Administration Of Norepinephrine Research Articles

Peripheral Use of Vasopressors in Shock: Clinical Considerations and Recommendations for Use in Obstetrics.

This study aimed to evaluate the safety of peripheral administration of vasopressor agents among patients with circulatory shock. We reviewed the published literature evaluating the use of peripheral norepinephrine in patients with shock and proposed a protocol for use in labor and delivery units. Peripheral administration of norepinephrine is a safe and potentially lifesaving intervention for patients in labor and delivery with extremely low complication rates. Adoption of a protocol for peripheral administration of vasopressors in labor and delivery is safe and may prevent life threatening delays in hemodynamic resuscitation. · Administering vasopressors through a peripheral line is safe and helps avoid delays in care.. · An established protocol is essential for the safe peripheral administration of vasopressors.. · Understanding continuous blood pressure monitoring is crucial for managing critically ill patients..

Identifying Patients at Increased Risk for Poor Outcomes Among Poor-Grade Aneurysmal Subarachnoid Hemorrhage Patients: The IPOGRO Risk Model

Background: A subarachnoid hemorrhage due to an aneurysmal rupture (aSAH) is a serious condition with severe neurological consequences. The World Federation of Neurosurgical Societies (WFNS) classification is a reliable predictor of death and long-term disability in patients with aSAH. Poor-grade neurological conditions on admission in aSAH (PG-aSAH) are often linked to high mortality rates and unfavorable outcomes. However, more than one-third of patients with PG-aSAH may recover and have good functional outcomes if aggressive treatment is provided. We developed a risk model called Identifying POor GRade Outcomes (IPOGRO) to predict 6-month mRS outcomes in PG-aSAH patients as a secondary analysis of a previously published study. Methods: All consecutive patients in poor-grade neurological conditions (WFNS IV-V) admitted to our institute from 2010 to 2020 due to aSAH were considered. Clinical and neuroradiological parameters were employed in the univariable analysis to evaluate the relationship with a 6-month modified Rankin Scale (mRS). Then, a multivariable multinomial regression model was performed to predict 6-month outcomes. Results: 149 patients with PG-aSAH were included. Most patients were surgically treated, with only 33.6% being endovascularly treated. The 6-month mRS score was significantly associated with clinical parameters on admission, such as lowered Glasgow Coma Scale (GCS), leukocytosis, hyperglycemia, raised Systolic Blood Pressure (SBP), greater Simplified Acute Physiology Score (SAPS II score), increased initial serum Lactic Acid (LA) levels, and the need for Norepinephrine (NE) administration. Neuroradiological parameters on the initial CT scan showed a significant association with a worsening 6-month mRS. The IPOGRO risk model analysis showed an association between a WFNS V on admission and a poor outcome (mRS 4-5), while raised SBP was associated with mortality. Conclusions: Our IPOGRO risk model indicates that PG-aSAH patients with higher SBP at admission had an increased risk of death at 6-month follow-up, whereas patients with WFNS grade V at admission had an increased risk of poor outcome but not mortality.

Non-invasive acquisition of vital data in anesthetized rats using laser and radar application.

The aim of this study was to verify the possibility of obtaining vital sign information using a laser and radar sensor in a manner that is non-invasive and painless for test animals. A dataset was obtained from respiratory movement of anaesthetized male F344 rats, signals of laser and radar sensors were recorded simultaneously with vital data acquired with an integrated multiple-channel intraoperative monitor. In addition, respiratory movements were also video recorded, and used as reference data of respiration rate (RR; ref-RR). Reference data for heart rate (HR; ref-HR) were obtained from the R wave of electrocardiogram data for each epoch. Signals recorded from the radar sensor (I- and Q-signals) were input to a computer, and HR (radar-HR) and RR (radar-RR) were estimated using the frequency analysis method. Among the six positions where respiratory movements were measured by the laser sensor, the number of peak counts matched the visual counts of respiratory movements in the video records. The respiratory movements were significantly the greatest over the most caudal rib in the dorsal (p < 0.001). The average radar-RR and ref-RR values showed correspondence (ref-RR, 69 ± 6.2 breaths/min; radar-RR, 68 ± 5.7 breaths/min (p = 0.04-1.00); equivalence ratio, 86%). The radar-HR data showed slight variability; however, there was 80% homology compared with the ref-HR values (ref-HR, 336 ± 19.6 beats/min; radar-HR, 348 ± 34.1 (p = 0.10-0.95)). Although comparison of the data under noradrenaline administration failed to track drug-induced changes in some cases, the HR and RR data of anesthetized rats measured from the radar sensor system showed comparable accuracy to other conventional methods.

