RESUMO
Background: Since the 1990's attempts to favorably modulate nitric oxide (NO) have been unsuccessful. We hypothesized that because NO is lipophilic it would preferentially localize into intravascularly infused hydrophobic nanoparticles, thereby reducing its bioavailability and adverse effects without inhibiting its production. We aimed to determine the efficacy and safety of intravenous infusion of a fluid comprised of hydrophobic phospholipid nanoparticles (VBI-S) that reversibly absorb NO in the treatment of hypotension of patients in severe septic shock. Methods: This is a multicentre, open-label, repeated measures, phase 2a clinical pilot trial done at six hospital centers in the USA. Patients in severe septic shock were enrolled after intravenous fluid therapy had failed to raise mean arterial blood pressure (MAP) to at least the generally accepted level of 65 mmHg, requiring the use of vasopressors. The primary endpoint of this study is the proportion of patients in whom MAP increased by at least 10 mmHg. VBI-S was administered intravenously to patients as boluses of 100 ml, 200 ml, 400 ml, and 800 ml at 999 ml/min until the blood pressure goal was reached after which the infusion was stopped, and the MAP was recorded. All patients who received any volume of VBI-S were included in the primary and safety analysis. The study is registered with ClinicalTrials.gov, NCT04257136. Findings: Between February 17, 2020 and January 3, 2023, 20 eligible patients were enrolled in the study. In all 20 (100%) patients, the goal of increasing MAP by at least 10 mmHg using VBI-S was achieved (p = 0.0087, effect size = 0.654). Mean VBI-S volume required to meet the primary goal was 561.0 ± 372.3 ml. The goal of lowering vasopressor dose was also achieved (p = 0.0017). Within 48 h or less after VBI-S, there was a statistically significant improvement in oxygenation, serum creatinine, clotting variables, procalcitonin, lactic acid, and the sequential organ failure assessment (SOFA) score. At 24 h and 48 h following administration of VBI-S, 12/15 (80%) and 9/12 (75%) patients developed hyperlipidemia, respectively. No severe adverse events of VBI-S were observed, and there were no treatment-related deaths. Interpretation: These preliminary findings suggest the safety and efficacy of VBI-S in treating hypotension in patients with septic shock. However, a definitive mortality benefit cannot be demonstrated without a randomized controlled study. Funding: The Naval Medical Research Command-Naval Advanced Medical Development program via the Medical Technology Enterprise Consortium.
RESUMO
The goal of this study was to develop an in vivo awake mouse model for extracellular bladder sensory nerve recording. A bipolar 125-µm silver electrode was positioned under a single postganglionic bladder nerve. Efferent nerve signals were eliminated by tying off the postganglionic bladder nerve between the major pelvic ganglion and the recording electrode. Sensory nerve activity was measured in the conscious animals 48 h after surgery during continuous intravesical infusion of 0.9% saline/0.5% acetic acid followed by 0.5% acetic acid with capsazepine (10 µM) at a rate of 0.75 ml/h. Continuous infusion of 0.9% NaCl led to a gradual increase in the frequency of sensory nerve firing that peaked upon reaching threshold pressure. Non-micturition contractions were observed in some animals during filling and other animals exhibited only minimal pressure fluctuations; both types of events were associated with a rise in sensory nerve activity. Intravesical infusion of 0.5% acetic acid reduced the intermicturition interval. This was associated with a 2.1-fold increase in bladder pressure during filling and a two-fold increase at both threshold and micturition pressures. Concurrent with these changes, sensory activity increased 2.8-fold during filling and 2.4-fold at threshold pressure. Subsequent intravesical infusion of capsazepine in 0.5% acetic acid reduced filling and threshold pressures by 21 and 31.2%, respectively, and produced corresponding decreases of 36 and 23.4% in sensory nerve activity. The current study shows that multifiber sensory nerve recordings can be reproducibly obtained from conscious mice.
