Myoendothelial feedback in mouse mesenteric resistance arteries is similar between the sexes, dependent on nitric oxide synthase, and independent of TPRV4.

Myoendothelial feedback (MEF), the endothelium-dependent vasodilation following sympathetic vasoconstriction (mediated by smooth muscle to endothelium gap junction communication), has been well studied in resistance arteries of males, but not females. We hypothesized that MEF responses would be similar between the sexes, but different in the relative contribution of the underlying nitric oxide and hyperpolarization mechanisms, given that these mechanisms differ between the sexes in agonist-induced endothelium-dependent dilation. We measured MEF responses (diameter changes) of male and female first- to second-order mouse mesenteric arteries to phenylephrine (10 µM) over 30 min using isolated pressure myography ± blinded inhibition of nitric oxide synthase (NOS) using Nω-nitro-l-arginine methyl ester (l-NAME; 0.1-1.0 mM), hyperpolarization using 35 mM KCl, or transient receptor potential vanilloid 4 (TRPV4) channels using GSK219 (0.1-1.0 µM) or RN-1734 (30 µM). MEF was similar [%dilation (means ± SE): males = 26.7 ± 2.0 and females = 26.1 ± 1.9 at 15 min] and significantly inhibited by l-NAME (1.0 mM) at 15 min [%dilation (means ± SE): males = 8.2 ± 3.3, P < 0.01; females = 6.8 ± 1.9, P < 0.001] and over time (P < 0.01) in both sexes. l-NAME (0.1 mM) + 35 mM KCl nearly eliminated MEF in both sexes (P < 0.001-0.0001). Activation of TRPV4 with GSK101 (0.1-10 µM) induced similar dilation between the sexes. Inhibition of TRPV4, which is reportedly involved in the hyperpolarization mechanism, did not inhibit MEF in either sex. Similar expression of eNOS was found between the sexes with Western blot. Thus, MEF is prominent and similar in murine first- and second-order mesenteric resistance arteries of both sexes, and reliant primarily on NOS and secondarily on hyperpolarization, but not TRPV4.NEW & NOTEWORTHY We found that female mesenteric resistance arteries have similar postconstriction dilatory responses (i.e., myoendothelial feedback) to a sympathetic neurotransmitter analog as male arteries. Both sexes use nitric oxide synthase (NOS) and hyperpolarization, but not TRPV4, in this response. Moreover, the key protein involved in this pathway (eNOS) is similarly expressed in these arteries between the sexes. These similarities are surprising given that agonist-induced endothelium-dependent dilatory mechanisms differ in these arteries between the sexes.

Phenylephrine alters phase synchronization between cerebral blood velocity and blood pressure in ME/CFS with orthostatic intolerance.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CBV compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO2 and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CBV.NEW & NOTEWORTHY We evaluated cognitive function before and after CO2, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO2 nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO2 significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Effects of phenylephrine on systemic and cerebral circulations in humans: a systematic review with mechanistic explanations.

We conducted a systematic review of the literature reporting phenylephrine-induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near-infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r = -0.54 and p = 0.09 in awake humans; r = -0.55 and p = 0.007 in anaesthetised humans), cerebral blood flow (r = 0.65 and p = 0.002 in awake humans; r = 0.80 and p = 0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r = -0.72 and p = 0.03 in awake humans; r = -0.24 and p = 0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine-induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine-induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care.

Prediction of preload dependency using phenylephrine-induced peripheral perfusion index during general anaesthesia: a prospective observational study.