Conservative fluid resuscitation protocol does not reduce the incidence of reoperation for bleeding after emergency CABG

Reoperation for bleeding (ROB) after emergency coronary artery bypass grafting (eCABG) has been identified as an independent risk factor for mortality. Consecutively, the influence of fluid intake, fluid output, fluid balance, blood loss, and inotropic demand on ROB were analyzed. This retrospective single-center study included 265 patients undergoing eCABG between 2011 and 2020. From 2018, postoperative hemodynamic management was performed with lower volume administration and higher vasoactive support. The primary outcome measure was the incidence of ROB within 48 h according to altered fluid resuscitation strategy. Consecutively, the influence of fluid intake, fluid output, fluid balance, blood loss, and inotropic demand on ROB were analyzed. Incidence of ROB was independent from the volume resuscitation protocol (P = .3). The ROB group had a higher perioperative risk, which was observed in EuroSCORE II. Fluid intake (P = .021), fluid balance (P = .001), and norepinephrine administration (P = .004) were associated with ROB. Fluid output and blood loss were not associated with ROB (P = .22). Post-test probability was low among all variables. Although fluid management might have an impact on specific postoperative complications, different fluid resuscitation protocols did not alter the incidence of ROB after emergency CABG.Trial registration: www.clinicaltrials.gov registration number NCT04533698; date of registration: August 31, 2020 (retrospectively registered due to nature of the study); URL: https://classic.clinicaltrials.gov/ct2/show/NCT04533698

Clinical Effect of Norepinephrine Combined with Esmolol Treatment in Patients with Septic Shock and Its Impact on Prognosis.

To unveil the influence of norepinephrine (NE) combined with esmolol treatment on cardiac function, hemodynamics, inflammatory factor levels, and prognosis in patients with septic shock. Ninety-six patients with septic shock admitted to our hospital from January 2021 to June 2023 were retrospectively analyzed and divided into the control and observation groups according to the different treatment methods. The control group was treated with standard anti-infection and fluid resuscitation, followed by NE administration [with an infusion rate of 0.1-0.5 μg/(kg-min)]. The observation group was treated with esmolol [starting pumping rate of 50 μg/(kg-min) and adjusting the pumping rate according to the target heart rate] in combination with the control group. Changes in hemodynamic parameters, including heart rate, mean arterial pressure, central venous pressure, cardiac index, stroke volume index, and systemic vascular resistance index, were monitored by pulse-indicating continuous cardiac output monitors before treatment (T0), 24h after treatment (T1), and 72h after treatment (T2); changes in cardiac function before and after 72h of treatment, indicators of inflammatory factors before and after treatment, and indicators of oxygenation metabolism were assessed; and adverse drug reactions during treatment were recorded in both groups. NE combined with esmolol treatment improved the efficacy of patients with septic shock; was beneficial for the enhancement of blood perfusion in patients; improved the patient's cardiac function, reduced myocardial injury, and suppressed the inflammatory response in patients; improved the oxygenation metabolism and the prognosis of patients; did not significantly increase the adverse drug reactions of patients and had a better safety profile. NE combined with esmolol treatment can improve the efficacy of patients with septic shock, improve their cardiac function and hemodynamic indices, reduce myocardial injury and inflammatory response, and have a better safety profile, which is conducive to improving patient prognosis and reducing mortality.

Clinical Interventions and Hemodynamic Monitoring in the Setting of Left Ventricular Systolic Heart Failure in Children: Insights From a Physiologic Simulator.

