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

BACKGROUND: 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. STUDY QUESTION: The aim of this study was to characterize the effect of vasoactive medications on various cardiovascular parameters in pediatric patient with decreased ejection fraction. STUDY DESIGN: Clinical-data based physiologic simulator study. MEASURE AND OUTCOMES: 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. RESULTS: 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. CONCLUSIONS: 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.

Scoping Review: Is Push-Dose Norepinephrine a Better Choice?

Introduction: The use of push-dose vasopressors to treat anesthesia-induced hypotension is a common evidence-based practice among anesthesiologists. In more recent years, the use of push-dose vasopressors has transitioned to the emergency department (ED) and critical care setting. There is debate on the best choice of a push-dose vasopressor, with push-dose epinephrine or phenylephrine being more commonly used. This scoping review evaluated publications regarding the clinical use of push-dose norepinephrine. Methods: We queried research studies in both PubMed and Google Scholar on the use of push-dose norepinephrine in human subjects, with numerous randomized controlled trials that compare norepinephrine to other vasopressors including phenylephrine, ephedrine, and epinephrine. Results: A large majority of the studies were performed in the setting of spinal anesthesia prior to cesarean section, while several involved the administration of general anesthesia, with limited-to-no literature in the emergency and critical care setting. Of the 27 studies that we included in the review, 17 were randomized controlled trials. These studies demonstrated that norepinephrine was safe and effective. Conclusion: Prior research has demonstrated the superiority of norepinephrine as a pressor of choice for various shock states. In this review, the safety and efficacy of push-dose norepinephrine is demonstrated, and favorable hemodynamic markers are shown in comparison to other agents. In addition, there are some safety and efficiency benefits to using push-dose norepinephrine from an administration standpoint, as well as clinically in decreased need for repeat doses. Further high-quality studies in the emergency and critical care realm would be beneficial to confirm these findings.

Biphasic effects of single-dose intravenous injection of uridine adenosine tetraphosphate on blood pressure in mice.

PURPOSE: To explore the effects of a single dose of uridine adenosine tetraphosphate (Up4A) administered through the tail vein, on the blood pressure of mice. METHODS: The mice were separated into three groups: the Up4A group, the norepinephrine (NA) group, and the α, ß-methylene adenosine triphosphate (α, ß-meATP) group. Each group of mice were injected drugs through the tail vein at 1, 3, 10, and 30 nmol/kg doses in an ascending order. Additionally, six mice were injected Up4A through the tail vein at 20, 40, 60, and 80 nmol/kg doses in an ascending order. The administration intervals for each dose were 20 min. RESULTS: Mice in these groups experienced a rapid increase in blood pressure, reaching its peak within 10 s after drug administration. It took approximately 120 s for the blood pressure to return to baseline levels after the administration of the drugs in both the NA and α, ß-meATP groups. After higher doses of Up4A were administered to the mice, their blood pressure exhibited biphasic changes. Initially, blood pressure of the mice rapidly dropped to a minimum within 10 s, then rose rapidly to a peak within 30 s. Subsequently, it gradually declined, taking around 10 min to return to the levels before the drug administration. CONCLUSION: Compared to NA and α, ß-meATP, Up4A, which contains purine and pyrimidine components, displayed a weaker blood pressure-elevating potency. Through its corresponding structure, Up4A exerted vasodilatory and vasoconstrictive effects throughout the entire experiment resulting in biphasic changes in blood pressure.

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.

Determination of ED90s of Phenylephrine and Norepinephrine Infusion for Prevention of Spinal Anesthesia-Induced Hypotension in Patients with Preeclampsia During Cesarean Delivery.

Background: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery. Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 µg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 µg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery. Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582-0.628) and 0.054 (95% CI: 0.053-0.056) µg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576-1.226) and 0.055 (95% CI: 0.047-0.109) µg/kg/min, respectively, with an efficacy ratio of 12.1:1. Conclusion: The administration of 0.6 µg/kg/min phenylephrine and 0.05 µg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.

Up-and-Down Determination of Different Crystalloid Coload Volumes on the ED 90 of Prophylactic Norepinephrine Infusion for Preventing Postspinal Anesthesia Hypotension During Cesarean Section.

