion: Based on the obtained results, the consumption of a low dose of NO supplements does not change hepatocellular damage markers, while the high dose of NO supplements causes degeneration of hepatic cells in athletes.

Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes

2012 ◽  
Vol 124 (3) ◽  
pp. 191-202 ◽  
Author(s):  
Mona Sedeek ◽  
Alex Gutsol ◽  
Augusto C. Montezano ◽  
Dylan Burger ◽  
Aurelie Nguyen Dinh Cat ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Disease Process ◽  
Thiobarbituric Acid ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
High Dose ◽  
Diabetic Mice ◽  
Mitogen Activated Protein

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.

Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice

1997 ◽  
Vol 272 (2) ◽  
pp. R563-R569 ◽  
Author(s):  
L. R. Leon ◽  
W. Kozak ◽  
J. Peschon ◽  
M. J. Kluger
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Motor Activity ◽  
Knockout Mice ◽  
Low Dose ◽  
Late Phase ◽  
High Dose ◽  
Wild Type ◽  
Inflammatory Stimuli ◽  
Necrosis Factor

We examined the effects of injections of systemic [lipopolysaccharide (LPS), 2.5 mg/kg or 50 pg/kg ip] or local (turpentine, 100 microl sc) inflammatory stimuli on fever, motor activity, body weight, and food intake in tumor necrosis factor (TNF) double receptor (TNFR)-knockout mice. A high dose of LPS resulted in exacerbated fevers in TNFR-knockout mice compared with wild-type mice for the early phase of fever (3-15 h); the late phase of fever (16-24 h) and fevers to a low dose of LPS were similar in both groups. Motor activity, body weight, and food intake were similarly reduced in both groups of mice after LPS administration. In response to turpentine, TNFR-knockout and wild-type mice developed virtually identical responses to all variables monitored. These results suggest that 1) TNF modulates fevers to LPS dose dependently, 2) TNF does not modulate fevers to a subcutaneous injection of turpentine, and 3) knockout mice may develop cytokine redundancy in the regulation of the acute phase response to intraperitoneally injected LPS or subcutaneously injected turpentine.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

Abstract 528: Dose- And Salt-dependency Of Angiogenesis Inhibition-induced Blood Pressure Rise And Renal Toxicity

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Stephanie Lankhorst ◽  
Mariëtte H Kappers ◽  
Stefan Sleijfer ◽  
A H Danser ◽  
Anton H van den Meiracker
Keyword(s):  
Low Dose ◽  
Renal Toxicity ◽  
Pressure Rise ◽  
High Salt ◽  
High Dose ◽  
Low Doses ◽  
High Salt Diet ◽  
Salt Diet ◽  
Angiogenesis Inhibition ◽  
Cystatine C

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy, inducing hypertension and nephrotoxicity. We explored the dose- and salt-dependency of these side effects. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with a high (27.5 mg/kg.day, n=14), an intermediate (14 mg/kg.day, n=6) and low dose (7 mg/kg.day, n=6) of sunitinib or vehicle (n=8) after normal salt diet for 2 weeks. The low dose-model was also combined with a high salt diet (8% NaCl and saline water). Eight days after administration rats were sacrificed and blood and 24h urine samples collected for biochemical measurements. With the high dose of sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). The intermediate and low doses induced MAP rises of 24.3±2.7 mmHg (p<0.001) and 13.4±3.3 mmHg (p<0.001), respectively. The low dose of sunitinib with high salt, induced a MAP rise of 43.5±2.2 mmHg (p<0.001 compared to normal salt). With the high dose, circulating ET-1 increased from 0.6±0.1 pg/ml to 1.6±0.2 pg/ml (p<0.01) and serum cystatine-C from 4.5±0.1 mg/L to 6.6±0.3 mg/L (p<0.001). Comparable increases in circulating ET-1 were seen with the intermediate and low doses, whereas serum cystatine-C did increase with the intermediate dose (to 6.3±0.1 mg/L, p0.05). Serum cystatine-C levels with low and high salt were identical. With the high dose of sunitinib, proteinuria increased from 7.5±1.3 to 33.3±4.8 mg/day (p<0.05). The rise in proteinuria was attenuated with the intermediate (16.2±2.1 mg/day, p<0.01) and low dose (19.9±3.3 mg/day, p<0.01), but increased to 40.4±30.1 mg/day (p>0.05) with high salt. Angiogenesis inhibition-induced hypertension and nephrotoxicity are dose-dependent with a lower threshold for the rise in BP than for renal toxicity. The BP rise observed with the low dose of sunitinib observed in normotensive rats is comparable to the sunitinib-induced BP rise observed in patients and clearly is salt-sensitive. Since cystatine-C levels during normal and high salt diet were comparable, the BP rise during high salt seems independent of renal dysfunction.

