Basolateral amygdala activation enhances object recognition memory by inhibiting anterior insular cortex activity.

Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.

Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p <0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p =0.12; D90: 78% vs. 68%, p =0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p <0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Clinical Response to Third-Line Angiotensin-II vs Epinephrine in Septic Shock: A Propensity-Matched Cohort Study.

BACKGROUND: The appropriate third-line vasopressor in septic shock patients receiving norepinephrine and vasopressin is unknown. Angiotensin-II (AT-II) offers a unique mechanism of action to traditionally used vasopressors in septic shock. OBJECTIVE: The objective of this study was to compare the clinical efficacy and safety of third-line AT-II to epinephrine in patients with septic shock. METHODS: A single-center, retrospective cohort study of critically ill patients was performed between April 1, 2019 and July 31, 2022. Propensity-matched (2:1) analysis compared adults with septic shock who received third-line AT-II to controls who received epinephrine following norepinephrine and vasopressin. The primary outcome was clinical response 24 hours after third-line vasopressor initiation. Additional efficacy and safety outcomes were investigated. RESULTS: Twenty-three AT-II patients were compared with 46 epinephrine patients. 47.8% of AT-II patients observed a clinical response at hour 24 compared with 28.3% of epinephrine patients (P = 0.12). In-hospital mortality (65.2% vs 73.9%, P = 0.45), cardiac arrhythmias (26.1% vs 26.1%, P = 0.21), and thromboembolism (4.3% vs 2.2%, P = 0.61) were not observed to be statistically different between groups. CONCLUSIONS AND RELEVANCE: Administration of AT-II as a third-line vasopressor agent in septic shock patients was not associated with significantly improved clinical response at hour 24 compared with epinephrine. Although underpowered to detect meaningful differences, the clinical observations of this study warrant consideration and further investigation of AT-II as a third-line vasopressor in septic shock.

The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients.

BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A Clinical Review of Vasopressors in Emergency Medicine.

BACKGROUND: Vasopressor medications raise blood pressure through vasoconstriction and are essential in reversing the hypotension seen in many critically ill patients. Previously, vasopressor administration was largely limited to continuous infusions through central venous access. OBJECTIVES OF THE REVIEW: This review addresses the clinical use of vasopressors in various shock states, including practical considerations and innovations in vasopressor administration. The focus is on the clinical administration of vasopressors across a range of shock states, including hypovolemic, distributive, cardiogenic, and obstructive shock. DISCUSSION: Criteria for starting vasopressors are not clearly defined, though early use may be beneficial. A number of physiologic factors affect the body's response to vasopressors, such as acidosis and adrenal insufficiency. Peripheral and push-dose administration of vasopressors are becoming more common. Distributive shock is characterized by inappropriate vasodilation and vasopressors play a crucial role in maintaining adequate blood pressure. The use of vasopressors is more controversial in hypovolemic shock, as the preferred treatment is correction of the volume deficit. Evidence for vasopressors is limited in cardiogenic shock. For obstructive shock, vasopressors can temporize a patient's blood pressure until definitive therapy can reverse the underlying cause. CONCLUSION: Across the categories of shock states, norepinephrine has wide applicability and is a reasonable first-line agent for shock of uncertain etiology. Keeping a broad differential when hypotension is refractory to vasopressors may help to identify adjunctive treatments in physiologic states that impair vasopressor effectiveness. Peripheral administration of vasopressors is safe and facilitates early administration, which may help to improve outcomes in some shock states.

Prophylactic norepinephrine infusion to treat hypotension after spinal anaesthesia during caesarean section: a meta-analysis.

