Project description:Our objective was to compare norepinephrine plus dobutamine versus epinephrine as the first-line agent in children with fluid refractory cold septic shock.DesignOpen-label randomized controlled study.SettingA single-center PICU from North India.PatientsChildren 2 months to less than 18 years old with fluid refractory cold septic shock.InterventionsIn the intervention group, norepinephrine and dobutamine were started and in the control group, epinephrine was started as the first-line vasoactive agent. The primary outcome was the proportion attaining shock resolution (attaining all the therapeutic endpoints) at 1 hour of therapy.Measurements and main resultsWe enrolled 67 children: 34 in the norepinephrine plus dobutamine group (intervention) and 33 in the epinephrine group (control). There was no difference in shock resolution at 1 hour (17.6% vs 9%; risk ratio [RR], 2.0; 95% CI, 0.54-7.35; p = 0.25), 6 hours (76.4% vs 54.5%; RR, 1.69; 95% CI, 0.92-3.13; p = 0.06), and 24 hours between the intervention and control groups, respectively. Children in the norepinephrine plus dobutamine group attained shock resolution earlier (measured from starting of vasoactive agents to attaining all the therapeutic endpoints) (hazard ratio, 1.84 [1.1-3.08]). The difference in 28-day mortality was not significant (23.5% vs 39.3% in the intervention and control groups, respectively [RR, 0.59; 95% CI, 0.28-1.25]).ConclusionsIn children with fluid refractory cold septic shock, with use of norepinephrine plus dobutamine as first-line agents, the difference in the proportion of children attaining shock resolution at 1 hour between the groups was inconclusive. However, the time to shock resolution was earlier in the norepinephrine plus dobutamine group. Also, fewer children in the intervention group were refractory to treatment. Further studies powered to detect (or exclude) an important difference would be required to test this intervention.
Project description:PurposeCrystalloid fluid and vasoactive drugs are used in the early treatment of sepsis. The purpose of the present study was to examine how these drugs alter plasma volume expansion, peripheral edema, and urinary excretion.MethodsTwenty-five anesthetized sheep were made septic by cecal puncture and a short infusion of lipopolysaccharide. After 50 min, a slow infusion of isotonic saline was initiated: the saline either contained no drug, norepinephrine (1 μg/kg/min), phenylephrine (3 μg/kg/min), dopamine (50 μg/kg/min), or esmolol (50 μg/kg/min). Ten min later, 20 mL/kg Ringer´s lactate solution was given over 30 min. Central hemodynamics, acid-base balance, and the urinary excretion were monitored. Frequent measurements of the blood hemoglobin concentration were used as input in a kinetic analysis, using a mixed effects modeling software.ResultsThe fluid kinetic analysis showed slow distribution and elimination of Ringer´s lactate, although phenylephrine and dopamine accelerated the distribution. Once distributed, the fluid remained in the peripheral tissues and did not equilibrate adequately with the plasma. Overall, stimulation of adrenergic alpha1-receptors accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. A pharmacodynamic Emax model showed that Ringer´s lactate increased stroke volume by 13 ml/beat. Alpha1-receptors, but not beta1-receptors, further increased stroke volume, while both raised the mean arterial pressure. Modulation of the beta1-receptors limited the acidosis.ConclusionsStimulation of adrenergic alpha1-receptors with vasoactive drugs accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. The tendency for peripheral accumulation of fluid was pronounced, in particular when phenylephrine was given.
Project description:Nitric oxide (NO) plays important physiological roles in the vasculature to regulate angiogenesis, blood flow, and hemostasis. In solid tumors, NO is generally acknowledged to mediate angiogenic responses to several growth factors. This contrasts with conflicting evidence that NO can acutely increase tumor perfusion through local vasodilation or diminish perfusion by preferential relaxation of peripheral vascular beds outside the tumor. Because thrombospondin 1 (TSP1) is an important physiological antagonist of NO in vascular cells, we examined whether, in addition to inhibiting tumor angiogenesis, TSP1 can acutely regulate tumor blood flow. We assessed this activity of TSP1 in the context of perfusion responses to NO as a vasodilator and epinephrine as a vasoconstrictor. Nitric oxide treatment of wild type and TSP1 null mice decreased perfusion of a syngeneic melanoma, whereas epinephrine transiently increased tumor perfusion. Acute vasoactive responses were also independent of the level of tumor-expressed TSP1 in a melanoma xenograft, but recovery of basal perfusion was modulated by TSP1 expression. In contrast, overexpression of truncated TSP1 lacking part of its CD47 binding domain lacked this modulating activity. These data indicate that TSP1 primarily regulates long-term vascular responses in tumors, in part, because the tumor vasculature has a limited capacity to acutely respond to vasoactive agents.