scholarly journals Effect of Astragalus membranaceus Oral Solution on Lifespan and Learning and Memory Ability of Honey Bees

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Tao Hong ◽  
Long-Xue Li ◽  
Xiao-ping Han ◽  
Jing-liang Shi ◽  
Cai-yun Dan ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Honey Bees ◽  
Dose Group ◽  
Low Dose ◽  
Oral Solution ◽  
Astragalus Membranaceus ◽  
Control Group ◽  
High Dose ◽  
The Mean ◽  
And Control

In this study, the effects of Astragalus membranaceus oral solution on lifespan and learning and memory abilities of honey bees were evaluated. Two groups of bees were fed with sucrose syrup (50%) containing low dose (1.33%) and high dose (13.3%) of A. membranaceus oral solution, respectively. The proboscis extension response (PER) analysis was applied to examine the learning and memory capabilities of bees. Two genes related to memory formation in honey bees were determined by real-time PCR. High dose (13.3%) of A. membranaceus significantly decreased the mean lifespan of bees compared to the bees fed with low dose (1.33%) and control bees. No significant differences in lifespan of bees were found between low-dose-fed bees and control bees. The results of PER experiments showed apparent improvement in the memorizing ability of the high-dose group (in comparison with the control group). Moreover, the relative expression levels of Nmdar1 in the low-dose group and control group were significantly lower than those in the high-dose group. It is preliminarily concluded that A. membranaceus has an adverse effect on the mean lifespan of honey bees but might be helpful in strengthening memories.

scholarly journals Glucocorticoid Receptor Agonists to Improve the Productivity and Health of Early-Weaned Pigs: What Is the Best Method of Delivery?

Animals ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1124
Author(s):  
Hailey Wooten ◽  
Hwanhee Kim ◽  
Amanda R. Rakhshandeh ◽  
Anoosh Rakhshandeh
Keyword(s):  
Body Weight ◽  
Glucocorticoid Receptor ◽  
Low Dose ◽  
Average Daily Gain ◽  
Feed Ratio ◽  
High Dose ◽  
Suitable Alternative ◽  
Treatment Groups ◽  
Daily Gain ◽  
All Treatment

The purpose of the current study was to determine the best method of delivery for glucocorticoid receptor agonist (GRA) treatment. A total of 167 Pig Improvement Company (PIC) piglets (body weight (BW) 7.35 ± 1.24 kg) were weaned at 25.0 ± 0.81 days of age and randomly assigned to 14 treatment groups based on a 2 × 7 factorial arrangement with sex (gilts vs. barrows), in-feed antibiotic (ANT; 110 mg/kg in-feed tylosin), repeated intramuscular (I.M.) injection of GRA (two injections, 0.2 mg/kg BW dexamethasone (DEX)), low dose in-feed GRA (LF, 2.5 mg/kg diet DEX ), high dose in-feed GRA (HF, 5 mg/kg diet DEX), low dose in-water GRA (LW, 0.8 mg/L DEX ), high dose in-water GRA (HW, 1.6 mg/L DEX ), and no treatment control (CON) as the main factors. Body weight and feed intake were measured daily from days 0 to 7 and weekly from days 7 to 28 post-weaning. The interaction effect for average daily gain (ADG) was significant with gilts performing better in the I.M., ANT, and LF groups (p = 0.05). All treatment groups, with the exception of the HW group, had a higher ADG than the CON group. Gilts in the I.M., LF, and HF groups had the highest ADG compared to other treatment groups (p ≤ 0.05). Sex and the interaction between sex and treatments had no effect on the gain-to-feed ratio (G:F; p ≥ 0.21). All treatment groups had a higher G:F than the CON group (p ≥ 0.04). These results suggest that the low-dose, in-feed GRA treatment is the best GRA delivery method and is a suitable alternative to in-feed sub-therapeutic antibiotics.

scholarly journals Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients

Critical Care ◽  
2020 ◽  
Vol 24 (1) ◽  
Author(s):  
Sandra Jonmarker ◽  
Jacob Hollenberg ◽  
Martin Dahlberg ◽  
Otto Stackelberg ◽  
Jacob Litorell ◽  
...  
Keyword(s):  
Body Weight ◽  
Confidence Intervals ◽  
Critically Ill ◽  
Low Dose ◽  
Cox Proportional Hazards ◽  
High Dose ◽  
Thromboembolic Events ◽  
Risk Of Death ◽  
Dosing Strategy ◽  
Medium Dose

Abstract Background A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. Method In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500–4500 IU tinzaparin or 2500–5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. Results A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13–0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43–1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. Conclusions Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. Trial registration Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

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