Background: Fluid loading improves hemodynamic stability and reduces the incidence rate of post-spinal anesthesia hypotension when prophylactic vasopressors are administered. We investigated the impact of different crystalloid coload volumes on the 90% effective dose (ED) of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension in non-hypertensive patients undergoing cesarean section. Methods: Patients were randomly allocated to receive one of the different crystalloid coload volumes (0mL/kg [0mL/kg Group], 5mL kg [5mL/kg Group], and 10mL kg [10mL/kg Group]) in combination with prophylactic norepinephrine infusion immediately after the induction of spinal anesthesia. The prophylactic norepinephrine infusion doses were determined using the up-and-down sequential allocation methodology, with an initial dose of 0.025 µg/kg/min and a gradient of 0.005 µg/kg/min. The primary endpoint was the effective dose at which 90% (ED 90) of patients responded to prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension. Results: The estimated effective dose of norepinephrine infusion, at which 90% (ED 90) of patients responded, was found to be 0.084 (95% CI, 0.070 to 0.86), 0.074 (95% CI, 0.059 to 0.077), and 0.063 (95% CI, 0.053 to 0.064) µg/kg/min in the three groups, respectively. Conclusion: A crystalloid coload of 5 mL/kg or 10 mL/kg, as opposed to the groups receiving 0 mL/kg crystalloid coloads, resulted in a reduction of approximately 11.9% and 25.0%, respectively, in the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean section.

Intravenous initial bolus during prophylactic norepinephrine infusion to prevent spinal hypotension for cesarean delivery: A randomized controlled, dose-finding trial.

BACKGROUND: Previous studies have shown that a 0.05 µg/kg/min of norepinephrine infusion in combination with an initial bolus reduces the incidence of spinal hypotension during cesarean delivery. The initial norepinephrine bolus influences the incidence of spinal hypotension during continuous norepinephrine infusion; however, the ideal initial bolus dose for 0.05 µg/kg/min of continuous infusion remains unknown. METHODS: This randomized, controlled, dose-finding study randomly allocated 120 parturients scheduled for elective cesarean delivery to receive initial bolus doses of 0, 0.05, 0.10, and 0.15 µg/kg of norepinephrine, followed by continuous infusion at a rate of 0.05 µg/kg/min. The primary outcome was the dose-response relationship of the initial norepinephrine bolus in preventing the incidence of spinal hypotension. Spinal hypotension was defined as systolic blood pressure (SBP) decreased to <80% of the baseline value or to an absolute value of <90 mmHg from intrathecal injection to delivery, and severe spinal hypotension was defined as SBP decreased to <60% of the baseline value. The secondary outcomes included the incidence of nausea and/or vomiting, hypertension, and bradycardia, as well as the Apgar scores and results of the umbilical arterial blood gas analysis. The effective dose (ED) 90 and ED95 were estimated using probit regression. RESULTS: The per-protocol analysis included 117 patients. The incidence of spinal hypotension varied significantly among the groups: Group 0 (51.7%), Group 0.05 (44.8%), Group 0.10 (23.3%), and Group 0.15 (6.9%). The ED90 and ED95 values were 0.150 µg/kg (95% confidence interval [CI], 0.114-0.241 µg/kg) and 0.187 µg/kg (95% CI, 0.141-0.313 µg/kg), respectively. However, the ED95 value fell outside the dose range examined in this study. The incidence of severe spinal hypotension differed significantly (P = 0.02) among Groups 0 (17.2%), 0.05 (10.3%), 0.10 (3.3%), and 0.15 (0.0%); however, the incidence of hypertension and bradycardia did not. The incidence of nausea and/or vomiting decreased with an increase in the initial bolus dose (P = 0.03). The fetal outcomes were comparable among the groups. CONCLUSIONS: An initial bolus of 0.150 µg/kg of norepinephrine may be the optimal dose for preventing spinal hypotension during cesarean delivery with a continuous infusion rate of 0.05 µg/kg/min, and does not significantly increase the incidence of hypertension but substantially reduces the risk of nausea and/or vomiting.

Early administration of norepinephrine in sepsis: Multicenter randomized clinical trial (EA-NE-S-TUN) study protocol.