BACKGROUND: Spinal anaesthesia is a common anaesthetic method for caesarean sections but often results in hypotension, posing potential risks to maternal and neonatal health. Norepinephrine, as a vasopressor, may be effective in preventing and treating this hypotension. This systematic review and meta-analysis aims to systematically evaluate the efficacy and safety of prophylactic norepinephrine infusion for the treatment of hypotension following spinal anaesthesia in caesarean sections. METHODS: Literature searches were conducted in PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP databases for relevant studies on prophylactic administration of norepinephrine for the treatment of hypotension after spinal anaesthesia in caesarean delivery. Reference lists of included articles were also searched. The latest search update was on March 20, 2024. Meta-analysis was conducted using R software. The methods recommended by the Cochrane Handbook, Begge's and Egger's tests were used for risk of bias evaluation of the included literature. RESULTS: Nine studies were finally included in this study. The results showed that prophylactic administration of norepinephrine was superior to the control group in four aspects of treating hypotension after spinal anaesthesia in caesarean delivery: the incidence of hypotension was reduced [RR = 0.34, 95%CI (0.27-0.43), P < 0.01]; the incidence of severe hypotension was reduced [RR = 0.32, 95%CI (0.21-0.51), P < 0.01]; and maternal blood pressure was more stable with MDPE [MD = -5.00, 95%CI (-7.80--2.21), P = 0.06] and MDAPE [MD = 4.11, 95%CI (1.38-6.85), P < 0.05], the incidence of nausea and vomiting was reduced [RR = 0.52, 95%CI (0.35-0.77), P < 0.01]. On the other hand, the incidence of reactive hypertension was higher than the control group [RR = 3.58, 95%CI (1.94-6.58), P < 0.01]. There was no difference between the two groups in one aspects: newborn Apgar scores [MD = -0.01, 95%CI (-0.10-0.09, P = 0.85)]. CONCLUSION: Prophylactic administration of norepinephrine is effective in treating hypotension after spinal anaesthesia in caesarean delivery patients; however, it does not provide improved safety and carries a risk of inducing reactive hypertension.

Hypotension, or low blood pressure, after spinal anaesthesia can threaten the health of both mothers and their babies during caesarean sections. Norepinephrine is a drug that affects heart rate less and does not easily cross the placental barrier, which may reduce its potential negative effects on the baby. However, there are not many studies on using norepinephrine as a preventive measure. Our study systematically evaluated the use of prophylactic norepinephrine infusion to prevent hypotension in caesarean section patients. We found that it is effective in preventing low blood pressure but does not show improved safety and carries some risk of causing high pressure as a reaction.

Impact of Norepinephrine and Dopamine Infusion on Renal Arterial Resistive Index during Pre-Emptive Living Donor Kidney Transplantation: Propensity Score Matching Analysis.

Background: Living donor kidney transplantation (LDKT) is a crucial treatment for end-stage renal disease, with pre-emptive LDKT (transplantation before dialysis initiation) offering significant benefits in graft function and patient survival. The selection of a vasopressor during LDKT, particularly between norepinephrine and dopamine, and its impact on renal arterial hemodynamics measured using the renal arterial resistive index (RARI) is poorly understood. Methods: This retrospective observational cohort study enrolled 347 eligible pre-emptive LDKT recipients from the Seoul St. Mary's Hospital between January 2019 and June 2023. Utilizing propensity score matching (PSM), the patients were categorized into dopamine and norepinephrine groups to compare the effects of these vasopressors on the intraoperative RARI, postoperative estimated glomerular filtration rate (eGFR), and hourly urine output. The RARI was measured via the Doppler ultrasonography of the renal hilum and parenchyma post-graft vascular and ureteral anastomoses. Results: The preoperative differences in the recipients' and donors' characteristics were mitigated following PSM. The dopamine group exhibited higher intraoperative RARI values at the renal hilum (0.77 ± 0.11 vs. 0.66 ± 0.13, p < 0.001) and parenchyma (0.71 ± 0.1 vs. 0.6 ± 0.1, p < 0.001) compared to those of the norepinephrine group. However, these differences were not statistically significant on postoperative day 7. The norepinephrine infusion adjusted for the propensity scores was associated with significantly lower odds of an RARI > 0.8 (hilum: OR = 0.214, 95% CI = 0.12-0.382, p < 0.001; parenchyma: OR = 0.1, 95% CI = 0.029-0.348, p < 0.001). The early postoperative outcomes showed a higher eGFR (day 1: 30.0 ± 13.3 vs. 25.1 ± 17.4 mL/min/1.73 m2, p = 0.004) and hourly urine output (day 1: 41.8 ± 16.9 vs. 36.5 ± 14.4 mL/kg/h, p = 0.002) in the norepinephrine group. Furthermore, the long-term outcomes were comparable between the groups. Conclusions: Norepinephrine infusion during pre-emptive LDKT is associated with more favorable intraoperative renal arterial hemodynamics, as evidenced by a lower RARI and improved early postoperative renal function compared to those of dopamine. These findings suggest a potential preferential role for norepinephrine in optimizing perioperative management and early graft functions in LDKT recipients. Given the retrospective nature of this study, further prospective studies are needed to confirm these observations. Additionally, the study limitations include the potential for unmeasured confounding factors and the inability to determine causality due to its observational design.