BACKGROUND: Tracking preload dependency non-invasively to maintain adequate tissue perfusion in the perioperative period can be challenging.The effect of phenylephrine on stroke volume is dependent upon preload. Changes in stroke volume induced by phenylephrine administration can be used to predict preload dependency. The change in the peripheral perfusion index derived from photoplethysmography signals reportedly corresponds with changes in stroke volume in situations such as body position changes in the operating room. Thus, the peripheral perfusion index can be used as a non-invasive potential alternative to stroke volume to predict preload dependency. Herein, we aimed to determine whether changes in perfusion index induced by the administration of phenylephrine could be used to predict preload dependency. METHODS: We conducted a prospective single-centre observational study. The haemodynamic parameters and perfusion index were recorded before and 1 and 2 min after administering 0.1 mg of phenylephrine during post-induction hypotension in patients scheduled to undergo surgery. Preload dependency was defined as a stroke volume variation of ≥ 12% before phenylephrine administration at a mean arterial pressure of < 65 mmHg. Patients were divided into four groups according to total peripheral resistance and preload dependency. RESULTS: Forty-two patients were included in this study. The stroke volume in patients with preload dependency (n = 23) increased after phenylephrine administration. However, phenylephrine administration did not impact the stroke volume in patients without preload dependency (n = 19). The perfusion index decreased regardless of preload dependency. The changes in the perfusion index after phenylephrine administration exhibited low accuracy for predicting preload dependency. Based on subgroup analysis, patients with high total peripheral resistance tended to exhibit increased stroke volume following phenylephrine administration, which was particularly prominent in patients with high total peripheral resistance and preload dependency. CONCLUSION: The findings of the current study revealed that changes in the perfusion index induced by administering 0.1 mg of phenylephrine could not predict preload dependency. This may be attributed to the different phenylephrine-induced stroke volume patterns observed in patients according to the degree of total peripheral resistance and preload dependency. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN000049994 on 9/01/2023).

A retrospective study of the effects of a vasopressor bolus on systolic slope (dP/dt) and dynamic arterial elastance (Eadyn).

BACKGROUND: To enhance the utility of functional hemodynamic monitoring, the variables systolic slope (dP/dt) and dynamic arterial elastance (Eadyn) are calculated by the Hypotension Prediction Index (HPI) Acumen® Software. This study was designed to characterize the effects of phenylephrine and ephedrine on dP/dt and Eadyn. METHODS: This was a retrospective, non-randomized analysis of data collected during two clinical studies. All patients required intra-operative controlled mechanical ventilation and had an indwelling radial artery catheter connected to an Acumen IQ sensor. Raw arterial pressure waveform data was downloaded from the patient monitor and all hemodynamic measurements were calculated off-line. The anesthetic record was reviewed for bolus administrations of either phenylephrine or ephedrine. Cardiovascular variables prior to drug administration were compared to those following vasopressor administrations. The primary outcome was the difference for dP/dt and Eadyn at baseline compared with the average after the bolus administration. All data sets demonstrated non-normal distributions so statistical analysis of paired and unpaired data followed the Wilcoxon matched pairs signed-rank test or Mann-Whitney U test, respectively. RESULTS: 201 doses of phenylephrine and 100 doses of ephedrine were analyzed. All data sets are reported as median [95% CI]. Mean arterial pressure (MAP) increased from 62 [54,68] to 78 [76,80] mmHg following phenylephrine and from 59 [55,62] to 80 [77,83] mmHg following ephedrine. Stroke volume and cardiac output both increased. Stroke volume variation and pulse pressure variation decreased. Both drugs produced significant increases in dP/dt, from 571 [531, 645] to 767 [733, 811] mmHg/sec for phenylephrine and from 537 [509, 596] to 848 [779, 930] mmHg/sec for ephedrine. No significant changes in Eadyn were observed. CONCLUSION: Bolus administration of phenylephrine or ephedrine increases dP/dt but does not change Eadyn. dP/dt demonstrates potential for predicting the inotropic response to phenylephrine or ephedrine, providing guidance for the most efficacious vasopressor when treating hypotension. TRIAL REGISTRATION: Data was collected from two protocols. The first was deemed to not require written, informed consent by the Institutional Review Board (IRB). The second was IRB-approved (Effect of Diastolic Dysfunction on Dynamic Cardiac Monitors) and registered on ClinicalTrials.gov (NCT04177225).

Multi-walled carbon nanotubes/carbon black/rPLA for high-performance conductive additive manufacturing filament and the simultaneous detection of acetaminophen and phenylephrine.

