Administration Of Norepinephrine Research Articles

Unmasking lower gastrointestinal bleeding under administration of norepinephrine.

Bleeding in the gastrointestinal tract is common and transarterial embolization enables the clinician to control gastrointestinal bleeding. Contrast extravasation is a prerequisite for successful embolization. Provocative angiography is helpful in the detection of elusive bleeding. We performed a retrospective analysis of angiographic treatment in patients with lower gastrointestinal hemorrhage and initially negative angiographies, as well as the role of norepinephrine (NE) in unmasking bleeding. We analyzed 41 patients with lower gastrointestinal bleeding after angiography who had undergone treatment over a period of 10 years. All patients had a positive shock index and needed intensive care. In three of four patients, angiography disclosed the site of bleeding when NE was used during the procedure for hemodynamic stabilization. We suggest that angiography performed after the administration of NE in unstable patients with gastrointestinal bleeding and an initially negative angiography has the potential to unmask bleeding sites for successful embolization. However, this statement must be confirmed in prospective studies.

1247: OUTCOMES ASSOCIATED WITH HIGH-DOSE NOREPINEPHRINE AT AN ACADEMIC MEDICAL CENTER

Introduction: Maximal vasopressor dosing is driven by institutional policy and may vary between intensive care units (ICUs) within an institution. The purpose of this project was to characterize use of and evaluate outcomes associated with high-dose norepinephrine (defined as norepinephrine ≥ 1 mcg/kg/min). Methods: This was a retrospective, observational cohort study of adult ICU patients at two academic medical centers over five years. Patients who received high-dose norepinephrine for ≥ 1 hour were included. Subsequent hospitalizations were excluded. Index ICU admission was defined as the ICU admission in which patients first received high-dose norepinephrine. Results: Among 1564 included patients, 277 (17.7%) survived to hospital discharge. The majority of patients were male (58.4%) and admitted to a medicine unit (75.6%). The median (IQR) age was 63 (53-76) years and the median (IQR) weight was 81.5 (67.1-99.3) kilograms. Patients received high-dose norepinephrine for a median (IQR) duration of 6.3 (3-15.9) hours with a median (IQR) maximum norepinephrine dose of 3 (1.6-3) mcg/kg/min. Patients who survived had a lower median (IQR) age compared to non-survivors [58 (48-68) vs. 65 (55-74) years, p < 0.0001], lower median (IQR) weight [72.8 (59.8-90.7) vs. 83.3 (68.8-100.8) kilograms, p < 0.0001], and received high-dose norepinephrine for a shorter median (IQR) duration [4.7 (2-13.0) vs. 6.6 (1.8-16.9) hours, p < 0.0001]. Survivors also required lower median (IQR) maximum doses [1.8 (1.4-3) vs. 3 (2-3) mcg/kg/min, p < 0.0001]. Among 857 patients that received norepinephrine ≥ 3 mcg/kg/min, 74 (8.6%) survived. On multivariable logistic regression, the odds of in-hospital survival were higher in patients who were less than 65 years (OR 2.14, 95% CI: 1.59-2.88, p < 0.001), had a maximum norepinephrine rate < 3 mcg/kg/min (OR 3.98, 95% CI: 1.9-4.16, p < 0.001) or achieved their maximum norepinephrine rate within 24 hours of index ICU admission (OR 2.83, 95% CI: 2.09-3.85, p < 0.001). Conclusions: Nearly one-fifth of patients survived to hospital discharge following administration of norepinephrine ≥ 1 mcg/kg/min. Younger age, lower maximum norepinephrine doses, and administration of high-dose norepinephrine earlier in the ICU course was associated with increased survival.