In pediatric critical care, vasoactive/inotropic support is widely used in patients with heart failure, but it remains controversial because the influence of multiple medications and the interplay between their inotropic and vasoactive effects on a given patient are hard to predict. Robust evidence supporting their use and quantifying their effects in this group of patients is scarce. The aim of this study was to characterize the effect of vasoactive medications on various cardiovascular parameters in pediatric patient with decreased ejection fraction. Clinical-data based physiologic simulator study. We used a physics-based computer simulator for quantifying the response of cardiovascular parameters to the administration of various types of vasoactive/inotropic medications in pediatric patients with decreased ejection fraction. The simulator allowed us to study the impact of increasing medication dosage and the simultaneous administration of some vasoactive agents. Correlation and linear regression analyses yielded the quantified effects on the vasoactive/inotropic support. Cardiac output and systemic venous saturation significantly increased with the administration of dobutamine and milrinone in isolation, and combination of milrinone with dobutamine, dopamine, or epinephrine. Both parameters decreased with the administration of epinephrine and norepinephrine in isolation. No significant change in these hemodynamic parameters was observed with the administration of dopamine in isolation. Milrinone and dobutamine were the only vasoactive medications that, when used in isolation, improved systemic oxygen delivery. Milrinone in combination with dobutamine, dopamine, or epinephrine also increased systemic oxygen delivery. The induced increment on afterload can negatively affect systemic oxygen delivery.

Human heart-on-a-chip microphysiological system comprising endothelial cells, fibroblasts, and iPSC-derived cardiomyocytes.

In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell-cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted integrity among vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The tri-culture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the bi-culture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such tri-culture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior.

Omitting the Escalating Dosage of Alpha-adrenergic Blockade Before Pheochromocytoma Resection: Implementation of a Treatment Strategy in Discordance With Current Guidelines.

This study describes the effects of introducing a protocol omitting preoperative α-blockade dose-escalation (de-escalation) in a prospective patient group. The decline of mortality and morbidity associated with pheochromocytoma resection is frequently attributed to the introduction of preoperative α-blockade. Current protocols require preoperative α-blockade dose-escalation and multiple-day hospital admissions. However, correlating evidence is lacking. Moreover, recent data suggest equal perioperative safety regardless of preoperative α-blockade escalation. Single-institution evaluation of protocol implementation, including patients who underwent adrenalectomy for pheochromocytoma between 2015 and 2023. Intraoperative hemodynamic control was regulated by active adjustment of blood pressure using vasoactive agents. The primary outcome was intraoperative hypertension, defined as the time-weighted average of systolic blood pressure (TWA-SBP) above 200mmHg. Secondary outcomes included perioperative hypotension, postoperative blood pressure support requirement, hospital stay duration, and complications. Of 102 pheochromocytoma patients, 82 were included; 44 in the de-escalated preoperative α-adrenergic protocol and 38 following the previous dose-escalation protocol. Median [IQR] TWA-SBP above 200mmHg was 0.01 [0.0-0.4]mmHg in the de-escalated group versus 0.0 [0.0-0.1]mmHg in the dose-escalated group ( P =0.073). The median duration of postoperative continuous norepinephrine administration was 0.3 hours [0.0-5.5] versus 5.1 hours [0.0-14.3], respectively ( P =0.003). Postoperative symptomatic hypotension occurred in 34.2% versus 9.1% of patients ( P =0.005). Median hospital stay was 2.5 days [1.9-3.6] versus 7.1 days [6.0-11.9] ( P <0.001). No significant differences in complication rates were observed. Our data suggest that adrenalectomy for pheochromocytoma employing a de-escalated preoperative α-blockade protocol is safe and results in a shorter hospital stay.

Design of a pharmacokinetic/pharmacodynamic model for administration of low dose peripheral norepinephrine during general anaesthesia.

Intraoperative hypotension is a risk factor for kidney, heart and cognitive postoperative complications. Literature suggests that the use of low-dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of NOR and its effect on mean arterial pressure (MAP). From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intraoperative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared 2 models for NOR PD on MAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex. We included 29 patients (age 52 [46-64] years, 69% female). NOR median time to peak effect on MAP was 74 [53-94] s. After bolus administration, MAP increased by 24% (15-31%). A 2-comparment model with depot best captured NOR PK. NOR PD effect on MAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters. We have developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on MAP over time, which could serve for target-controlled infusion.