The combination of multi-walled carbon nanotubes (MWCNT) and carbon black (CB) is presented to produce a high-performance electrically conductive recycled additive manufacturing filament. The filament and subsequent additively manufactured electrodes were characterised by TGA, XPS, Raman, and SEM and showed excellent low-temperature flexibility. The MWCNT/CB filament exhibited an improved electrochemical performance compared to an identical in-house produced bespoke filament using only CB. A heterogeneous electrochemical rate constant, [Formula: see text] of 1.71 (± 0.19) × 10-3 cm s-1 was obtained, showing an almost six times improvement over the commonly used commercial conductive CB/PLA. The filament was successfully tested for the simultaneous determination of acetaminophen and phenylephrine, producing linear ranges of 5-60 and 5-200 µM, sensitivities of 0.05 µA µM-1 and 0.14 µA µM-1, and limits of detection of 0.04 µM and 0.38 µM, respectively. A print-at-home device is presented where a removable lid comprised of rPLA can be placed onto a drinking vessel and the working, counter, and reference components made from our bespoke MWCNT/CB filament. The print-at-home device was successfully used to determine both compounds within real pharmaceutical products, with recoveries between 87 and 120% over a range of three real samples. This work paves the way for fabricating new highly conductive filaments using a combination of carbon materials with different morphologies and physicochemical properties and their application to produce additively manufactured electrodes with greatly improved electrochemical performance.

Vasoconstriction with phenylephrine increases cardiac output in preload dependent patients.

General Anaesthesia (GA) is accompanied by a marked decrease in sympathetic outflow and thus loss of vasomotor control of cardiac preload. The use of vasoconstriction during GA has mainly focused on maintaining blood pressure. Phenylephrine (PE) is a pure α1-agonist without inotropic effects widely used to correct intraoperative hypotension. The potential of PE for augmenting cardiac stroke volume (SV) and -output (CO) by venous recruitment is controversial and no human studies have explored the effects of PE in preload dependent circulation using indicator dilution technique. We hypothesized that PE-infusion in patients with cardiac stroke volume limited by reduced preload would restore preload and thus augment SV and CO. 20 patients undergoing GA for gastrointestinal surgery were monitored with arterial catheter and LiDCO unity monitor. Upon stable haemodynamics after induction patients were placed in head-up tilt (HUT). All patients became preload responsive as verified by a stroke volume variation (SVV) of > 12%. PE-infusion was then started at 15-20mikrg/min and adjusted until preload was restored (SVV < 12%). Li-dilution cardiac output (CO) was initially measured after induction (baseline), again with HUT in the preload responsive phase, and finally when preload was restored with infusion of PE.At baseline SVV was 10 ± 3% (mean ± st.dev.), CI was 2,6 ± 0,4 L/min*m2, and SVI 43 ± 7mL/m2. With HUT SVV was 19 ± 4%, CI was 2,2 ± 0,4 L/min*m2, SVI 35 ± 7mL/m2. During PE-infusion SVV was reduced to 6 ± 3%, CI increased to 2,6 ± 0,5 L/min*m2, and SVI increased to 49 ± 11mL/m2. All differences p < 0,001. In conclusion: Infusion of phenylephrine during preload dependency increased venous return abolishing preload dependency as evaluated by SVV and increased cardiac stroke volume and -output as measured by indicator-dilution technique. (ClinicalTrials.gov NCT05193097).

The effect of three different mydriatic eye drops on retinal vessel diameters.

PURPOSE: To investigate the effects of topically applied 1% tropicamide, 2.5% phenylephrine and 1% cyclopentolate on retinal vessel calliper (VC) using optical coherence tomography (OCT). METHODS: Patients who came to the ophthalmology clinic for routine examination and whose OCT films were taken before dilatation and after 30 min of last dilatation drop were included in the study. 90 ophthalmologically healthy subjects were divided into 3 groups of 30 subject each according to the application of the drops as follows: Tropicamide group (Group 1), Phenylephrine group (Group 2), Cyclopentolate group (Group 3). The right eyes of the subjects were dilated with drops and the left eyes were taken as the control group. VC of retinal artery and vein passing through an area one-half to one-disc diameter from the optic disc margin were measured from OCT films. The mean of the sum of superior retinal artery (SRA) and inferior retinal artery (IRA) VC and the mean of the sum of superior retinal vein (SRV) and inferior retinal vein (IRV) VC before and after the drop were compared. RESULTS: There was no statistically significant change in the mean sum of SRA and IRA VC and the mean sum of SRV and IRV VC before and after dilatation drops in all three groups. CONCLUSION: Dilatation drops have no statistically significant effect on retinal artery and vein VC.