Intravenous Infusion of Cortisol, Adrenaline, or Noradrenaline Alters Porcine Immune Cell Numbers and Promotes Innate over Adaptive Immune Functionality.

Despite the importance of pigs (Sus scrofa domestica) in livestock production and their increasing role as a model organism for human physiology, knowledge about the porcine immune system under the influence of stress hormones is fragmentary. Exceptionally little is known about the effects of catecholamines. Therefore, the aim of this study was to examine the in vivo effects of adrenaline, noradrenaline, and cortisol on number and functionality of porcine blood immune cells. Castrated male pigs (n = 34) were treated with physiological doses of either adrenaline, noradrenaline, or cortisol via i.v. infusion for 48 h. Blood samples were collected before treatment (-24 h, -22 h, 0 h), during treatment (+2 h, +24 h, +48 h), and at 72 h postinfusion. Immune cell numbers and phagocytic activity were evaluated by flow cytometry and lymphocyte proliferation by 3H-thymidine incorporation. Total IgG and IgM Ab levels were determined via ELISA. Pigs receiving cortisol showed strongly decreased adaptive immune cell numbers and increased neutrophils, accompanied by hampered lymphocyte proliferation but increased monocyte phagocytosis. Catecholamine effects on immune cell numbers were mostly similar to cortisol in direction but smaller in intensity and duration. Lymphocyte proliferation was inhibited after 2 h of noradrenaline infusion, and both catecholamines promoted monocyte and neutrophil phagocytosis. These findings indicate a shift from adaptive to innate immunity in stressful situations. This study is the first (to our knowledge) to systematically investigate specific glucocorticoid and catecholamine actions on the porcine immune system in this level of detail and confirms many similarities to humans, thus strengthening the pig as a human model in psychoneuroimmunology.

Lower versus higher oxygenation targets in critically ill patients with severe hypoxaemia: secondary Bayesian analysis to explore heterogeneous treatment effects in the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial.

BACKGROUND: In the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial, a lower (8 kPa) vs a higher (12 kPa) PaO2 target did not affect mortality amongst critically ill adult patients. We used Bayesian statistics to evaluate any heterogeneity in the effect of oxygenation targets on mortality between different patient groups within the HOT-ICU trial. METHODS: We analysed 90-day all-cause mortality using adjusted Bayesian logistic regression models, and assessed heterogeneous treatment effects according to four selected baseline variables using both hierarchical models of subgroups and models with interactions on the continuous scales. Results are presented as mortality probability (%) and relative risk (RR) with 95% credibility intervals (CrI). RESULTS: All 2888 patients in the intention-to-treat cohort of the HOT-ICU trial were included. The adjusted 90-day mortality rates were 43.0% (CrI: 38.3-47.8%) and 42.3% (CrI: 37.7-47.1%) in the lower and higher oxygenation groups, respectively (RR 1.02 [CrI: 0.93-1.11]), with 36.5% probability of an RR <1.00. Analyses of heterogeneous treatment effects suggested a dose-response relationship between baseline norepinephrine dose and increased mortality with the lower oxygenation target, with 95% probability of increased mortality associated with the lower oxygenation target as norepinephrine doses increased. CONCLUSIONS: A lower oxygenation target was unlikely to affect overall mortality amongst critically ill adult patients with acute hypoxaemic respiratory failure. However, our results suggest an increasing mortality risk for patients with a lower oxygen target as the baseline norepinephrine dose increases. These findings warrant additional investigation. CLINICAL TRIAL REGISTRATION: NCT03174002.

Low-Concentration Norepinephrine Infusion for Major Surgery: A Safety and Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension. METHODS: We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively. RESULTS: We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg. CONCLUSIONS: A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.

Norepinephrine versus phenylephrine infusion for preventing postspinal hypotension during cesarean section for twin pregnancy: a double-blinded randomized controlled clinical trial.