Comparison of Early and Late Norepinephrine Administration in Patients With Septic Shock: A Systematic Review and Meta-analysis

BACKGROUNDVasopressor administration at an appropriate time is crucial but the optimal timing remains controversial. RESEARCH QUESTIONDoes early versus late norepinephrine (NE) administration impact the prognosis of septic shock? STUDY DESIGN AND METHODSSearches were conducted on PubMed, EMBASE, the Cochrane Library, and KMBASE. We included studies of adults with sepsis and categorized patients into early and late NE group according to specific time points or differences in norepinephrine use protocols. The primary outcome was overall mortality. The secondary outcomes included length of stay in the intensive care unit, days free from ventilator use, days free from renal replacement therapy, days free from vasopressor use, adverse events, and total fluid volume. RESULTSTwelve studies (4 randomized controlled trials [RCTs], 8 observational) comprising 7,281 patients were analyzed. For overall mortality, no significant difference was found between the early NE group and late NE group in RCTs (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.41–1.19) or observational studies (OR, 0.83; 95% CI, 0.54–1.29). In the two RCTs without a restrictive fluid strategy that prioritized vasopressors and lower intravenous fluid volumes, the early NE group showed significantly lower mortality than the late NE group (OR 0.49, 95%, CI, 0.25–0.96). The early NE group demonstrated more mechanical ventilator–free days in observational studies (MD, 4.06; 95% CI, 2.82–5.30). The incidence of pulmonary edema was lower in the early NE group in the three RCTs that reported this outcome (OR 0.43; 95% CI, 0.25–0.74). No differences were found in the other secondary outcomes. INTERPRETATIONOverall mortality did not differ significantly between early and late NE administration for septic shock. However, early NE administration appeared to reduce pulmonary edema incidence, and mortality improvement was observed in studies without fluid restriction interventions, favoring early NE use.

The Impact of Intraoperative Hyperlactatemia on Weaning from Cardiopulmonary Bypass in Patients Undergoing on-Pump Coronary Artery Bypass Grafting Surgery: An Observational Study

Abstract Background: Hyperlactatemia after cardiac surgery is common. However, the association and the implications of hyperlactatemia on the prognosis after cardiopulmonary bypass (CPB) remains controversial. This study investigated the associations between early-onset hyperlactatemia and the need for doses of inotropes and vasopressors during weaning from CPB, hemodynamic stability after weaning from CPB, and the duration of postoperative mechanical ventilation. Patients and Methods: This prospective cohort study included 300 patients who underwent elective on-pump coronary artery bypass grafting (CABG) surgery and had normal systolic function &gt;55%. Serum lactate levels were measured 1 h before induction, upon initiation of CPB, after removal of aortic cannula and on admission to the intensive care unit (ICU). Patients were divided into two groups: patients with lactate levels &lt;4 mmol/L (Group N) and those with lactate levels ≥4 mmol/L (Group H). Results: Patients with hyperlactatemia constituted 20.7% of the study population. The number of patients who required adrenaline and noradrenaline administration upon weaning from CPB, as well as the doses of these drugs, were significantly higher in Group H (P &lt; 0.001). Arterial blood pressure levels after weaning from CPB and upon admission to the ICU were significantly lower in Group H patients (P &lt; 0.001). The duration of post-operative mechanical ventilation was longer in Group H patients (P &lt; 0.001). Conclusion: Early-onset hyperlactatemia was associated with worse outcomes after CABG surgery. There was difficult weaning from CPB with increased inotrope and vasopressor drug support, early post-operative hemodynamic instability, and a prolonged duration of post-operative mechanical ventilation.