Epinephrine vs. phenylephrine infusion for prophylaxis against maternal hypotension after spinal anesthesia for cesarean delivery: a randomized controlled trial.

BACKGROUND: The hemodynamic effects of relatively low-dose epinephrine and phenylephrine infusions during cesarean delivery under spinal anesthesia were compared. METHODS: This randomized controlled trial included full-term pregnant women who underwent elective cesarean delivery. After spinal anesthesia, participants received either epinephrine (0.03 mcg/kg/min) or phenylephrine (0.4 mcg/kg/min) infusion that continued until 5 min after delivery. The primary outcome was a composite outcome of the occurrence of any of hypotension, hypertension, bradycardia, and/or tachycardia. Neonatal outcomes, including umbilical artery blood gas and Apgar scores, were assessed. RESULTS: In total, 98 patients in each group were analyzed, and the number of patients with the composite outcome was comparable between the epinephrine and phenylephrine groups (30/98 [31%] vs. 31/98 [32%], respectively; P = 0.877). However, the incidence of hypotension was likely lower in the epinephrine group than in the phenylephrine group (P = 0.066), and the number of hypotensive episodes per patient was lower in the epinephrine group than in the phenylephrine group. On the other hand, the incidence of tachycardia was higher in the epinephrine group than that in the phenylephrine group. The incidence of hypertension was comparable between the two groups and none of the participants developed bradycardia. Neonatal outcomes were comparable between the two groups. CONCLUSIONS: Epinephrine and phenylephrine infusion produced comparable maternal hemodynamics and neonatal outcomes. Epinephrine was associated with a higher incidence of maternal tachycardia and likely lower incidence of maternal hypotension than phenylephrine. IRB number: MD-245-2022. CLINICAL TRIAL REGISTRATION: This study was registered on May 31, 2023 at clinicaltrials.gov registry, NCT05881915, URL: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05881915term=NCT05881915&draw=2&rank=1.

Novel HPTLC method for simultaneous estimation from ternary mixture of chlorpheniramine maleate, dextromethorphan hydrobromide and phenylephrine hydrochloride in syrup formulations.

OBJECTIVES: A synergic antihistamine, cough suppressant, and decongestant combination of chlorpheniramine, dextromethorphan, and phenylephrine is used to treat acute respiratory infections caused by seasonal viruses. The effective qualitative and quantitative methods require the simultaneous measurement of a ternary combination in the pharmaceutical syrup dosage form. Therefore, a new, simple, fast and robust high performance thin layer chromatographic (HPTLC) method has been developed and validated for chlorpheniramine maleate (CPM), dextromethorphan hydrobromide (DEXO) and phenylephrine hydrochloride (PE). MATERIAL AND METHODS: The chromatographic separation was carried out on precoated aluminium plates with silica gel 60 F254 as the stationary phase. Mobile phase used was chloroform: methanol: ammonia (2.5:7.5:0.3, v/v/v) for proper separation. The detection was carried out at 270nm wavelength in absorbance mode. Developed method was validated as per International Council for Harmonization (ICH) Q2 (R1) guideline. RESULTS: The linearity range is 400 to 1400ng/band for CPM, 3000 to 11500ng/band for DEXO and 1000 to 3500ng/band for PE with correlation coefficient ≥ 0.995. The consistent lower values of relative standard deviation (RSD, %) for precision and robustness study indicate the method reliability. The percent recovery ranged from 97.82 to 102.03% indicates the good accuracy of the method. CONCLUSION: The proposed method was complying for the analytical method validation parameters suggested by the ICH Q2 (R1) guideline. The method was found to be simple, rapid and reliable for the simultaneous estimation of CPM, DEXO and PE from its pharmaceutical syrup dosage form. The method was successfully applied to quantify these analytes from the several pharmaceutical syrup dosage form.

Comparison of Prophylactic Phenylephrine Infusion and Rescue Bolus Administration for Maintaining Blood Pressure During Spinal Anaesthesia for Caesarean Delivery in Obese Parturient: A Randomised Control Trial.