BACKGROUND: Compared with singleton pregnancy, twin gestation is featured by a greater increase in cardiac output. Therefore, norepinephrine might be more suitable than phenylephrine for maintaining blood pressure during cesarean section for twins, as phenylephrine causes reflex bradycardia and a resultant decrease in cardiac output. This study was to determine whether norepinephrine was superior to phenylephrine in maintaining maternal hemodynamics during cesarean section for twins. METHODS: Informed consent was obtained from all the patients before enrollment. In this double-blinded, randomized clinical trial, 100 parturients with twin gestation undergoing cesarean section with spinal anesthesia were randomized to receive prophylactic norepinephrine (3.2 µg/min) or phenylephrine infusion (40 µg/min). The primary outcome was the change of heart rate and blood pressure during the study period. The secondary outcomes were to compare maternal complications, neonatal outcomes, Apgar scores and umbilical blood acid-base status between the two vasopressors. RESULTS: There was no significant difference observed for the change of heart rate between two vasopressors. The mean standardized area under the curve of heart rate was 78 ± 12 with norepinephrine vs. 74 ± 11 beats/min with phenylephrine (mean difference 4.4, 95%CI - 0.1 to 9.0; P = .0567). The mean standardized area under the curve of systolic blood pressure (SBP) was significantly lower in parturients with norepinephrine, as the mean of differences in standardized AUC of SBP was 6 mmHg, with a 95% CI from 2 to 9 mmHg (P = .0013). However, requirements of physician interventions for correcting maternal hemodynamical abnormalities (temporary cessation of vasopressor infusion for reactive hypertension, rescuing vasopressor bolus for hypotension and atropine for heart rate less < 50 beats/min) and neonatal outcomes were also not significantly different between two vasopressors. CONCLUSION: Infusion of norepinephrine was not associated with less overall decrease in heart rate during cesarean section for twins, compared with phenylephrine. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR1900021281 ).

Obesity protects against sepsis-induced and norepinephrine-induced white adipose tissue browning.

Sepsis is a dysregulated systemic response to infection and can lead to organ damage and death. Obesity is a significant problem worldwide and affects outcomes from sepsis. Our laboratory demonstrated that white adipose tissue (WAT) undergoes browning during sepsis, a process whereby WAT adopts a brown adipose tissue phenotype. However, this browning process was not observed in obese mice during sepsis. White adipose tissue browning is detrimental in patients with burn injury and cancer. We hypothesize that norepinephrine (NE) induces WAT browning in nonobese mice but not in obese mice similarly to sepsis-induced WAT browning. Six-week-old C57BL/6 male mice were randomized to a high-fat diet or normal diet. After 6-7 wk of feeding, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Norepinephrine was administered intraperitoneally via osmotic minipumps for 18 h or 72 h (no CLP) at which time tissue and plasma were harvested. Controls were mice that underwent CLP (no NE) with 18-h harvest. A separate group of mice underwent pretreatment with NE or vehicle infusion for 72 h, CLP was performed, and at 18 h had tissue and plasma harvested. Sepsis resulted in significant weight loss in both nonobese and obese mice. NE treatment alone caused weight loss in obese mice. Septic nonobese mice had higher uncoupling protein-1 (UCP1) expression compared with control and obese septic mice. NE treatment increased UCP1 expression in nonobese, but not obese mice. NE-treated obese septic mice had lower lung myeloperoxidase (MPO) activity, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNFα, and IL-6 levels compared with NE-treated nonobese septic mice. Obesity protects mice from septic-induced and NE-induced WAT browning.NEW & NOTEWORTHY White adipose tissue browning is detrimental in patients with burn injury and cancer. WAT browning occurs in nonobese mice and can be induced by ß receptor norepinephrine infusion, but obese mice are resistant to sepsis-induced and norepinephrine-induced WAT browning. We propose that the lack of WAT browning and unchanged inflammatory cytokine response may contribute to the protection of obese mice from sepsis.

Norepinephrine in the avian auditory cortex enhances developmental song learning.