1258: USE OF CAUSAL INFERENCE TO COMPARE NOREPINEPHRINE- AND VASOPRESSIN-RELATED ICU MORTALITY

Introduction: The choice of vasopressor has been studied extensively in septic shock, however limited data exists in other shock types. Norepinephrine and vasopressin were compared in a retrospective study of the cardiac surgery population. Vasopressin as first-line treatment of post-cardiac surgery vasoplegic shock was found to improve clinical outcomes. However, the study was associated with biases which limits its validity. As there are no prospective studies, we use causal inference to analyze retrospective data. An observational study allows individual observation under one treatment scenario, while a counterfactual outcome is unknown. Targeted Maximum Likelihood Estimation (TMLE) models counterfactual outcomes with limited confounding by generating a pseudo-population. By adjusting for common causes of death, we were able to compare mortality outcomes between norepinephrine and vasopressin. Methods: An anonymous, publicly available database was analyzed using pre-existing IRB approval. The eICU Collaborative Research Database contains data on over 200,000 ICU admissions. The analysis used 27,388 patients with 25 initial features. Missing values greater than 50% were dropped. Machine Learning Extensions Library (MLxtend) was used to select features sequentially. The primary outcome was ICU mortality. Imputation was performed using Sklearn Iterative Imputuer, data scaled using Sklearn Standard Scaler. Our primary model was TMLE with Logistic Regression. We analyzed vasopressin and norepinephrine administration, accounting for their co-administration by using them as covariates. Net fluid balance, Apache IV, albumin, admission weight, age, diabetes, and metastatic cancer were confounder covariates for both groups. Before analysis, a causal diagram was constructed based on these covariates. Our primary metric was Average Treatment Effect (ATE). Results: Mortality analysis on the norepinephrine group showed an ATE of -0.179, 95% CI [-0.188, -0.167]. Vasopressin showed an ATE of 0.03 (95% CI [0.01,0.051]). Compared to vasopressin, norepinephrine showed a reduction in mortality. Conclusions: We found that norepinephrine was associated with decreased mortality compared to vasopressin in this setting. We hope this study’s results will help guide prospective studies moving forward.

815: TIME TO HEMODYNAMIC STABILITY AFTER IMPLEMENTATION OF A NOREPINEPHRINE RAPID TITRATION PROTOCOL

Introduction: Norepinephrine (NE) is the primary vasoactive medication for many different shock states and is titrated to have a hemodynamic effect. A rapid titration protocol was recently implemented at our institution to provide nurses the ability to quickly titrate NE and comply with Joint Commission regulations. The purpose of this study is to evaluate whether implementing a rapid titration protocol for NE impacted time to hemodynamic stability in critically ill patients. Methods: A single-center, retrospective study of adult ICU patients receiving NE as a first line agent at a large academic medical center was performed. The patients were categorized into the pre-implementation group with standard titration instructions from April 2022 and the post implementation group with the rapid titration instructions from July 2022. Our primary outcome was to evaluate the time to hemodynamic stability based on mean arterial pressure (MAP) goals. Secondary outcomes included ICU and hospital length of stay (LOS), all-cause mortality and safety outcomes with NE administration. Results: A total of 64 patients were included in our analysis, of which, 30 patients were included in the pre-implementation group and 34 in the post-implementation group. Baseline characteristics were similar in both the groups, including NE starting rate (0.07 mcg/kg/min vs 0.08 mcg/kg/min, p=0.9), and Modified Early Warning Score (5 vs. 4, p=0.07). The primary outcome of time to hemodynamic stability based on MAP did not differ between the groups (median 12.5 minutes [IQR 0-28] vs. 11.5 minutes [IQR 0-36], p=0.7). However, the rapid titration group received significantly less concomitant IV vasopressors in the first 24 hours (50% vs. 18%, p=0.006) and experienced longer time to second vasopressor initiation (median 2.5 hours [IQR 0.10-3.6] vs. 10 hours [IQR 2.5-20]). Conclusions: At our institution, rapid titration instructions for NE did not shorten time to hemodynamic stability compared to the standard titration protocol. Our study shows that utilizing the NE rapid titration protocol may be safe and may reduce the need for an additional vasopressor. Further prospective studies are warranted to assess compliance with implementing a rapid titration protocol and its potential benefits.