One of the most important components of sepsis management is hemodynamic restoration. If the target mean arterial pressure (MAP) is not obtained, the first recommendation is for volume expansion, and the second is for norepinephrine (NE). We describe the methodology of a randomized multicenter trial aiming to assess the hypothesis that low-dose NE given early in adult patients with sepsis will provide better control of shock within 6 hours from therapy starting compared to standard care. This trial includes ICU septic patients in whom MAP decrease below 65 mmHg to be randomized into 2 groups: early NE-group versus standard care-group. The patient's attending clinician will determine how much volume expansion is necessary to meet the target of a MAP > 65 mm Hg. If this target not achieved, after at least 30 ml/kg and guided by the available indices of fluid responsiveness, NE will be used in a usual way. The latter must follow a consensual schedule elaborated by the investigating centers. Parameters to be taken at inclusion and at H6 are: lactates, cardiac ultrasound parameters (stroke volume (SV), cardiac output (CO), E/E' ratio), and P/F ratio. MAP and diuresis are recorded hourly. Our primary outcome is the shock control defined as a composite criterion (MAP > 65 mm Hg for 2 consecutive measurements and urinary output > 0.5 ml/kg/h for 2 consecutive hours) within 6 hours. Secondary outcomes: Decrease in serum lactate> 10% from baseline within 6 hours, the received fluid volume within 6 hours, variation of CO and E/E', and 28 days-Mortality. The study is ongoing and aims to include at least 100 patients per arm. This study is likely to contribute to support the indication of early initiation of NE with the aim to restrict fluid intake in septic patients. (ClinicalTrials.gov ID: NCT05836272).

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.

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.

Association between maximum norepinephrine dosage and mortality risk in neonates with septic shock.

The high-dose usage of norepinephrine is thought to cause high mortality in patients with septic shock. This study aims to explores the correlation between the maximum norepinephrine (NE) dosage (MND) and mortality in neonates with septic shock. This retrospective cohort study included neonates with evidence of septic shock and those who received NE infusion. The study included 123 neonates, with 106 in the survival group and 17 in the death group. The death group exhibited significantly lower birth weight (p = 0.022), 1-min Apgar score (p = 0.005), serum albumin (p < 0.001), and base excess (BE) (p = 0.001) levels, but higher lactate (LAC) levels (p = 0.009) compared to the survival group. MND demonstrated an ROC area under the curve of 0.775 (95% CI 0.63-0.92, p < 0.001) for predicting mortality, with an optimal threshold of 0.3 µg/(kg·min), a sensitivity of 82.4%, and a specificity of 75.5%. Multivariate logistic regression indicated that an MND > 0.3 µg/(kg·min) (OR, 12.08, 95% CI 2.28-64.01) was associated with a significantly higher mortality risk. Spearman rank correlation showed a positive correlation between MND and LAC (r = 0.252, p = 0.005), vasoactive-inotropic score (VIS) (r = 0.836, p < 0.001), and a negative correlation with BE (r = - 0.311, p = 0.001). MND > 0.3 µg/(kg min) is a useful predictive marker of mortality in neonatal septic shock.

Norepinephrine weaning guided by the Hypotension Prediction Index in vasoplegic shock after cardiac surgery: protocol for a single-centre, open-label randomised controlled trial - the NORAHPI study.

INTRODUCTION: Norepinephrine (NE) is the first-line recommended vasopressor for restoring mean arterial pressure (MAP) in vasoplegic syndrome (vs) following cardiac surgery with cardiopulmonary bypass. However, solely focusing on target MAP values can lead to acute hypotension episodes during NE weaning. The Hypotension Prediction Index (HPI) is a machine learning algorithm embedded in the Acumen IQ device, capable of detecting hypotensive episodes before their clinical manifestation. This study evaluates the clinical benefits of an NE weaning strategy guided by the HPI. MATERIAL AND ANALYSIS: The Norahpi trial is a prospective, open-label, single-centre study that randomises 142 patients. Inclusion criteria encompass adult patients scheduled for on-pump cardiac surgery with postsurgical NE administration for vs patient randomisation occurs once they achieve haemodynamic stability (MAP>65 mm Hg) for at least 4 hours on NE. Patients will be allocated to the intervention group (n=71) or the control group (n=71). In the intervention group, the NE weaning protocol is based on MAP>65 mmHg and HPI<80 and solely on MAP>65 mm Hg in the control group. Successful NE weaning is defined as achieving NE weaning within 72 hours of inclusion. An intention-to-treat analysis will be performed. The primary endpoint will compare the duration of NE administration between the two groups. The secondary endpoints will include the prevalence, frequency and time of arterial hypotensive events monitored by the Acumen IQ device. Additionally, we will assess cumulative diuresis, the total dose of NE, and the number of protocol weaning failures. We also aim to evaluate the occurrence of postoperative complications, the length of stay and all-cause mortality at 30 days. ETHICS AND DISSEMINATION: Ethical approval has been secured from the Institutional Review Board (IRB) at the University Hospital of Amiens (IRB-ID:2023-A01058-37). The findings will be shared through peer-reviewed publications and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT05922982.

Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output.

STUDY OBJECTIVE: Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia. DESIGN: Prospective, randomized, double-blinded study. SETTING: Operating room. PATIENTS: We recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia. INTERVENTIONS: The patients received prophylactic intravenous infusion of either 0.08 µg/kg/min norepinephrine or 0.5 µg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension. MEASUREMENTS: Changes in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound. MAIN RESULTS: 90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.02), it remained within the normal range. CONCLUSIONS: Prophylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.

The REPERFUSE study protocol: The effects of vasopressor therapy on renal perfusion in patients with septic shock-A mechanistically focused randomised control trial.

INTRODUCTION: Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI, renal cortical perfusion is deficient despite normal macrovascular organ blood flow. This intra-renal perfusion abnormality may be amenable to pharmacological manipulation, which may offer mechanistic insight into the pathophysiology of septic AKI. The aim of the current study is to investigate the effects of vasopressin and angiotensin II on renal microcirculatory perfusion in a cohort of patients with septic shock. METHODS AND ANALYSIS: In this single centre, mechanistically focussed, randomised controlled study, 45 patients with septic shock will be randomly allocated to either of the study vasopressors (vasopressin or angiotensin II) or standard therapy (norepinephrine). Infusions will be titrated to maintain a mean arterial pressure (MAP) target set by the attending clinician. Renal microcirculatory assessment will be performed for the cortex and medulla using contrast-enhanced ultrasound (CEUS) and urinary oxygen tension (pO2), respectively. Renal macrovascular flow will be assessed via renal artery ultrasound. Measurement of systemic macrovascular flow will be performed through transthoracic echocardiography (TTE) and microvascular flow via sublingual incident dark field (IDF) video microscopy. Measures will be taken at baseline, +1 and +24hrs following infusion of the study drug commencing. Blood and urine samples will also be collected at the measurement time points. Longitudinal data will be compared between groups and over time. DISCUSSION: Vasopressors are integral to the management of patients with septic shock. This study aims to further understanding of the relationship between this therapy, renal perfusion and the development of AKI. In addition, using CEUS and urinary pO2, we hope to build a more complete picture of renal perfusion in septic shock by interrogation of the constituent parts of the kidney. Results will be published in peer-reviewed journals and presented at academic meetings. TRIAL REGISTRATION: The REPERFUSE study was registered on Clinical Trials.gov (NCT06234592) on the 30th Jan 24.

Dose-Response Study of Norepinephrine Infusion for Maternal Hypotension in Preeclamptic Patients Undergoing Cesarean Delivery Under Spinal Anesthesia.