Sensory learning during critical periods in development has lasting effects on behavior. Neuromodulators like dopamine and norepinephrine (NE) have been implicated in various forms of sensory learning, but little is known about their contribution to sensory learning during critical periods. Songbirds like the zebra finch communicate with each other using vocal signals (e.g., songs) that are learned during a critical period in development, and the first crucial step in song learning is memorizing the sound of an adult conspecific's (tutor's) song. Here, we analyzed the extent to which NE modulates the auditory learning of a tutor's song and the fidelity of song imitation. Specifically, we paired infusions of NE or vehicle into the caudomedial nidopallium (NCM) with brief epochs of song tutoring. We analyzed the effect of NE in juvenile zebra finches that had or had not previously been exposed to song. Regardless of previous exposure to song, juveniles that received NE infusions into NCM during song tutoring produced songs that were more acoustically similar to the tutor song and that incorporated more elements of the tutor song than juveniles with control infusions. These data support the notion that NE can regulate the formation of sensory memories that shape the development of vocal behaviors that are used throughout an organism's life.NEW & NOTEWORTHY Although norepinephrine (NE) has been implicated in various forms of sensory learning, little is known about its contribution to sensory learning during critical periods in development. We reveal that pairing infusions of NE into the avian secondary auditory cortex with brief epochs of song tutoring significantly enhances auditory learning during the critical period for vocal learning. These data highlight the lasting impact of NE on sensory systems, cognition, and behavior.

Hitting the Vasopressor Ceiling: Finding Norepinephrine Associated Mortality in the Critically Ill.

BACKGROUND: There is no consensus on what dose of norepinephrine corresponds with futility. The purpose of this study was to investigate the maximum infusion and cumulative doses of norepinephrine associated with survival for patients in medical and surgical intensive care units (MICU and SICU). MATERIALS AND METHODS: A retrospective review was conducted of 661 critically ill patients admitted to a large academic medical center who received norepinephrine. Univariate, multivariate, and area under the curve analyses with optimal cut offs for maximum infusion rate and cumulative dosage were determined by Youden Index. RESULTS: The population was 54.9% male, 75.8% white, and 58.7 ± 16.1 y old with 384 (69.8%) admitted to the MICU and 166 (30.2%) admitted to the SICU, including 38 trauma patients. Inflection points in mortality were seen at 18 mcg/min and 17.6 mg. The inflection point was higher in MICU patients at 21 mcg/min and lower in SICU patients at 11 mcg/min. MICU patients also had a higher maximum cumulative dosage of 30.7 mg, compared to 2.7 mg in SICU patients. In trauma patients, norepinephrine infusions up to 5 mcg/min were associated with a 41.7% mortality rate. CONCLUSION: A maximum rate of 18 mcg/min and cumulative dose of 17.6 mg were the inflection points for mortality risk in ICU patients, with SICU patients tolerating lower doses. In trauma patients, even low doses of norepinephrine were associated with higher mortality. These data suggest that MICU, SICU, and trauma patients differ in need for, response to, and outcome from escalating norepinephrine doses.

Hepatic Arterial Blood Flow Modulation in Patients with Hepatocellular Carcinoma: A Pilot Study of the Influence of Intraarterial Norepinephrine Assessed with CT Perfusion.

PURPOSE: This pilot study aims to evaluate the effect of hepatic intraarterial norepinephrine injection in vasculature modulation for hepatocellular carcinoma (HCC) tumors. MATERIALS AND METHODS: This is a single-center prospective study of patients with HCC with proven single-lobe tumors > 3 cm. Eight patients were included, with a mean age of 63 y ± 8. All patients had Barcelona Clinic Liver Cancer stage B HCC and an Eastern Cooperative Oncology Group performance status of 0. Mean tumor size was 6.1 cm ± 1.8; all tumors were hypervascular. Patients underwent CT hepatic perfusion before and after injection of 24 µg of norepinephrine intraarterially (4 µg/mL; total 6 mL injected at a rate of 1 mL/s). Color-coded perfusion maps were used to assess the effects of local therapy on hepatic perfusion values. Tumor-to-liver ratio (TLR) was calculated from the ratio of tumor perfusion to background liver perfusion value. RESULTS: Seven of 8 patents had significant (P = .04) absolute increase in tumor perfusion vs background liver, varying from incremental (-2 mL/min/100 mL) to 290 mL/min/100 mL. There was a nonsignificant increase in TLR from 2.7 ± 1.3 to 2.9 ± 1.4 after norepinephrine injection (P = .8). Mean peak time to maximal increase in tumor perfusion after injection was 6.1 s (range, 4.5-9.1 s). Norepinephrine injection was well tolerated without major adverse events. CONCLUSIONS: Norepinephrine causes increased blood flow toward HCC tumors, but with a corresponding smaller increase in blood flow to noncancerous liver tissue, with no observed systemic side effects.