1253: EFFECT OF PERIPHERALLY INFUSED NOREPINEPHRINE ON REDUCING CENTRAL VENOUS CATHETER UTILIZATION

Introduction: Vasoactive agents like norepinephrine have been historically administered via central venous catheters (CVCs) due to the perceived risk of local tissue injury with peripheral infusion. While infusion-related complications may be reduced with CVC administration, the higher rates of bacteremia, pneumothorax, and air embolism must be weighed, along with delays in administration and achievement of hemodynamic stability. This study is designed to add to the available safety data of peripheral norepinephrine administration while also investigating the direct cost savings associated with CVC avoidance. Methods: This is a retrospective analysis of adult patients who received norepinephrine between January 1 and September 1, 2021. A hospital guideline allows peripheral infusion of norepinephrine via dedicated, 16 – 20 gauge, mid-to-upper arm IV catheters for up to 24 hours. The primary outcome was the need for central venous access in patients initially started on peripherally infused norepinephrine. Safety outcomes included local tissue injury attributed to norepinephrine infusion. Results: Ninety-eight of 124 total patients initially received peripheral norepinephrine infusions, most of which required vasopressors for distributive or mixed shock. Thirty-six patients (37%) avoided the need for central line placement. The median duration of vasopressors was 6 hours [IQR 3.3 – 11.3] at a median maximum rate of 0.08 mcg/kg/min [IQR 0.05 – 0.15]. In the remaining 62 patients who progressed from peripheral to central line placement, the median duration was 15.5 hours [IQR 6 – 38.5] at a median maximum rate of 0.15 mcg/kg/min [IQR 0.06 – 0.25]. Eighty of the 98 patients (82%) who started peripherally infused norepinephrine required therapy for ≤12 hours. No extravasation or local complications were observed regardless of site of infusion. Avoiding progression to a CVC in 37 of every 100 peripheral lines resulted in an estimated direct supply cost savings of $8,900. Conclusions: Initial administration of norepinephrine via a dedicated peripheral IV site was safe and led to a reduction in the need for subsequent CVC access. To minimize cost while achieving timely resuscitation goals and maintaining patient safety, initial peripheral administration should be considered for all patients.

Association between the blood urea nitrogen to creatinine ratio and in‑hospital mortality among patients with acute myocardial infarction: A retrospective cohort study.

The present study aimed to determine the association between the blood urea nitrogen (BUN) and creatinine (Cr) ratio and in-hospital mortality in patients with acute myocardial infarction (AMI). The present retrospective cohort study included adult patients (≥18 years of age) who were admitted to the intensive care unit (ICU) with a primary diagnosis of AMI. Medical records were obtained from the electronic ICU collaborative research database, which includes data from throughout continental USA. Data included demographic characteristics, vital signs, laboratory tests and comorbidities. The clinical endpoint was in-hospital mortality. The Cox proportional hazards model was used to evaluate the prognostic values of the basic BUN/Cr ratio and the Kaplan-Meier method was used to plot survival curves. Subgroup analyses were performed to measure mortality across various subgroups. In total, 5,965 eligible patients were included. In the Cox regression analysis, after being adjusted for age, sex, ethnicity and other confounding factors, the BUN/Cr ratio was found to be a significant risk predictor of in-hospital mortality. There was a non-linear relationship between the BUN/Cr ratio and in-hospital mortality after adjusting for potential confounders. A two-piecewise regression model was used to obtain a threshold inflection point value of 18. Furthermore, after adjusting for additional confounding factors (age, sex, ethnicity, BMI, heart rate, oxygen saturation, platelets, total protein, AMI category, heart failure, history of diabetes, history of hypertension, percutaneous coronary intervention, and administration of norepinephrine, dopamine and epinephrine), the BUN/Cr ratio remained a significant predictor of in-hospital mortality (third vs. first tertile: Hazard ratio, 1.50; 95% CI, 1.08-2.09; P<0.05). The Kaplan-Meier curve for tertiles of the BUN/Cr ratio indicated that in-hospital mortality rates were highest when the BUN/Cr ratio was ≥18.34 after adjustment for age, sex and ethnicity (P<0.05). The present findings demonstrated that a higher BUN/Cr ratio was associated with an increased risk of in-hospital mortality in patients with non-ST-segment elevation myocardial infarction. These results support a revision of how the prognosis of patients with AMI is predicted.

