Decreased Extracellular Vesicle Vasorin in Severe Preeclampsia Plasma Mediates Endothelial Dysfunction.

Background: Preeclampsia (PE) is a serious pregnancy complication affecting 5-8% of pregnancies globally. It is a leading cause of maternal and neonatal morbidity and mortality. Despite its prevalence, the underlying mechanisms of PE remain unclear. This study aimed to determine the potential role of vasorin (VASN) in PE pathogenesis by investigating its levels in extracellular vesicles (EV) and its effects on vascular function. Methods & Results: We conducted unbiased proteomics on urine-derived EV from severe PE (sPE) and normotensive pregnant women (NTP), identifying differential protein abundances. Out of one hundred and twenty proteins with ≥ ±1.5-fold regulation at P<0.05 between sPE and NTP, we focused on Vasorin (VASN), which is downregulated in sPE in urinary EV, in plasma EV and in the placenta and is a known regulator of vascular function. We generated EV with high VASN content from both human and murine placenta explants (Plex EV), which recapitulated disease-state-dependent effects on vascular function observed when treating murine aorta rings (MAR) or human aortic endothelial cells (HAEC) with murine or human plasma-derived EV. In normal murine pregnancy, VASN increases with gestational age (GA), and VASN is decreased in plasma EV, in placenta tissue and in Plex EV after intravenous administration of adenovirus encoding short FMS-like tyrosine kinase 1 (sFLT-1), a murine model of PE (murine-PE). VASN is decreased in plasma EV, in placenta tissue and in EV isolated from conditioned media collected from placenta explants (Plex EV) in patients with sPE as compared to NTP. Human sPE and murine-PE plasma EV and Plex EV impair migration, tube formation, and induces apoptosis in human aortic endothelial cells (HAEC) and inhibit acetylcholine-induced vasorelaxation in murine vascular rings (MAR). VASN over-expression counteracts the effects of sPE EV treatment in HAEC and MAR. RNA sequencing revealed that over-expression or knock down of VASN in HAEC results in contrasting effects on transcript levels of hundreds of genes associated with vasculogenesis, endothelial cell proliferation, migration and apoptosis. Conclusions: The data suggest that VASN, delivered to the endothelium via EV, regulates vascular function and that the loss of EV VASN may be one of the mechanistic drivers of PE. CLINICAL PERSPECTIVE: What is NewVASN in circulating plasma EV in sPE is reduced compared with VASN content in plasma EV of gestational age-matched pregnant women.VASN is encapsulated and transported in EV and plays a pro-angiogenic role during pregnancy.VASN should be explored both for its pro-angiogenic mechanistic role and as a novel biomarker and potential predictive diagnostic marker for the onset and severity of PE.What Are the Clinical Implications?VASN plays a role in maintaining vascular health and the normal adaptive cardiovascular response in pregnancy. A decrease of VASN is observed in sPE patients contributing to cardiovascular maladaptation.Strategies to boost diminished VASN levels and/or to pharmacologically manipulate mechanisms downstream of VASN may be explored for potential therapeutic benefit in PE.The decrease in EV-associated VASN could potentially be used as a (predictive) biomarker for PE.

Sugammadex versus neostigmine for routine reversal of neuromuscular blockade and the effect on perioperative efficiency.