Norepinephrine potentiates the efficacy of volume expansion on mean systemic pressure in septic shock.

BACKGROUND: Through venous contraction, norepinephrine (NE) increases stressed blood volume and mean systemic pressure (Pms) and exerts a "fluid-like" effect. When both fluid and NE are administered, Pms may not only result from the sum of the effects of both drugs. Indeed, norepinephrine may enhance the effects of volume expansion: because fluid dilutes into a more constricted, smaller, venous network, fluid may increase Pms to a larger extent at a higher than at a lower dose of NE. We tested this hypothesis, by mimicking the effects of fluid by passive leg raising (PLR). METHODS: In 30 septic shock patients, norepinephrine was decreased to reach a predefined target of mean arterial pressure (65-70 mmHg by default, 80-85 mmHg in previously hypertensive patients). We measured the PLR-induced increase in Pms (heart-lung interactions method) under high and low doses of norepinephrine. Preload responsiveness was defined by a PLR-induced increase in cardiac index ≥ 10%. RESULTS: Norepinephrine was decreased from 0.32 [0.18-0.62] to 0.26 [0.13-0.50] µg/kg/min (p < 0.0001). This significantly decreased the mean arterial pressure by 10 [7-20]% and Pms by 9 [4-19]%. The increase in Pms (∆Pms) induced by PLR was 13 [9-19]% at the higher dose of norepinephrine and 11 [6-16]% at the lower dose (p < 0.0001). Pms reached during PLR at the high dose of NE was higher than expected by the sum of Pms at baseline at low dose, ∆Pms induced by changing the norepinephrine dose and ∆Pms induced by PLR at low dose of NE (35.6 [11.2] mmHg vs. 33.6 [10.9] mmHg, respectively, p < 0.01). The number of preload responders was 8 (27%) at the high dose of NE and 15 (50%) at the low dose. CONCLUSIONS: Norepinephrine enhances the Pms increase induced by PLR. These results suggest that a bolus of fluid of the same volume has a greater haemodynamic effect at a high dose than at a low dose of norepinephrine during septic shock.

Hemodynamic and anti-inflammatory effects of early esmolol use in hyperkinetic septic shock: a pilot study.

BACKGROUND: Several studies have shown that heart rate control with selective beta-1 blockers in septic shock is safe. In these trials, esmolol was administered 24 h after onset of septic shock in patients who remained tachycardic. While an earlier use of beta-blockers might be beneficial, such use remains challenging due to the difficulty in distinguishing between compensatory and non-compensatory tachycardia. Therefore, the Esmosepsis study was designed to study the effects of esmolol aimed at reducing the heart rate by 20% after the initial resuscitation process in hyperkinetic septic shock patients on (1) cardiac index and (2) systemic and regional hemodynamics as well as inflammatory patterns. METHODS: Nine consecutive stabilized tachycardic hyperkinetic septic shock patients treated with norepinephrine for a minimum of 6 h were included. Esmolol was infused during 6 h in order to decrease the heart rate by 20%. The following data were recorded at hours H0 (before esmolol administration), H1-H6 (esmolol administration) and 1 h after esmolol cessation (H7): systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, central venous pressure, heart rate, PICCO transpulmonary thermodilution, sublingual and musculo-cutaneous microcirculation, indocyanine green clearance and echocardiographic parameters, diuresis, lactate, and arterial and venous blood gases. RESULTS: Esmolol was infused 9 (6.4-11.6) hours after norepinephrine introduction. Esmolol was ceased early in 3 out of 9 patients due to a marked increase in norepinephrine requirement associated with a picture of persistent cardiac failure at the lowest esmolol dose. For the global group, during esmolol infusion, norepinephrine infusion increased from 0.49 (0.34-0.83) to 0.78 (0.3-1.11) µg/min/kg. The use of esmolol was associated with a significant decrease in heart rate from 115 (110-125) to 100 (92-103) beats/min and a decrease in cardiac index from 4.2 (3.1-4.4) to 2.9 (2.5-3.7) l/min/m-2. Indexed stroke volume remained unchanged. Cardiac function index and global ejection fraction also markedly decreased. Using echocardiography, systolic, diastolic as well as left and right ventricular function parameters worsened. After esmolol cessation, all parameters returned to baseline values. Lactate and microcirculatory parameters did not change while the majority of pro-inflammatory proteins decreased in all patients. CONCLUSION: In the very early phase of septic shock, heart rate reduction using fast esmolol titration is associated with an increased risk of hypotension and decreased cardiac index despite maintained adequate tissue perfusion (NCT02068287).