Risk factors for peripheral venous catheter-related phlebitis stratified by body mass index in critically ill patients: A post-hoc analysis of the AMOR-VENUS study.

Phlebitis is an important complication in patients with peripheral intravascular catheters (PIVCs). Although an association between body mass index (BMI) and phlebitis has been suggested, the risk of phlebitis according to BMI has not been well elucidated. Therefore, in this study, we analyzed the risk of phlebitis according to BMI in patients in the intensive care unit (ICU). This study undertook a secondary analysis of the data from a prospective multicenter observational study assessing the epidemiology of phlebitis at 23 ICUs in Japan. Patients admitted into the ICU aged ≥18 years with a new PIVC inserted after ICU admission were consecutively enrolled and stratified into the following groups based on BMI: Underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25.0 kg/m2), and overweight/obese (BMI ≥ 25.0 kg/m2). The primary outcome was phlebitis. The risk factors for phlebitis in each BMI-based group were investigated using a marginal Cox regression model. In addition, hazard ratios and 95% confidence intervals were calculated. A total of 1,357 patients and 3,425 PIVCs were included in the analysis. The mean BMI for all included patients was 22.8 (standard deviation 4.3) kg/m2. Among the eligible PIVCs, 455; 2,041; and 929 were categorized as underweight, normal weight, and overweight/obese, respectively. In the underweight group, catheter size ≥ 18 G and amiodarone administration were independently associated with the incidence of phlebitis. Drug administration standardization was associated with the reduction of phlebitis. In the normal weight group, elective surgery as a reason for ICU admission, and nicardipine, noradrenaline, and levetiracetam administration were independently associated with the incidence of phlebitis. Heparin administration was associated with the reduction of phlebitis. In the overweight/obese group, the Charlson comorbidity index, catheter size ≥ 18 G, and levetiracetam administration were independently associated with the incidence of phlebitis. Catheters made from PEU-Vialon (polyetherurethane without leachable additives) and tetrafluoroethylene were associated with the reduction of phlebitis. We investigated the risk factors for peripheral phlebitis according to BMI in ICU and observed different risk factors in groups stratified by BMI. For example, in underweight or overweight patients, large size PIVCs could be avoided. Focusing on the various risk factors for phlebitis according to patients' BMIs may aid the prevention of phlebitis.

Mobilisation of critically ill patients receiving norepinephrine: a retrospective cohort study