Noradrenaline infusion prevents anesthesia-induced hypotension in severe aortic stenosis patients undergoing transcatheter aortic valve replacement: a retrospective observational study

BackgroundPatients with severe aortic valve stenosis (AS) are particularly prone to developing hypotension during general anesthesia induction, which increases postoperative morbidity and mortality. Although the preventive effect of a single vasopressor dose on anesthesia-induced hypotension has been reported, the effects of continuous vasopressor infusion are unknown. This study aimed to assess the effect of noradrenaline (NAd) infusion on hemodynamic stability during general anesthesia induction in severe AS patients undergoing transcatheter aortic valve replacement (TAVR).MethodsThis single-center, retrospective study included severe AS patients who underwent elective TAVR. Patients in the NAd group received a continuous prophylactic NAd infusion of 0.1 μg/kg/min from the time of anesthesia induction. The control group received inotropes and vasopressors as indicated by the occurrence of hypotension. The primary outcome was the lowest mean blood pressure (MBP) before the start of surgery.ResultsThe study included 68 patients in the NAd group and 113 in the control group. The lowest MBP before the start of surgery was significantly higher in the NAd group than in the control group (63 ± 15 vs 47 ± 13 mmHg, P < 0.01). MBP immediately before intubation was also significantly higher in the NAd group (75 ± 17 vs 57 ± 16 mmHg, P < 0.01). Differences in postoperative complications between the groups were negligible.ConclusionContinuous administration of NAd at 0.1 μg/kg/min in patients with severe AS might prevent hypotension during general anesthesia induction for TAVR.

Skeletal muscle contractions attenuate the norepinephrine-related reduction in interstitial oxygen pressures in the rat spinotrapezius

Increased sympathetic nerve activity with exercise plays a key role in the control of arterial blood pressure and redistribution of blood flow. Within the microcirculation, elevated sympathetic outflow promotes the release of norepinephrine and smooth muscle contraction. Exercise-induced attenuation of sympathetic vasoconstriction (i.e., functional sympatholysis) is thus critical for active muscle oxygen delivery-utilization matching. However, the extent to which muscle contractions impact noradrenergic regulation of interstitial oxygen pressures (PO2is) is unknown. This is important because, as dictated by Fick’s law, PO2is provides the sole driving force for oxygen diffusion into the myocyte thereby supporting oxidative phosphorylation. PURPOSE: To determine the effects of norepinephrine administration on resting and contracting rat skeletal muscle PO2is. We tested the hypothesis that topical application (superfusion) of norepinephrine would result in blunted decreases in skeletal muscle PO2is during contractions compared to rest. METHODS: PO2is was determined via phosphorescence quenching in the exposed spinotrapezius muscle of anesthetized male Sprague-Dawley rats (n=7, 2-3 months old) at rest and during electrically-induced submaximal contractions (0.5 Hz, 3-6 V) for 6 minutes in response to norepinephrine superfusion (5x10−4 M). Functional sympatholysis was determined as the difference between the norepinephrine-induced changes in PO2is at rest and during the contraction steady-state (i.e., 2 min following the onset of muscle contractions) using (i) the absolute PO2is fall with norepinephrine (ΔPO2is), and (ii) the area under the PO2is curve plotted as a function of time (AUC). The tail (caudal) artery was cannulated for measurements of mean arterial pressure (MAP) and heart rate (HR). RESULTS: Consistent with our hypothesis, skeletal muscle contractions attenuated norepinephrine-evoked reductions in spinotrapezius interstitial oxygenation as evaluated by ΔPO2is (rest: -8.7±1.4, contractions: -4.3±1.1 mmHg, p&lt;0.05) and AUC (rest: 2246±368, contractions: 1066±273 mmHg·s, p&lt;0.05). Although MAP increased significantly with norepinephrine both at rest (+5±1%, p&lt;0.05) and during contractions (+8±1%, p&lt;0.05), this mild hypertensive response to norepinephrine was not different between conditions (p&gt;0.05). Norepinephrine superfusion did not affect HR at rest or during contractions (p&gt;0.05). CONCLUSIONS: That muscle contractions blunted the decrease in spinotrapezius PO2is with norepinephrine compared to the resting condition is consistent with functional sympatholysis. The latter serves to match active muscle O2 delivery-utilization in the face of elevated sympathetic nerve activity during exercise. The current results indicate that a novel combination of phosphorescence quenching (interstitial oxygenation, PO2is) and superfusion techniques may be used to evaluate functional sympatholysis in the intact rat spinotrapezius muscle. Showalter Research Trust, Purdue University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication

Background Septic shock, is associated with a high mortality rate and increased expenses. Currently, the first-line therapy for septic shock entails administering resuscitation fluids followed by infusing vasopressors when the blood pressure goal is not achieved. The recommended first-line vasopressor is norepinephrine, followed by vasopressin, epinephrine, angiotensin II, and dopamine. There is still a controversy on when each vasopressor should be administered. Therefore, we conducted this review to determine the impact and implications of vasopressor timing in septic shock patients. Methods PubMed, Medline, Cochrane Library, Web of Science, and Google Scholar databases were comprehensively searched for potential studies until October 2023. The methodological quality and bias assessment of valid records was examined with the Newcastle Ottawa Scale and Cochrane’s risk of bias tool. Additionally, all the meta-analyses were performed with Review Manager software. Results Twelve articles were eligible for review and analysis. Pooled analyses of data from 7 of these studies demonstrated lower incidence of mortality and shorter duration to achieve target mean arterial pressure in the early vs. late epinephrine groups (OR:0.44; 95%CI: 0.35–0.55; p&lt;0.00001 and MD:-1.17; 95%CI:-2.00– -0.34; p=0.0006). However, the length of ICU stay didn’t differ between the early and late norepinephrine group (MD:0.55; 95%CI: -0.52–1.62; p=0.31). The subgroup analyses show that early vasopressin is associated with a decreased mortality than late administration (OR:0.60; 95%CI:0.41–0.90; p=0.01). Similarly, the pooled analysis has shown that early concomitant administration of vasopressin and norepinephrine is associated with a shorter duration to achieve target MAP than norepinephrine alone (MD:-3.15; 95%CI:-4.40– -1.90;p&lt;0.00001). Conclusion Early administration of norepinephrine has a mortality benefit and improves the duration taken to attain and sustain the goal MAP. Furthermore, early vasopressin possesses the potential to lower the fatality rate in individuals experiencing septic shock. However, further research is required to validate this finding.

Incidence of Extravasation during Norepinephrine Administration via Peripheral Venous Catheter in Emergency Patients

Objective: To describe the incidence of extravasation resulting from the administration of norepinephrine through a peripheral venous catheter in emergency patients.Material and Methods: This prospective observational study was conducted on 150 adult patients in the emergency department at Siriraj Hospital, Thailand. Physicians closely monitored patients who received norepinephrine via a peripheral venous catheter examining the intravenous access sites during the period of treatment and for up to 48 hours after discontinuation of treatment. We collected demographic data, norepinephrine administration details, potential risk factors for extravasation, the incidence of extravasation, and mortality rate.Results: The median age of the patients was 67 years, and 60.7% were male. Most patients (93.3%) received peripheral intravenous norepinephrine for septic shock, administered below the wrist joint (47.3%) through a 22-gauge catheter (82.7%). The median duration of total peripheral intravenous norepinephrine administration was 19.92 hours (interquartile range (IQR) 9.48-38.09). The median maximum dose was 0.07 mcg/kg/min (IQR 0.04-0.10). Extravasation occurred in three patients (2.0%) (95% CI: 0.6 - 6.1), none of which resulted in significant morbidity. The timing from shock diagnosis to peripheral intravenous norepinephrine administration did not statistically differ between survivors and non-survivors at both 7 and 30 days. However, the median time from shock diagnosis to achieve mean arterial pressure (MAP)≥65 mmHg, and time from norepinephrine administration to achieve MAP ≥65 mmHg, was shorter in the survivors compared to the non-survivors.Conclusion: Given that the incidence of extravasation events was low and did not result in significant morbidity, we suggest that peripheral intravenous norepinephrine administration is safe under close observation and for a limited duration.

Circulating noradrenaline leads to release of neuropeptide Y from cardiac sympathetic nerve terminals via activation of β-adrenergic receptors.