Background: Phenylephrine (PE) is one of the vasopressor used to treat hypotension during anaesthesia. The primary aim of this study was to compare the effect of prophylactic infusion and rescue bolus of PE on the haemodynamic changes during spinal anaesthesia (SA) for Caesarean section (CS) in obese parturients. Methods: A total of 74 obese parturients scheduled for elective CS under SA were randomised into two groups; Group A (n = 37) received prophylactic PE infusion starting at 50 µg min-1 and adjusted according to the given algorithm and Group B (n = 37) received 100 µg PE bolus to treat hypotension. The measured parameters were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), the total requirement of PE and neonatal Apgar score. Results: Six patients were excluded from the analysis due to missing data and only 68 were analysed. Group A showed significantly higher SBP, DBP and MAP than Group B (P < 0.05). The requirement of PE was higher in Group A than Group B [817.7 (265.7) µg versus 360.6 (156.0) µg; P = < 0.05]. Both groups had no difference in terms of the neonatal Apgar score. Conclusion: Prophylactic PE infusion provided better haemodynamic control than therapeutic boluses in obese parturients undergoing CS under SA.

Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function.

KV1.5 channels are key players in the regulation of vascular tone and atrial excitability and their impairment is associated with cardiovascular diseases including pulmonary arterial hypertension (PAH) and atrial fibrillation (AF). Unfortunately, pharmacological strategies to improve KV1.5 channel function are missing. Herein, we aimed to study whether the chaperone sigma-1 receptor (S1R) is able to regulate these channels and represent a new strategy to enhance their function. By using different electrophysiological and molecular techniques in X. laevis oocytes and HEK293 cells, we demonstrate that S1R physically interacts with KV1.5 channels and regulate their expression and function. S1R induced a bimodal regulation of KV1.5 channel expression/activity, increasing it at low concentrations and decreasing it at high concentrations. Of note, S1R agonists (PRE084 and SKF10047) increased, whereas the S1R antagonist BD1047 decreased, KV1.5 expression and activity. Moreover, PRE084 markedly increased KV1.5 currents in pulmonary artery smooth muscle cells and attenuated vasoconstriction and proliferation in pulmonary arteries. We also show that both KV1.5 channels and S1R, at mRNA and protein levels, are clearly downregulated in samples from PAH and AF patients. Moreover, the expression of both genes showed a positive correlation. Finally, the ability of PRE084 to increase KV1.5 function was preserved under sustained hypoxic conditions, as an in vitro PAH model. Our study provides insight into the key role of S1R in modulating the expression and activity of KV1.5 channels and highlights the potential role of this chaperone as a novel pharmacological target for pathological conditions associated with KV1.5 channel dysfunction.

Norepinephrine combined with phenylephrine versus norepinephrine in patients with septic shock: a retrospective cohort study.

BACKGROUND: Phenylephrine (PE) and norepinephrine (NE) may be used to maintain adequate blood pressure and tissue perfusion in patients with septic shock, but the effect of NE combined with PE (NE-PE) on mortality remains unclear. We hypothesized that NE-PE would not inferior to NE alone for all-cause hospital mortality in patients with septic shock. METHODS: This single-center, retrospective cohort study included adult patients with septic shock. According to the infusion type, patients were divided into the NE-PE or NE group. Multivariate logistic regression, propensity score matching and doubly robust estimation were used to analyze the differences between groups. The primary outcome was the all-cause hospital mortality rate after NE-PE or NE infusion. RESULTS: Among 1, 747 included patients, 1, 055 received NE and 692 received NE-PE. For the primary outcome, the hospital mortality rate was higher in patients who received NE-PE than in those who received NE (49.7% vs. 34.5%, p < 0.001), and NE-PE was independently associated with higher hospital mortality (odds ratio = 1.76, 95% confidence interval = 1.36-2.28, p < 0.001). Regarding secondary outcomes, patients in the NE-PE group had longer lengths of stay in ICU and hospitals. Patients in the NE-PE group also received mechanical ventilation for longer durations. CONCLUSIONS: NE combined with PE was inferior to NE alone in patients with septic shock, and it was associated with a higher hospital mortality rate.