Automated closed-loop versus manually controlled norepinephrine infusion in patients undergoing intermediate- to high-risk abdominal surgery: a randomised controlled trial.

BACKGROUND: Hypotension occurs frequently during surgery and may be associated with adverse complications. Vasopressor titration is frequently used to correct hypotension, but requires considerable time and attention, potentially reducing the time available for other clinical duties. To overcome this issue, we have developed a closed-loop vasopressor (CLV) controller to help correct hypotension more efficiently. The aim of this randomised controlled study was to evaluate whether the CLV controller was superior to traditional vasopressor management at minimising hypotension in patients undergoing abdominal surgery. METHODS: Thirty patients scheduled for elective intermediate-to high-risk abdominal surgery were randomised into two groups. In the CLV group, hypotension was corrected automatically via the CLV controller system, which adjusted the rate of a norepinephrine infusion according to MAP values recorded using an advanced haemodynamic device. In the control group, management of hypotension consisted of standard, manual adjustment of the norepinephrine infusion. The primary outcome was the percentage of time that a patient was hypotensive, defined as MAP <90% of their baseline value, during surgery. RESULTS: The percentage of time patients were hypotensive during surgery was 10 times less in the CVL group than in the control group (1.6 [0.9-2.3]% vs 15.4 [9.9-24.3]%; difference: 13 [95% confidence interval: 9-19]; P<0.0001). The CVL group also spent much less time with MAP <65 mm Hg (0.2 [0.0-0.4]% vs 4.5 [1.1-7.9]%; P<0.0001). CONCLUSIONS: In patients undergoing intermediate- to high-risk surgery under general anaesthesia, computer-assisted adjustment of norepinephrine infusion significantly decreases the incidence of hypotension compared with manual control. CLINICAL TRIAL REGISTRATION: NCT04089644.

Do Elderly Patients With Diastolic Dysfunction Require Higher Doses of Norepinephrine During General Anesthesia for Noncardiac Surgeries? A Prospective Observational Study.

BACKGROUND: Diastolic dysfunction is a risk factor for postoperative major cardiovascular events. During anesthesia, patients with diastolic dysfunction might experience impaired hemodynamic function and worsening of diastolic function, which in turn, might be associated with a higher incidence of postoperative complications.We aimed to investigate whether patients with diastolic dysfunction require higher doses of norepinephrine during general anesthesia. Furthermore, we aimed to examine the association between the grade of diastolic dysfunction and the E/e' ratio during anesthesia. A high E/e' ratio corresponds to elevated filling pressures and is an important measure of impaired diastolic function. METHODS: We conducted a prospective observational cohort study at a German university hospital from February 2017 to September 2018. Patients aged ≥60 years and undergoing general anesthesia (ie, propofol and sevoflurane) for elective noncardiac surgery were enrolled. Exclusion: mitral valve disease, atrial fibrillation, and implanted mechanical device.The primary outcome parameter was the administered dose of norepinephrine within 30 minutes after anesthesia induction (µg·kg-1 30 min-1). The secondary outcome parameter was the change of Doppler echocardiographic E/e' from ECHO1 (baseline) to ECHO2 (anesthesia). Linear models and linear mixed models were used for statistical evaluation. RESULTS: A total of 247 patients were enrolled, and 200 patients (75 female) were included in the final analysis. Diastolic dysfunction at baseline was not associated with a higher dose of norepinephrine during anesthesia (P = .6953). The grade of diastolic dysfunction at baseline was associated with a decrease of the E/e' ratio during anesthesia (P < .001). CONCLUSIONS: We did not find evidence for an association between diastolic dysfunction and impaired hemodynamic function, as expressed by high vasopressor support during anesthesia. Additionally, our findings suggest that diastolic function, as expressed by the E/e' ratio, does not worsen during anesthesia.