Sugammadex produces recovery from neuromuscular blockade more rapidly and reliably than neostigmine. We sought to determine if sugammadex is associated with improved perioperative efficiency when compared to traditional neuromuscular blockade reversal with neostigmine, potentially offsetting the higher medication cost. This retrospective analysis involved patients receiving either neostigmine or sugammadex for reversal of neuromuscular blockade at a single academic tertiary care hospital. The final propensity-matched groups consisted of 4060 in each group (neostigmine or sugammadex). The primary outcome measured was total time in the operating room. Secondary outcomes included specific measures of perioperative efficiency as well as postoperative pulmonary failure. The average operating room time for patients was 169.59 [1.27] minutes for neostigmine and 157.06 [1.33] minutes for sugammadex (P < 0.001). The difference was primarily accounted for by shorter surgical times (121.45 [1.18] vs 109.62 [1.22] minutes, P < 0.011). Sugammadex was also associated with a shorter post-anesthesia care unit length of stay (102.47 [1.04] vs 98.67 [1.02] minutes, P < 0.001). For 8120 patients, sugammadex use was associated with shorter operating room and surgical durations as well as shorter post-anesthesia care unit stay. The favorable pharmacodynamic profile of sugammadex may improve surgical and perioperative efficiency and offset higher medication cost.

Comparing Bupivacaine, Lidocaine, and a Combination of Bupivacaine and Lidocaine for Labor Epidural Activation: A Prospective, Randomized, Double-Blind Study

Objective: Epidural anesthesia for the parturient is often provided in a clinical context where rapid onset of segmental analgesia is important; however, little is published on the ideal local anesthetic to safely achieve this onset. To fi ll this gap in knowledge, we studied bupivacaine and lidocaine, two local anesthetics (LA) commonly used for labor epidural activation, either as a single drug or in combination to determine the onset of epidural analgesia. Methods: In this double-blinded study, seventy-five patients were randomized into three groups (n = 25 each) for labor epidural activation: 10 mL of 0.25% bupivacaine, 10 mL of 1% lidocaine, or 5 mL of 0.25% bupivacaine plus 5 mL of 1% lidocaine. Patients were assessed for the fi rst 20 min after drug administration at 5-min intervals. Data collected included sensory level to pinprick, maternal blood pressure, vasopressor administration, and peak motor blockade. Results: Data were analyzed on 71 of 75 patients. Time to loss of sensation to pinprick at the T10 dermatome in the bupivacaine group was signifi cantly longer than the lidocaine group (p = 0.006), but the time to loss of sensation to pinprick at the T10 dermatome did not signifi cantly differ in the bupivacaine plus lidocaine group when compared to both the bupivacaine (p = 0.114) as well as the lidocaine (p = 0.203) groups. Phenylephrine usage did not signifi cantly differ amongst the three groups (p = 0.062). Conclusion: Lidocaine provides statistically signifi cant faster onset of epidural analgesia when compared to bupivacaine only. Combining the two LA did not signifi cantly affect onset.

Utility of ultrasonography in identification of midline and epidural placement in severely obese parturients.

BACKGROUND: Due to body habitus, lumbar epidural placement can be challenging in severely obese parturients. Several studies have been published assessing the usefulness of ultrasonography in the placement of neuraxial blocks. One patient population that is under-represented in these studies is the severely obese parturient. We sought to determine if performing an abbreviated ultrasound exam of the lumbar spine to determine midline by locating spinous process could facilitate lumbar epidural placement in severely obese parturients. METHODS: One hundred fifty patients with a Body Mass Index (BMI) of ≥35 kg/m2 were randomized into two groups. The palpation (P) group had midline identified by the traditional palpation technique. The ultrasonography (U) group had midline identified by ultrasound visualization of the spinous process in the transverse plane. Midline identification and epidural placement were done by both junior and senior anesthesiology residents at our teaching institution. RESULTS: Data were analyzed on all 150 patients. BMI was similar in the U and P groups (43.3 vs. 44.4 kg/m2, P=0.359). Time for epidural placement (6.2 vs. 9.0 minutes, P<0.01) and total procedure time (6.9 vs. 9.5 minutes, P<0.01) were significantly less in the U group. The number of needle passes (2.1 vs. 2.8, P=0.02) was also less in the U group. There was no significant difference in the failure rates of the U and P groups (4.0% vs. 9.3%, P=0.19). CONCLUSIONS: The use of an abbreviated ultrasound exam to identify midline in severely obese parturients can reduce the time required for lumbar epidural placement.