Cardiac disease is marked by sympathoexcitation and elevated levels of noradrenaline (NA) and cotransmitter neuropeptide Y (NPY). Increased NPY levels are associated with a greater risk of ventricular arrhythmias and mortality. Nonetheless, the factors that cause NPY release remain poorly understood. We hypothesized that circulating catecholamines might lead to NPY release from myocardial sympathetic nerve terminals via a β-receptor-mediated mechanism that enhances sympathoexcitation. Ventricular interstitial NA and NPY levels were measured in six Yorkshire pigs after i.v. administration of NA (1mg) and before and after propranolol infusion (1mg/kg). Real-time interstitial NPY levels were measured using ventricular capacitive immunoprobes (CIs) affixed with NPY antibodies and quantified as the change in CI input current (INPY ) upon binding of NPY. Interstitial NA was measured with adjacent fast-scan cyclic voltammetry probes (INA ). A left ventricular pressure catheter and continuous ECGs were used for haemodynamic recordings, and an epicardial 56-electrode sock was used for measurements of activation recovery interval, a surrogate of action potential duration. Upon administration of NA, heart rate and left ventricular pressure increased, and activation recovery interval shortened. Notably, NA significantly increased interstitial myocardial NPY levels. After propranolol, changes in heart rate and activation recovery interval were largely mitigated. The INA increased to a similar extent post-propranolol vs. pre-propranolol, but changes in INPY were significantly reduced post-propranolol. Coronary sinus plasma analyses confirmed fast-scan cyclic voltammetry and CI findings. Hence, this study demonstrates that circulating NA induces NPY release from ventricular sympathetic nerve terminals, the mechanism for which is mediated via β-adrenergic receptors and can be blocked by the non-selective β-blocker, propranolol. KEY POINTS: Cardiovascular disease is characterized by sympathovagal imbalance, with increased plasma noradrenaline (NA) and neuropeptide Y (NPY) concentrations. Increased NPY levels are associated with increased ventricular arrhythmias and mortality in heart failure. Limited data are available on the specific factors that cause NPY release. In this study, fast-scan cyclic voltammetry and capacitive immunoprobes were used to allow for real-time in vivo measurements of interstitial myocardial neurotransmitters and neuropeptides, respectively. Using an in vivo porcine model with cardiac fast-scan cyclic voltammetry and capacitive immunoprobes, it was shown that systemic NA can increase ventricular interstitial NPY levels, suggesting that NA induces NPY release from postganglionic sympathetic nerves. The release of NPY was blocked by administration of the non-selective β-blocker propranolol, suggesting that release of NPY is dependent on activation of β-adrenergic receptors by NA.

Norepinephrine-Activated p38 MAPK Pathway Mediates Stress-Induced Cytotoxic Edema of Basolateral Amygdala Astrocytes.

The amygdala is a core region in the limbic system that is highly sensitive to stress. Astrocytes are key players in stress disorders such as anxiety and depression. However, the effects of stress on the morphology and function of amygdala astrocytes and its potential mechanisms remain largely unknown. Hence, we performed in vivo and in vitro experiments using a restraint stress (RS) rat model and stress-induced astrocyte culture, respectively. Our data show that norepinephrine (NE) content increased, cytotoxic edema occurred, and aquaporin-4 (AQP4) expression was up-regulated in the basolateral amygdala (BLA) obtained from RS rats. Additionally, the p38 mitogen-activated protein kinase (MAPK) pathway was also observed to be significantly activated in the BLA of rats subjected to RS. The administration of NE to in vitro astrocytes increased the AQP4 level and induced cell edema. Furthermore, p38 MAPK signaling was activated. The NE inhibitor alpha-methyl-p-tyrosine (AMPT) alleviated cytotoxic edema in astrocytes, inhibited AQP4 expression, and inactivated the p38 MAPK pathway in RS rats. Meanwhile, in the in vitro experiment, the p38 MAPK signaling inhibitor SB203580 reversed NE-induced cytotoxic edema and down-regulated the expression of AQP4 in astrocytes. Briefly, NE-induced activation of the p38 MAPK pathway mediated cytotoxic edema in BLA astrocytes from RS rats. Thus, our data provide novel evidence that NE-induced p38 MAPK pathway activation may be one of the mechanisms leading to cytotoxic edema in BLA under stress conditions, which also could enable the development of an effective therapeutic strategy against cytotoxic edema in BLA under stress and provide new ideas for the treatment of neuropsychiatric diseases.