BackgroundMobilisation and exercise intervention in general are safe and feasible in critically ill patients. For patients requiring catecholamines, however, doses of norepinephrine safe for mobilisation in the intensive care unit (ICU) are not defined. This study aimed to describe mobilisation practice in our hospital and identify doses of norepinephrine that allowed a safe mobilisation.MethodsWe conducted a retrospective single-centre cohort study of 16 ICUs at a university hospital in Germany with patients admitted between March 2018 and November 2021. Data were collected from our patient data management system. We analysed the effect of norepinephrine on level (ICU Mobility Scale) and frequency (units per day) of mobilisation, early mobilisation (within 72 h of ICU admission), mortality, and rate of adverse events. Data were extracted from free-text mobilisation entries using supervised machine learning (support vector machine). Statistical analyses were done using (generalised) linear (mixed-effect) models, as well as chi-square tests and ANOVAs.ResultsA total of 12,462 patients were analysed in this study. They received a total of 59,415 mobilisation units. Of these patients, 842 (6.8%) received mobilisation under continuous norepinephrine administration. Norepinephrine administration was negatively associated with the frequency of mobilisation (adjusted difference -0.07 mobilisations per day; 95% CI − 0.09, − 0.05; p ≤ 0.001) and early mobilisation (adjusted OR 0.83; 95% CI 0.76, 0.90; p ≤ 0.001), while a higher norepinephrine dose corresponded to a lower chance to be mobilised out-of-bed (adjusted OR 0.01; 95% CI 0.00, 0.04; p ≤ 0.001). Mobilisation with norepinephrine did not significantly affect mortality (p > 0.1). Higher compared to lower doses of norepinephrine did not lead to a significant increase in adverse events in our practice (p > 0.1). We identified that mobilisation was safe with up to 0.20 µg/kg/min norepinephrine for out-of-bed (IMS ≥ 2) and 0.33 µg/kg/min for in-bed (IMS 0–1) mobilisation.ConclusionsMobilisation with norepinephrine can be done safely when considering the status of the patient and safety guidelines. We demonstrated that safe mobilisation was possible with norepinephrine doses up to 0.20 µg/kg/min for out-of-bed (IMS ≥ 2) and 0.33 µg/kg/min for in-bed (IMS 0–1) mobilisation.

Association Between Changes in Norepinephrine Infusion Rate and Urinary Oxygen Tension After Cardiac Surgery

To determine if the administration of norepinephrine to patients recovering from on-pump cardiac surgery is associated with changes in urinary oxygen tension (PO2), an indirect index of renal medullary oxygenation. Single center, prospective observational study. Surgical intensive care unit (ICU). A nonconsecutive sample of 93 patients recovering from on-pump cardiac surgery. In the ICU, norepinephrine was the most commonly used vasopressor agent (90% of patients, 84/93), with fewer patients receiving epinephrine (48%, 45/93) or vasopressin (4%, 4/93). During the 30-to-60-minute period after increasing the infused dose of norepinephrine (n=89 instances), urinary PO2 decreased by (least squares mean ± SEM) 1.8 ± 0.5 mmHg from its baseline level of 25.1 ± 1.1 mmHg. Conversely, during the 30-to-60-minute period after the dose of norepinephrine was decreased (n=134 instances), urinary PO2 increased by 2.6 ± 0.5 mmHg from its baseline level of 22.7 ± 1.2 mmHg. No significant change in urinary PO2 was detected when the dose of epinephrine was decreased (n=21). There were insufficient observations to assess the effects of increasing the dose of epinephrine (n=11) or of changing the dose of vasopressin (n <4). In patients recovering from on-pump cardiac surgery, changes in norepinephrine dose are associated with reciprocal changes in urinary PO2, potentially reflecting an effect of norepinephrine on renal medullary oxygenation.

Association of Early Norepinephrine Administration With 24-Hour Mortality Among Patients With Blunt Trauma and Hemorrhagic Shock

