Atrial natriuretic peptide does not degrade the endothelial glycocalyx: A secondary analysis of a randomized porcine model.

BACKGROUND: The atrial natriuretic peptide (ANP) released from the heart regulates intravascular volume and is suspected to increase capillary permeability. Contradictory results regarding ANP and glycocalyx degradation have been reported. The aim of this study was to investigate if an infusion of ANP causes degradation of the endothelial glycocalyx. METHODS: Twenty pigs, pretreated with 250 mg methylprednisolone, were randomized to receive an infusion of either ANP (50 ng/kg/min) (n = 10) or 0.9% NaCl (n = 10) during 60 min. Endothelial glycocalyx components (heparan sulphate proteoglycan and hyaluronic acid), Hct, calculated plasma volume and colloid osmotic pressure were measured from baseline to 60 min. RESULTS: There was no difference between the control and intervention groups for heparan sulphate proteoglycan and hyaluronic acid corrected for the change in plasma volume (P = .333 and 0.197). Hct increased with 1.8 ± 2.2% in the intervention group (P = .029) with no change -0.5 ± 2.3% in the control group (P = .504). The plasma volume decreased in the intervention group with -8.4 ± 10% (P = .034) with no change in the control group 3.1 ± 12% (P = .427). Median changes in colloid osmotic pressures in the control and intervention group were -0.39 [95% CI, -1.88-0.13] and 0.9 [95% CI, 0.00-1.58], respectively (P = .012). CONCLUSIONS: In this randomized porcine study, an ANP infusion did not cause endothelial glycocalyx degradation but decreased the plasma volume most probably due to precapillary vasodilation and increased filtration.

Effects of different mean arterial pressure targets on plasma volume, ANP and glycocalyx-A randomized trial.

BACKGROUND: Arterial haematocrit (Hct) has been shown to decrease after anaesthesia induction, most probably because of an increased plasma volume (PV). The primary objective was to quantify change in PV if mean arterial pressure (MAP) was kept at baseline level or allowed to decrease to 60 mm Hg. Our secondary objective was to evaluate underlying mechanisms of this response. METHODS: Twenty-four coronary artery bypass patients were randomized to a higher (90 mm Hg, intervention group) or lower (60 mm Hg, control group) MAP by titration of norepinephrine. During the experimental procedure, no fluids were administered. Baseline PV was measured by 125 I-albumin and the change in PV was calculated from the change in Hct. Changes in MAP, plasma 125 I-albumin, colloid osmotic pressure, albumin, Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and endothelial glycocalyx components were measured from baseline to 50 minutes after anaesthesia induction. RESULTS: The MAP during the trial was 93 ± 9 mm Hg in the intervention group and 62 ± 5 mm Hg in the control group. PV increased with up to 420 ± 180 mL in the control group and 45 ± 130 mL in the intervention group (P < .001). Albumin and colloid osmotic pressure decreased significantly more in the control group. MR-proANP increased in the control group but no shedding of the glycocalyx layer was detected in either of the groups. CONCLUSION: Allowing mean arterial pressure to fall to 60 mm Hg during anaesthesia induction, increases the plasma volume due to reabsorption of interstitial water, with no ANP-induced degradation of the endothelial glycocalyx.

Circulating concentrations of glycocalyx degradation products in preeclampsia.

Background and Objectives: Preeclampsia is a multisystem disorder that affects maternal endothelium. The glycocalyx lines and protects the endothelial surface. In severe systemic diseases, like sepsis, it is shed and glycocalyx degradation products can be detected in increased concentrations in plasma. The aim of this study was to compare circulating concentrations of glycocalyx degradation products in degrees of preeclampsia severity. Study design: In this observational study, we included women from the South African PROVE biobank. Women were divided into normotensive controls, women with preeclampsia without end-organ complications, women with a single end-organ complication and women with multiple end-organ complications. Plasma samples taken at inclusion after diagnosis (preeclampsia cases) or at admission for delivery (normotensive controls) were analyzed with ELISA for syndecan-1, hyaluronic acid and thrombomodulin and compared between groups. Results: Women with preeclampsia (n = 47) had increased plasma concentrations of hyaluronic acid (100.3 ng/ml IQR 54.2-204 vs. 27.0 ng/ml IQR (13.5-66.6), p < 0,001) and thrombomodulin (4.22 ng/ml IQR 3.55-5.17 vs. 3.49 ng/ml IQR 3.01-3.68, p = 0.007) but not syndecan-1 compared with normotensive women (n = 10). There were no differences in plasma concentration in any of these biomarkers in women with preeclampsia with no end-organ complications (n = 10) compared with women with preeclampsia and one end-organ complication (n = 24). Women with preeclampsia with two or more end-organ complications (n = 13) had increased plasma concentrations of thrombomodulin (5.46 ng/ml, IQR 4.85-7.83 vs. 4.66 ng/ml, IQR 3.45-4.88, p = 0.042) compared with women with preeclampsia and no end-organ complications. Conclusion: Thrombomodulin was associated with disease severity and may be valuable for risk-stratifying women with preeclampsia.

Effects of atrial natriuretic peptide on renal function during cardiopulmonary bypass: a randomized pig model.