Norepinephrine versus phenylephrine for treating hypotension during general anaesthesia in adult patients undergoing major noncardiac surgery: a multicentre, open-label, cluster-randomised, crossover, feasibility, and pilot trial.

BACKGROUND: Intraoperative hypotension is associated with postoperative complications. The use of vasopressors is often required to correct hypotension but the best vasopressor is unknown. METHODS: A multicentre, cluster-randomised, crossover, feasibility and pilot trial was conducted across five hospitals in California. Phenylephrine (PE) vs norepinephrine (NE) infusion as the first-line vasopressor in patients under general anaesthesia alternated monthly at each hospital for 6 months. The primary endpoint was first-line vasopressor administration compliance of 80% or higher. Secondary endpoints were acute kidney injury (AKI), 30-day mortality, myocardial injury after noncardiac surgery (MINS), hospital length of stay, and rehospitalisation within 30 days. RESULTS: A total of 3626 patients were enrolled over 6 months; 1809 patients were randomised in the NE group, 1817 in the PE group. Overall, 88.2% received the assigned first-line vasopressor. No drug infiltrations requiring treatment were reported in either group. Patients were median 63 yr old, 50% female, and 58% white. Randomisation in the NE group vs PE group did not reduce readmission within 30 days (adjusted odds ratio=0.92; 95% confidence interval, 0.6-1.39), 30-day mortality (1.01; 0.48-2.09), AKI (1.1; 0.92-1.31), or MINS (1.63; 0.84-3.16). CONCLUSIONS: A large and diverse population undergoing major surgery under general anaesthesia was successfully enrolled and randomised to receive NE or PE infusion. This pilot and feasibility trial was not powered for adverse postoperative outcomes and a follow-up multicentre effectiveness trial is planned. CLINICAL TRIAL REGISTRATION: NCT04789330 (ClinicalTrials.gov).

Application of the C-C3N4/Li2CoMn3O8//IL nanocomposite for design a sensitive electrochemical sensor inorder to detection of cetirizine, acetaminophen and phenylephrine in biological and pharmaceuticals samples.

Due to the side effects of cetirizine overdose and the need to monitor its concentration in the human body, in this work, an electrochemical sensor has been prepared by utilizing a carbon paste electrode modified with Li2CoMn3O8/CC3N4 nanocomposite and ethyl-3-methyl-imidazolium chloride ionic liquid ([EMIM][Cl]) to determine cetirizine in the human blood serum sample and urine as well as drug samples. Li2CoMn3O8/CC3N4 nanocomposite was characterized by Fourier transform infrared (FT-IR), field emission scanning electron microscope (FESEM), and X-ray diffraction (XRD) analysis. The investigation of the influence of each modifier component showed that the existence of all components in modification has a synergistic effect. Li2CoMn3O8/CC3N4/IL nanocomposite has a larger surface area relative to the components alone, thus providing a more fine-grained media to facilitate electron transfer during the reaction between analyte and electrode. Determination of cetirizine was performed in phosphate buffer solution with pH 7.0 and detection limits obtained in the concentration ranges of 0.03-0.9 and 3-300 µM was 11.8 × 10-9 M. The diffusion coefficient (D = 9.2 × 10-6 cm2s-1) of cetirizine at the surface of the modified electrode was determined by chronoamperometry. Finally, simultaneous detection of cetirizine, phenylephrine and acetaminophen was performed using the suggested sensor without any interference.

Phenylephrine-Induced Contraction in Guinea Pig Thoracic Aorta Is Triggered by Stimulation of α1L-Adrenoceptors Functionally Coupled with Store-Operated Ca2+ Channels and Voltage-Dependent Ca2+ Channels.