Hemorrhagic shock is a common cause of preventable death after injury. Vasopressor administration for patients with blunt trauma and hemorrhagic shock is often discouraged. To evaluate the association of early norepinephrine administration with 24-hour mortality among patients with blunt trauma and hemorrhagic shock. This retrospective, multicenter, observational cohort study used data from 3 registries in the US and France on all consecutive patients with blunt trauma from January 1, 2013, to December 31, 2018. Patients were alive on admission with hemorrhagic shock, defined by prehospital or admission systolic blood pressure less than 100 mm Hg and evidence of hemorrhage (ie, prehospital or resuscitation room transfusion of packed red blood cells, receipt of emergency treatment for hemorrhage control, transfusion of >10 units of packed red blood cells in the first 24 hours, or death from hemorrhage). Blunt trauma was defined as any exposure to nonpenetrating kinetic energy, collision, or deceleration. Statistical analysis was performed from January 15, 2021, to February 22, 2022. Continuous administration of norepinephrine in the prehospital environment or resuscitation room prior to hemorrhage control, according to European guidelines. The primary outcome was 24-hour mortality, and the secondary outcome was in-hospital mortality. The average treatment effect (ATE) of early norepinephrine administration on 24-hour mortality was estimated according to the Rubin causal model. Inverse propensity score weighting and the doubly robust approach with 5 distinct analytical strategies were used to determine the ATE. A total of 52 568 patients were screened for inclusion, and 2164 patients (1508 men [70%]; mean [SD] age, 46 [19] years; median Injury Severity Score, 29 [IQR, 17-36]) presented with acute hemorrhage and were included. A total of 1497 patients (69.1%) required emergency hemorrhage control, 128 (5.9%) received a prehospital transfusion of packed red blood cells, and 543 (25.0%) received a massive transfusion. Norepinephrine was administered to 1498 patients (69.2%). The 24-hour mortality rate was 17.8% (385 of 2164), and the in-hospital mortality rate was 35.6% (770 of 2164). None of the 5 analytical strategies suggested any statistically significant association between norepinephrine administration and 24-hour mortality, with ATEs ranging from -4.6 (95% CI, -11.9 to 2.7) to 2.1 (95% CI, -2.1 to 6.3), or between norepinephrine administration and in-hospital mortality, with ATEs ranging from -1.3 (95% CI, -9.5 to 6.9) to 5.3 (95% CI, -2.1 to 12.8). The findings of this study suggest that early norepinephrine infusion was not associated with 24-hour or in-hospital mortality among patients with blunt trauma and hemorrhagic shock. Randomized clinical trials that study the effect of early norepinephrine administration among patients with trauma and hypotension are warranted to further assess whether norepinephrine is safe for patients with hemorrhagic shock.

Study of damage control strategy for non-traumatic diseases: a single-center observational study

BackgroundDamage control strategy (DCS) has been introduced not only for trauma but also for acute abdomen, but its indications and usefulness have not been clarified. We examined clinical characteristics of patients who underwent DCS and compared clinical characteristics and results with and without DCS in patients with septic shock.MethodsWe targeted a series of endogenous abdominal diseases in Kansai Medical University Hospital from April 2013 to March 2019. Clinical characteristics of 26 patients who underwent DCS were examined. Then, clinical characteristics and results were compared between the DCS group (n = 26) and non-DCS group (n = 31) in 57 patients with septic shock during the same period.ResultsAll 26 patients who underwent DCS had septic shock, low mean arterial pressure (MAP) before the start of surgery, and required high-dose norepinephrine administration intraoperatively. Their discharge mortality rate was 12%. Among the patients with septic shock, the DCS group had a higher SOFA score (P = 0.008) and MAP was lower preoperatively, but it did not increase even with intraoperative administration of large amounts of fluid replacement and vasoconstrictor. There was no significant difference in 28-day mortality and discharge mortality between the two groups.ConclusionsDCS may be useful in patients with severe septic shock.

Low-dose norepinephrine in combination with hypotensive resuscitation may prolong the golden window for uncontrolled hemorrhagic shock in rats.

Hypotension resuscitation is an important principle for the treatment after trauma. Current hypotensive resuscitation strategies cannot obtain an ideal outcome for remote regions. With the uncontrolled hemorrhagic shock (UHS) model in rats, the effects of norepinephrine (NE) on the tolerance time of hypotensive resuscitation, blood loss, vital organ functions, and animal survival were observed. Before bleeding was controlled, only the LR infusion could effectively maintain the MAP to 50–60 mmHg for 1 h, while the MAP gradually decreased with prolonging time, even with increasing infusion volume. Low-dose NE during hypotensive resuscitation prolonged the hypotensive tolerance time to 2–3 h, and the effect of 0.3 μg/kg/min NE was the best. Further studies showed that 0.3 μg/kg/min NE during hypotensive resuscitation significantly lightened the damage of organ function induced by UHS via protecting mitochondrial function, while the LR infusion did not. At the same time, NE administration improved Hb content, DO2, and VO2, and restored liver and kidney blood flow. The survival results showed that low-dose NE administration increased the survival rate and prolonged the survival time. Together, low-dose NE during hypotensive resuscitation was suitable for the early treatment of UHS, which can strive for the golden window of emergency treatment for serious trauma patients by reducing blood loss and protecting vital organ functions.

