The systemic and regional hemodynamic effects of phenylephrine in sheep under normal conditions and during early hyperdynamic sepsis.
ABSTRACT Phenylephrine treatment of hypotension in sepsis raises concern because it may decrease vital organ bloodflow. Accordingly, we investigated the effects of phenylephrine on systemic and regional bloodflow in normal and septic sheep.
Responses to phenylephrine or vehicle infusion for 6 hours were determined in conscious normal sheep and sheep with early sepsis induced by administration of live Escherichia coli. Cardiac output and coronary, mesenteric, and renal bloodflow were measured with implanted flow probes.
In normal sheep, phenylephrine decreased cardiac output and heart rate (HR) but increased stroke volume and mean arterial blood pressure (MAP) (84 ± 6 to 108 ± 6 mm Hg, magnitude of mean difference [diff.] 19 [22.6%]; 95% confidence intervals [CI], 17-21). There were significant decreases in regional conductance values with a transient decrease in mesenteric bloodflow, no change in coronary bloodflow, and increased renal bloodflow (222 ± 53 to 271 ± 55 mL/min; diff. 31 [13.9%]; 95% CI, 26-36). During hyperdynamic sepsis, vasodilatation and increased bloodflow occurred in all vascular beds. Phenylephrine restored MAP and stroke volume to baseline values, but HR, cardiac output, and total peripheral conductance progressively decreased. Phenylephrine decreased mesenteric and coronary conductance, with no sustained reduction in flows, but renal conductance was significantly decreased and overall renal bloodflow increased (293 ± 22 vs 347 ± 100 mL/min; diff. 55 [18.8%]; 95% CI, 47-65).
In sheep with early hyperdynamic sepsis, phenylephrine, at a dose that restored MAP, increased stroke volume and renal bloodflow while decreasing HR and coronary bloodflow but not mesenteric bloodflow. Similar responses were seen in normal animals.
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ABSTRACT: Contrast-enhanced ultrasound (CEUS) is a new technique that might enable portable and non-invasive organ perfusion quantification at the bedside. However, it has not yet been tested in critically ill patients. We sought to establish CEUS's feasibility, safety, reproducibility and potential diagnostic value in the assessment of renal cortical perfusion in the peri-operative period in cardiac surgery patients. We recruited twelve patients deemed at risk of acute kidney injury (AKI) planned for elective cardiac surgery. We performed renal CEUS with destruction-replenishment sequences before the operation, on ICU arrival and the day following the admission. Enhancement was obtained with Sonovue(R) (Bracco, Milano, Italy) at an infusion rate of 1 ml/min. We collected hemodynamic parameters before, during and after contrast agent infusion. At each study time, we obtained five video sequences, which were analysed using dedicated software by two independent radiologists blinded to patient and time. The main output was a perfusion index (PI), corresponding to the ratio of relative blood volume (RBV) over mean transit time (mTT). All 36 renal CEUS studies, including 24 in the immediate post-operative period could be performed and were well tolerated. Correlation between readers for PI was excellent (R2=0.96, p<0.0001). Compared with baseline, there was no overall difference in median PI's on ICU admission. However, the day after surgery, median PI's had decreased by 50% (p<0.01) [22% decrease in RBV (p=0.09); 48% increase in mTT (p=0.04), both suggestive of decreased perfusion]. These differences persisted after correction for haemoglobin; vasopressors use and mean arterial pressure. Four patients developed AKI in the post-operative period. CEUS appears feasible and well tolerated in patients undergoing cardiac surgery even immediately after ICU admission. CEUS derived-parameters suggest a decrease in renal perfusion occurring within 24 hours of surgery.Critical care (London, England) 07/2013; 17(4):R138. · 4.72 Impact Factor
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ABSTRACT: RATIONALE: Tie2 is predominantly expressed by endothelial cells and is involved in vascular integrity control during sepsis. Changes in Tie2 expression during sepsis development may contribute to microvascular dysfunction. Understanding the kinetics and molecular basis of these changes may assist in the development of therapeutic intervention to counteract microvascular dysfunction. OBJECTIVE: To investigate the molecular mechanisms underlying the changes in Tie2 expression upon lipopolysaccharide (LPS) challenge. METHODS AND RESULTS: Studies were performed in LPS and pro-inflammatory cytokine challenged mice as well as in mice subjected to hemorrhagic shock, primary endothelial cells were used for in vitro experiments in static and flow conditions. Eight hours after LPS challenge, Tie2 mRNA loss was observed in all major organs, while loss of Tie2 protein was predominantly observed in lungs and kidneys, in the capillaries. A similar loss could be induced by secondary cytokines TNF-α and IL-1β. Ang2 protein administration did not affect Tie2 protein expression nor was Tie2 protein rescued in LPS-challenged Ang2-deficient mice, excluding a major role for Ang2 in Tie2 down regulation. In vitro, endothelial loss of Tie2 was observed upon lowering of shear stress, not upon LPS and TNF-α stimulation, suggesting that inflammation related haemodynamic changes play a major role in loss of Tie2 in vivo, as also hemorrhagic shock induced Tie2 mRNA loss. In vitro, this loss was partially counteracted by pre-incubation with a pharmacologically NF-кB inhibitor (BAY11-7082), an effect further substantiated in vivo by pre-treatment of mice with the NF-кB inhibitor prior to the inflammatory challenge. CONCLUSIONS: Microvascular bed specific loss of Tie2 mRNA and protein in vivo upon LPS, TNFα, IL-1β challenge, as well as in response to hemorrhagic shock, is likely an indirect effect caused by a change in endothelial shear stress. This loss of Tie2 mRNA, but not Tie2 protein, induced by TNFα exposure was shown to be controlled by NF-кB signaling. Drugs aiming at restoring vascular integrity in sepsis could focus on preventing the Tie2 loss.European Journal of Intensive Care Medicine 04/2013; · 5.17 Impact Factor
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ABSTRACT: To describe recent insights into glomerular haemodynamics in septic acute kidney injury (AKI). We reviewed the literature with particular emphasis on recent findings in animal experiments and human studies in relation to renal macro- and micro-renal haemodynamics during septic AKI. The dominant paradigm is that septic AKI is due to decreased renal perfusion with ischaemic loss of glomerular filtration rate (GFR), ischaemic tubular cell injury and acute tubular necrosis (ATN). However, recent experimental and human studies challenge this view of the pathogenesis of septic AKI. In addition, rapid post-mortem and experimental histological studies do not support ATN as the histological substrate of septic AKI. Finally, more recent experimental evidence suggests that changes in the glomerular and peri-glomerular haemodynamics provide a more likely explanation for the loss of GFR seen in the early phases of septic AKI. Despite a long-standing paradigm that septic AKI is due to renal hypo-perfusion and associated ATN, experimental and human studies increasingly suggest that changes in the state of the glomerular and peri-glomerular micro-vasculature are a more likely additional explanation for this condition.Nephrology Dialysis Transplantation 03/2014; · 3.37 Impact Factor