We examined whether the α1L-adrenoceptor (AR), which shows low affinity (pA2 < 9) for prazosin (an α1-AR antagonist) and high affinity (pA2 ≈ 10) for tamsulosin/silodosin (α1A-AR antagonists), is involved in phenylephrine-induced contractions in the guinea pig (GP) thoracic aorta (TA). Intracellular signaling induced by α1L-AR activation was also examined by focusing on Ca2+ influx pathways. Tension changes of endothelium-denuded TAs were isometrically recorded and mRNA encoding α-ARs/Ca2+ channels and their related molecules were measured using RT-quantitative PCR. Phenylephrine-induced contractions were competitively inhibited by prazosin/tamsulosin, and their pA2 value were calculated to be 8.53/9.74, respectively. These contractions were also inhibited by silodosin concentration-dependently. However, the inhibition was not competitive fashion with the apparent pA2 value being 9.48. In contrast, phenylephrine-induced contractions were not substantially suppressed by L-765314 (an α1B-AR antagonist), BMY 7378 (an α1D-AR antagonist), yohimbine, and idazoxan (α2-AR antagonists). Phenylephrine-induced contractions were markedly inhibited by YM-254890 (a Gq protein inhibitor) or removal of extracellular Ca2+, and partially inhibited by verapamil (a voltage-dependent Ca2+ channel (VDCC) inhibitor). The residual contractions in the presence of verapamil were slightly inhibited by LOE 908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) and strongly inhibited by SKF-96365 (a store-operated Ca2+ channel (SOCC) and ROCC inhibitor). Among the mRNA encoding α-ARs/SOCC-related molecules, α1A-AR (Adra1a)/Orai3, Orai1, and Stim2 were abundant in this tissue. In conclusion, phenylephrine-induced contractions in the GP TA can be triggered by stimulation of Gq protein-coupled α1L-AR, followed by activation of SOCCs and VDCCs.

The effect of combining prewarming with intraoperative phenylephrine infusion on the prevention of hypothermia in patients undergoing urological surgery: a prospective, randomized, and controlled trial.

Background: Hypothermia is common in patients undergoing urological surgery; however, no single preventative modality is completely effective. This study evaluated the effects of combining prewarming with intraoperative phenylephrine infusion for the prevention of hypothermia in patients undergoing urological surgery. Methods: This prospective study enrolled 58 patients scheduled for urological surgery under general anesthesia. The patients were randomized into two groups (n = 29). Patients in the experimental (prewarming and phenylephrine infusion) group (PP group) received prewarming for 20 min and intraoperative phenylephrine infusion, whereas those in the control group (C group) received no active prewarming with only intermittent administration of vasoactive agents. The patient's sublingual temperatures before and after anesthesia and nasopharyngeal temperature during anesthesia were recorded as core temperatures. Results: The incidence of intraoperative hypothermia was higher in the C group than in the PP group (57.7% [15/26] vs. 23.1% [6/26], P = 0.01). The severity of intraoperative hypothermia was higher in the C group than in the PP group (P = 0.004). The nasopharyngeal temperature at the end of surgery was lower in the C group than in the PP group (35.8 ± 0.6°C vs. 36.3 ± 0.4°C, P = 0.002). The trend of core temperature decline during the first hour after anesthesia induction differed between the two groups (P = 0.003; its decline was more gradual in the PP group). Conclusions: The combination of prewarming for 20 min and intraoperative phenylephrine infusion reduced the incidence and severity of intraoperative hypothermia and modified the trend of decreasing core temperatures in patients undergoing urological surgery.

Resolving phenylephrine HCl and guaifenesin enantiomers on cellulose-based chiral stationary phases: Separation of four enantiomers on 50-mm column.

Chiral high performance liquid chromatographic technique usually employs polysaccharide-based stationary phases in a normal phase mode. This frequently generates large waste of organic solvents. Using shorter columns of 50 mm length as well as a mobile phase with a high water percentage are common approaches for greening this analytical technique. In this context, a new chiral chromatographic technique was developed for simultaneous enantio-separation of phenylephrine HCl and guaifenesin racemates. Four 50 mm cellulose-based columns were experimented to separate the four enantiomers in a reversed phase mode. A face centered design was then employed to optimize the mobile phase acetonitrile% and flow rate on Lux Cellulose-1 (50 × 4.6 mm, 5 µm). The simultaneous resolution of the cited drugs enantiomers was achieved using acetonitrile-water (30:70, by volume), with a flow rate of 0.5 ml min-1 . These optimized chromatographic conditions separate the enantiomers in 7 min running time, generating about 1.0 ml acetonitrile per run. The proposed method was favorably compared with other reported chiral ones in terms of waste volume generated and analysis time required.