OBJECTIVES: Acute kidney injury is a well-known complication after cardiac surgery and cardiopulmonary bypass (CPB). In this experimental animal study, we evaluated the effects of atrial natriuretic peptide (ANP) on renal function, perfusion, oxygenation and tubular injury during CPB. METHODS: Twenty pigs were blindly randomized to continuous infusion of either ANP (50 ng/kg/min) or placebo before, during and after CPB. Renal blood flow as well as cortical and medullary perfusion was measured. Blood was repeatedly sampled from the renal vein. Glomerular filtration rate was measured by infusion clearance of 51Cr-EDTA. RESULTS: Glomerular filtration rate was higher (P < 0.001), whereas renal blood flow or renal oxygen delivery was not affected by ANP during CPB. Renal oxygen consumption did not differ between groups during CPB, whereas renal oxygen extraction was higher in the ANP group (P = 0.03). Urine flow and sodium excretion were higher in the ANP group during CPB. Blood flow in the renal medulla, but not in the cortex, dropped during CPB, an effect that was not seen in the animals that received ANP. CONCLUSIONS: ANP improved renal function during CPB. Despite impaired renal oxygenation, ANP did not cause tubular injury, suggesting a renoprotective effect of ANP during CPB. Also, CPB induced a selectively reduced blood flow in the renal medulla, an effect that was counteracted by ANP.

Intraoperative infusion of noradrenaline improves platelet aggregation in patients undergoing coronary artery bypass grafting: a randomized controlled trial.

Essentials Strategies to improve platelet function may reduce excessive bleeding during cardiac surgery. Patients were randomized to standard care or standard care + noradrenaline infusion. Low-dose noradrenaline improved intraoperative platelet aggregation and clot formation. Noradrenaline may be considered to improve intraoperative hemostasis during cardiac surgery. SUMMARY: Background New approaches to prevent bleeding complications during cardiac surgery are needed. Objective To investigate if noradrenaline (NA) enhances platelet aggregation in patients undergoing coronary artery bypass grafting (CABG). Patients/Methods Twenty-four patients undergoing coronary artery bypass grafting (CABG) were included in a prospective parallel-group randomized study. All patients but one were treated with acetylsalicylic acid (ASA). In the treatment group (n = 12), mean arterial blood pressure (MAP) was maintained at pre-induction levels by NA infusion. In the control group (n = 12), NA was administered only if MAP decreased below 60 mmHg. Platelet aggregation (impedance aggregometry with ADP, arachidonic acid [AA] and thrombin-receptor activating peptide [TRAP] as initiators) and clot formation (clotting time, clot formation time and maximum clot firmness by EXTEM, INTEM and FIBTEM tests with thromboelastometry) were assessed before and 50 min after anesthesia induction (before cardiopulmonary bypass was initiated). Results All patients in the treatment group received NA (median dose after 50 min 0.09 (range 0-0.26) µg kg-1  min-1 ). Four patients in the control group also received NA (0.03-0.12 µg kg-1  min-1 ). There were differences between the treatment group and the control group in ADP- and AA-induced aggregation changes (ADP, +16 [25th-75th percentiles, 5-26] vs. -7 [-19 to -1] U; AA, +12 [-4 to 16] vs. -9 [-13 to 1] U). INTEM maximum clot firmness increased in the treatment group but not in the control group. Conclusion Infusion of clinically relevant doses of NA enhanced platelet aggregation and clot firmness in ASA-treated CABG patients. NA infusion is hence a potential new method to acutely improve platelet reactivity in patients on antiplatelet therapy undergoing surgery.

Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers.

BACKGROUND: Administration of agents that enhance platelet reactivity may reduce the perioperative bleeding risk in patients treated with the adenosine diphosphate (ADP)-receptor antagonist ticagrelor. Adrenaline potentiates ADP-induced aggregation and activation in blood samples from ticagrelor-treated patients, but it has not previously been evaluated in vivo. METHODS: Ten healthy male subjects were included in an interventional study. A loading dose of ticagrelor (180 mg) was administered, followed 2 hours later by a gradually increased intravenous adrenaline infusion (0.01, 0.05, 0.10 and 0.15 µg/kg/min; 15 minutes at each step). Blood pressure, heart rate, platelet aggregation (impedance aggregometry), platelet activation (flow cytometry), clot formation (rotational thromboelastometry) and adrenaline plasma concentration were determined before and after ticagrelor administration and at the end of each adrenaline step. RESULTS: Infusion of adrenaline increased ADP-induced aggregation at all doses above 0.01 µg/kg/min. The aggregation increased from median 17 (25-75th percentiles: 14-31) to 25 (21-34) aggregation units (p = 0.012) at 0.10 µg/kg/min. Adrenaline infusion also increased ADP-induced fibrinogen receptor activation (from 29 [22-35] to 46 [38-57%]) and P-selectin expression (from 3.7 [3.0-4.3] to 7.7 [4.7-8.6%]), both p = 0.012. Adrenaline infusion reduced clot formation time (97 [89-110] to 83 [76-90] seconds, p = 0.008) and increased maximum clot firmness (59 [57-60] to 62 [61-64] mm, p = 0.007). CONCLUSION: Infusion of adrenaline at clinically relevant doses improves in vivo platelet reactivity and clot formation in ticagrelor-treated subjects. Adrenaline could thus potentially be used to prevent perioperative bleeding complications in ticagrelor-treated patients. Studies in patients are necessary to determine the clinical importance of our observations. TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT03441412.

Inverted valve after initially successful transfemoral aortic valve implantation.

A 73-year-old woman with severe aortic stenosis was accepted for transcatheter aortic valve implantation. There was minimal paravalvular leakage after the implantation, and the patient was stable. Twelve minutes after the implantation, the arterial pressure suddenly dropped. Transesophageal echocardiography showed severe left ventricular dysfunction. Cardiopulmonary resuscitation was started, and initially was successful with a systolic blood pressure of 90 mm Hg. However, despite initiation of extracorporeal circulation support, the patient deteriorated, pulmonary edema developed, and she died. Autopsy revealed an inverted aortic valve. The reasons why the patient had cardiac arrest and an inverted transfemoral aortic valve remain unclear.