Project description:Background: Acute mesenteric ischaemia (AMI) is a surgical emergency which has an associated high mortality. The mainstay of active treatment includes early surgical intervention, with resection of non-viable bowel, and revascularisation of the ischaemic bowel where possible. Due to the physiological insult of AMI however, perioperative care often involves critical care and the use of vasoactive agents to optimise end organ perfusion. A number of these vasoactive agents are currently available with varied mechanism of action and effects on splanchnic blood flow. However, specific guidance on which is the optimal vasoactive drug to use in these settings is limited. This systematic review aimed to evaluate the current evidence comparing vasoactive drugs in AMI. Methods: A systematic search of Ovid Medline, Ovid Embase, Cochrane CENTRAL and the Cochrane Database of Systematic Review was performed on the 5th of November 2020 to identify randomised clinical trials comparing different vasoactive agents in AMI on outcomes including mortality. The search was performed through the Royal College of Surgeons of England (RCSEng) search support library. Results were analysed using the Rayyan platform, and independently screened by four investigators. Results: 614 distinct papers were identified. After screening, there were no randomised clinical trials meeting the inclusion criteria. Conclusions: This review identifies a gap in literature, and therefore recommends an investigation into current practice and clinician preference in relation to vasoactive agents in AMI. Multicentre randomised controlled trials comparing these medications on clinical outcomes will therefore be required to address this question.
Project description:Lanping black-boned (LPBB) sheep are a unique and rare ruminant species, characterized by black pigmentation in the skin and internal organs. Thus far, LPBB are the only known animal with heritable melanin characteristics besides the black-boned chicken, and the only mammal known to contain a large amount of melanin in the body. LPBB have therefore attracted substantial research attention, due to their potential contribution to medicine. However, long periods of grazing freely and crossbreeding with Lanping normal sheep (LPN) have diluted LPBB breeding resources, posing a challenge to the protection of species. To ensure the effective conservation and management of LPBB genetic resources, the construction of a large-scale database of genotypic information is therefore very important. To achieve this, we established the first LPBB-specific SNP database, named Black-boned Sheep Genome SNP Database (BbGSD, http://202.203.179.115:3838/oarsnpdb) using sheep genotype data (100 LPBB and 50 LPN) across 46 894 242 SNP sites. In this database, we implemented four main function modules: (i) the "LD heatmap" module, which uses a heatmap to enable the interactive visualization of pairwise linkage disequilibrium (LD) measurements between SNPs; (ii) the "SNP distribution" module, which allows users to interactively visualize tabular genotype data as heat maps; (iii) the "Phylogenetics" module which enables phylogenetic analysis to explore the evolutionary history or genetic relationships of the LPBB sheep; and the "Diversity" module, which can be used to calculate and display the nucleotide diversity among sheep populations in user-specified genomic regions. BbGSD is essential for accelerating studies on the functional genomics and screening of molecular markers of molecular-assisted breeding in black-boned sheep. Database URL: http://202.203.179.115:3838/oarsnpdb.
Project description:ObjectiveBlack wool can effectively prevent sheep from DNA damage as well as fungal infection, and can improve reproductive performance. In order to explore the candidate genes related to black wool formation in Qira sheep.MethodsWe selected 123 adult healthy ewes with different coat colors in Qira sheep groups (black (B), brown (Y) and grey (G)) and extracted DNA from their venous blood to obtain Illumina Ovine SNP 50K chip data. Subsequently, our PCA, NJ-tree, and Admixture population structure analyses of the 3 wool color Qira sheep populations showed that the 3 middle wool color populations exhibited the same genetic traits. Fst, xp-EHH, iHS, and π were detected for selection signals, and the 5% SNPs loci positively selected from the analyses were annotated based on SheepOar_v4.0. The region of exon 1 of the TYRP1 gene was further screened, amplified and sequenced through the DNA of the Qira sheep and associated with goodness-of-fit using the chi-square test.ResultsThe results showed that 71 SNPs associated with black wool traits, among which TYRP1, PARD3 and CDH2 genes were strongly associated with black wool production. Three mutations were detected in the exon 1 region of the TYRP1 gene that were significantly associated with coat color variation inQira sheep (2:81,183,168, 2:81,183,281 and 2:81,183,284).ConclusionIn this paper, Qira sheep could not differentiate the genetic structure of this population by wool color, and obtained 71 SNPs related to black wool. Detection of mutation sites on the TYRP1 gene affecting hair color change provides a basis for black sheep line selection as well as breed conservation.
Project description:BackgroundAn increasing number of patients undergo surgical procedures worldwide each year, and despite advances in quality and care, morbidity and mortality rates remain high. Perioperative hypotension is a well-described condition, and is associated with adverse outcomes. Both fluids and vasoactive agents are commonly used to treat hypotension, however, whether one vasoactive agent is preferable over another has yet to be explored.MethodsIn accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement, we plan to conduct a scoping review of studies assessing the use of vasoactive agents in patients undergoing non-cardiac surgery. We will provide an overview of indications, agents used and outcomes assessed. We will assess and report the certainty of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.ResultsWe will provide descriptive analyses of the included studies accompanied by tabulated results.ConclusionThe outlined scoping review will provide a summary of the body of evidence on the use of vasoactive agents in the non-cardiac surgical population.