Oxytocin infusion for maintenance of uterine tone under prophylactic phenylephrine infusion for prevention of post-spinal hypotension in cesarean delivery: a prospective randomised double-blinded dose-finding study.

BACKGROUND: Prior studies have shown that, when administered as an intravenous bolus to prevent uterine atony, prophylactic phenylephrine infusion increased the dose requirement of oxytocin and second-line uterotonics. For the prevention of uterine atony, oxytocin should be delivered by continuous infusion. Here, we aimed to determine the ED50 and ED90 parameters (the effective doses for 50 and 90% patients without uterine atony) of oxytocin for co-infusion with prophylactic phenylephrine during cesarean delivery. METHODS: In this prospective randomized double-blinded dose-finding study, one hundred patients were divided into four groups to receive 2.5, 5.0, 7.5, or 10 IU/h oxytocin infusion, after the umbilical cord was clamped during the study period. The uterine tone was evaluated and defined as either adequate or inadequate. Probit regression analysis was applied to calculate the ED50 and ED90 of oxytocin infusion. Uterine tone, the percentage of patients who needed additional oxytocin bolus, second-line uterotonics, side effects, estimated blood loss, and neonatal outcomes were monitored. RESULTS: The estimated ED50 and ED90 values of the oxytocin infusion doses for the prevention of uterine atony were 1.9 IU/h (95% CI -4.6-3.8) IU/h and 9.3 IU/h (95% CI 7.3-16.2) IU/h, respectively. Across groups, there was a significant linear trend between the infusion dose and the percentage of patients who required additional oxytocin (p-value = 0.002). No differences were observed in the incidence of side effects and neonatal outcomes. CONCLUSION: Under the conditions of this study, the ED90 of oxytocin infusion for the prevention of uterine atony was 9.3 IU/h, which is higher than the current recommendation. This finding is helpful for clinical practice, because of the routine use of phenylephrine in cesarean delivery. Further studies are needed to determine the appropriate initial bolus of oxytocin after neonatal delivery. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial Register (register no. ChiCTR2200059556 ).

Impact of hyperoxia and phenylephrine on cerebral oxygenation: An experimental clinical study.

BACKGROUND: Oxygen supply to the brain is of special importance during intracranial surgery because it may be compromised by intracranial pathology. A high arterial blood pressure (mean arterial pressure above 80 mmHg) and a high arterial oxygen tension (PaO2 above 12 kPa) is therefore often targeted in these patients, when for example intracranial pressure is increased or when a mass effect on brain tissue from a tumour is present, and it is pursued by administering vasopressors such as phenylephrine and by increasing inspiratory oxygen fraction (FiO2 ). However, whether these interventions increase cerebral oxygenation remains uncertain. We aimed to investigate the effect of hyperoxia and phenylephrine on brain tissue oxygen tension (PbtO2 ) in patients undergoing craniotomy. METHODS: In this experimental study, we included 17 adult patients scheduled for elective craniotomy. After securing a stable baseline of the oxygen probe, PbtO2 was measured in white matter peripherally in the surgical field during general anaesthesia. Primary comparisons were PbtO2 before versus after an increase in FiO2 from 0.30 to 0.80 as well as before versus after a bolus dose of phenylephrine (0.1-0.2 mg depending on patient haemodynamics). Data were analysed with the Wilcoxon signed rank test. RESULTS: We obtained complete data sets in 11 patients undergoing the FiO2 increase and six patients receiving the phenylephrine bolus. PbtO2 was 22 (median; 5%-95% range, 4.6-54) mmHg during 30% oxygen, 68 (8.4-99) mmHg during 80% oxygen (p = .004 compared to 30% oxygen), 21 (4.5-81) mmHg before phenylephrine, and 19 (4.2-56) mmHg after phenylephrine (p = .56 compared to before phenylephrine). CONCLUSION: In patients undergoing craniotomy under general anaesthesia, brain tissue oxygen tension increased with a high inspiratory oxygen fraction but remained unchanged after a bolus dose of phenylephrine.