BACKGROUND AND OBJECTIVE: Spinal anesthesia remains the preferred mode of anesthesia for preeclamptic patients during cesarean delivery. We investigated the incidence of maternal hypotension under spinal anesthesia during cesarean delivery, by comparing different prophylactic infusion rates of norepinephrine with normal saline. METHODS: We randomly allocated 180 preeclamptic patients (45 in each groups) aged 18-45 scheduled for cesarean delivery to receive one of four prophylactic norepinephrine infusions at doses of 0 (normal saline group), 0.025 (0.025 group), 0.05 (0.05 group), or 0.075 (0.075 group) µg/kg/min following spinal anesthesia. The primary endpoint was the incidence of maternal hypotension (systolic blood pressure < 80% of baseline). RESULTS: The incidence of maternal hypotension was reduced with different prophylactic infusion rates of norepinephrine (26.7%, 15.6%, and 6.7%) compared with normal saline (37.8%) with a significant decreasing trend (p = 0.002). As the infusion doses of norepinephrine increased, there is a significant decreasing trend in deviation of systolic blood pressure control (median performance error; median absolute performance error) from baseline (p < 0.001; p < 0.001) and need for rescue norepinephrine boluses (p = 0.020). The effective dose 50 and effective dose 90 of prophylactic norepinephrine infusion were - 0.018 (95% confidence interval - 0.074, 0.002) µg/kg/min and 0.065 (95% confidence interval 0.048, 0.108) µg/kg/min, respectively. CONCLUSIONS: Prophylactic infusion of norepinephrine, as compared to no preventive measures, can effectively reduce the incidence of maternal hypotension in preeclamptic patients under spinal anesthesia during cesarean delivery, without increasing other adverse events for either the mother or neonate. REGISTRATION: Clinical trials.gov identifier number NCT04556370.

Agenesis of inferior vena cava in pregnancy: A case report and narrative review.

Agenesis of inferior vena cava (AIVC) is an extremely rare congenital abnormality. In AIVC, venous flow from the lower extremities enter superior vena cava mainly through the azygous and hemiazygous system, forming anastomotic collateral vessels. A global increase in intra-abdominal pressure by the gravid uterus may further stress the collateral system, increase venous stasis and decrease venous return. We present the management of a 37-year old pregnant woman with AIVC who underwent caesarean section with norepinephrine infusion and general anaesthesia. She presented with shortness of breath when seated, episodes of dizziness while walking or sitting upright with subsequent tachycardia. Cardiac status was monitored using an arterial pulse contour CO monitor. We did not observe large fluctuations in CO, SV, MAP during induction and intubation as well as during delivery. We believe that administration of an infusion of norepinephrine from induction to anaesthesia through caesarean section contributed to this result. Sympathetic activation caused venoconstriction, which significantly increased venous return and maintained haemodynamic stability.

Effect of lipid emulsion on vasoconstriction induced by epinephrine or norepinephrine in isolated rat aorta.

BACKGROUND: Epinephrine (EPI) or norepinephrine (NOR) is widely used to treat cardiovascular collapse during lipid emulsion (LE) resuscitation for drug toxicity. However, the effect of LE on the vasoconstriction caused by EPI or NOR remains unknown. The purpose of this study was to examine the effect of an LE (Intralipid) on the vasoconstriction caused by EPI and NOR in isolated rat aorta. METHODS: The effect of LE on the vasoconstriction caused by EPI or NOR in isolated rat aorta was examined. Additionally, the effect of LE on the calcium increase caused by EPI or NOR was investigated. The distribution constant (KD: lipid to aqueous phase) of EPI or NOR between a LE (1%) and an aqueous phase was determined. RESULTS: LE (1 and 2%) did not significantly alter vasoconstriction caused by EPI or NOR in isolated endothelium-intact aorta. Moreover, the LE did not significantly alter the increased calcium level caused by EPI or NOR. The log KD of EPI in the LE (1%) was -0.71, -0.99, and -1.00 at 20, 50, and 100 mM ionic strength, respectively. The log KD of NOR in the LE (1%) was -1.22, -1.25, and -0.96 at 20, 50, and 100 mM ionic strength, respectively. CONCLUSIONS: Taken together, the Intralipid emulsion did not alter vasoconstriction induced by EPI or NOR that seems to be due to the hydrophilicity of EPI or NOR, leading to sustained hemodynamic support produced by EPI or NOR used during LE resuscitation.

Norepinephrine dosing in France: Time to move forward!

Norepinephrine is the first-line vasopressor used in acute cardio-circulatory failure. At the bedside, its dose is critical as it serves to determine the severity of patients, to compare the patients between different studies, and to start specific interventions. Recently, several investigators underlined differences in the expression of norepinephrine doses according to countries and manufacturers. For various reasons, all norepinephrine products are processed to a salt formulation thereby generating a stable and soluble conjugated acid in a slightly acidic solution. Depending on the salt used, the total weight will differ, but the weight of pure norepinephrine base is the same. This results in at-risk situations with large variations in terms of practices, evaluation and treatment. In this technical note, we summarized the evidence and provided a few suggestions to improve the practices at different levels.