Tonic noradrenergic input to neurons in the dorsal raphe nucleus mediates food intake in male mice

The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in the control of food intake. However, the neurotransmitters released in the DRN related to the control of food intake are not known. We have previously demonstrated that a tonic α1 action on DRN neurons contributes to satiety in the fed rats. In this study we investigated the participation of norepinephrine (NE) signaling in the DRN in the satiety response. Intra-DRN administration of NE causes an increase in the 2-hour food intake of sated mice, an effect that was blocked by previous administration of yohimbine, an α2 antagonist. Similarly, Intra-DRN administration of clonidine, an α2 agonist, increases food intake in sated mice. This result indicates that in the satiated mice exogenous NE acts on α2 receptors to increase food intake. Furthermore, administration of phenylephrine, an α1 agonist, decreases food intake in fasted mice and prazosin, an α1 antagonist, increases food intake in the sated mice. Taken together these results indicate that, in a satiated condition, a tonic α1 adrenergic action on the DRN neurons inhibits food intake and that exogenous NE administered to the DRN acts on α2 adrenergic receptors to increase food intake. These data reinforce the intricate neuronal functioning of the DRN and its effects on feeding.

Prevention of arterial hypotension during cesarean section under spinal anesthesia: trial of a baby norepinephrine protocol at the Owendo University Hospital Center (Gabon)

Spinal anesthesia is a commonly used technique in cesarean section. This technique causes frequent maternal hypotension responsible for a reduction in placental perfusion rate causing fetal acidosis. Prophylactic vasopressor treatment is systematically recommended. Noradrenaline is today a molecule of choice. The objective of this work was to describe the benefit of using baby norepinephrine in the prevention of arterial hypotension in the context of cesarean section under spinal anesthesia. Methodology: Through a prospective observational study, parturients undergoing a planned or relative emergency cesarean section under spinal anesthesia during this period were included. Norepinephrine was administered by slow venous infusion at a rate of 0.028 to 0.057, or 4 to 10 drops/minute. Results: During the study period, 28 women were included. Their mean age was 30.1 ± 5.6. Scarred uterus (32%) and narrowed pelvis (25%) were the main indications. Parturients were classified according to the American Society of Anesthesia (ASA) as ASA1 in 82.1%. The systolic blood pressure recorded after the start of the baby norepinephrine infusion at the 1st minute, between the 5th and 15th minutes and between the 15th and 30th respectively between 100 and 140 mmHg in 71.4%, 85.7 % and 96.4% cases. Heart rate remained normal throughout norepinephrine administration. Conclusion: Low-dose norepinephrine ensures good hemodynamic stability perioperatively for cesarean section under spinal anesthesia.

Adverse Events of Peripherally Administered Norepinephrine During Surgery: A Prospective Multicenter Study.

Perioperative treatment of hypotension by intravenous administration of norepinephrine in a peripheral vein can lead to adverse events, for example, tissue necrosis. However, the incidence and severity of adverse events during perioperative administration are unknown. This was a prospective observational study conducted at 3 Swedish hospitals from 2019 to 2022. A total of 1004 patients undergoing surgery, who met the criteria for perioperative peripheral norepinephrine administration, were included. The infusion site was inspected regularly. If swelling or paleness of skin was detected, the infusion site was changed to a different peripheral line. Systolic blood pressure and pulse frequency were monitored during the infusion time and defined as adverse events at >220 mm Hg and <40 beats•min -1 . In case of adverse events, patients were observed for up to 48 hours. The primary outcome was prevalence of extravasation, defined as swelling around the infusion site. Secondary outcomes were all types of adverse events and associations between predefined clinical variables and risk of adverse events. We observed 2.3% (95% confidence interval [CI], 1.4%-3.2%) extravasation of infusion and 0.9% (95% CI, 0.4%-1.7%) bradycardia. No cases of tissue necrosis or severe hypertension were detected. All adverse events had dissipated spontaneously within 48 hours. Proximal catheter placement was associated with more adverse events. Extravasation of peripherally administrated norepinephrine in the perioperative period occurred at similar rates as in previous studies in critically ill patients. In our setting, where we regularly inspected the infusion site and shifted site in case of swelling or paleness of skin, we observed no case of severe adverse events. Given that severe adverse events were absent, the potential benefit of this preventive approach requires confirmation in a larger population.