The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis.

Hepatorenal syndrome (HRS) is associated with high rates of morbidity and mortality. Evidence examining commonly used drug treatments remains uncertain. We assessed the comparative effectiveness of inpatient treatments for HRS by performing a network meta-analysis of randomized clinical trials (RCTs). We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process & Other Non-Indexed Citations, Scopus, and Web of Science from inception. Pairs of reviewers independently identified eligible RCTs that enrolled patients with type 1 or 2 HRS. Pairs of reviewers independently extracted data. We assessed risk of bias using the Cochrane tool for RCTs and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Our main outcomes are all-cause mortality, HRS reversal, and serious adverse events. Of 3,079 citations, we included 26 RCTs examining 1,736 patients. Based on pooled analysis, terlipressin increases HRS reversal compared with placebo (142 reversals per 1,000 [95% CI, >87.7 to >210.9]; high certainty). Norepinephrine (112.7 reversals per 1,000 [95% CI, 52.6 to >192.3]) may increase HRS reversal compared with placebo (low certainty). The effect of midodrine+octreotide (67.8 reversals per 1,000 [95% CI, <2.8 to >177.4]; very low) on HRS reversal is uncertain. Terlipressin may reduce mortality compared with placebo (93.7 fewer deaths [95% CI, 168.7 to <12.5]; low certainty). Terlipressin probably increases the risk of serious adverse events compared with placebo (20.4 more events per 1,000 [95% CI, <5.1 to >51]; moderate certainty). Terlipressin increases HRS reversal compared with placebo. Terlipressin may reduce mortality. Until access to terlipressin improves, initial norepinephrine administration may be more appropriate than initial trial with midodrine+octreotide. Our review has the potential to inform future guideline and practice in the treatment of HRS.

Does Fluid Administration Based on Fluid Responsiveness Tests such as Passive Leg Raising Improve Outcomes in Sepsis?

The management of sepsis requires the rapid administration of fluid to support blood pressure and tissue perfusion. Guidelines suggest that patients should receive 30 ml per kg of fluid over the first one to three hours of management. The next concern is to determine which patients need additional fluid. This introduces the concept of fluid responsiveness, defined by an increase in cardiac output following the administration of a fluid bolus. Dynamic tests, measuring cardiac output, identify fluid responders better than static tests. Passive leg raising tests provide an alternative approach to determine fluid responsiveness without administering fluid. However, one small randomized trial demonstrated that patients managed with frequent passive leg raising tests had a smaller net fluid balance at 72 hours and reduced requirements for renal replacement therapy and mechanical ventilation, but no change in mortality. A meta-analysis including 4 randomized control trials reported that resuscitation guided by fluid responsiveness does not improve mortality outcomes in patients with sepsis. Recent studies have demonstrated that the early administration of norepinephrine may improve outcomes in patients with sepsis. The concept of fluid responsiveness helps clinicians analyze the clinical status of patients, but this information must be integrated into the overall management of the patient. This review considers the use and benefit of fluid responsiveness tests to direct fluid administration in patients with sepsis.

The Association of Norepinephrine Utilization With Mortality Risk in Trauma Patients

IntroductionWhile the pillars of trauma resuscitation are surgical hemostasis and blood product administration, norepinephrine (NE) can be used as an adjunct. The goal of this study was to evaluate the relationship between the maximum dose of NE, timing of NE administration, and mortality in trauma patients. MethodsPatients admitted between January 2013 and January 2021 treated with NE were reviewed. Univariate and multivariate logistic regression were used to assess whether maximum NE dose was independently associated with mortality. Optimal dosage rates for NE were determined via Youden Index. Subgroup analyses comparing those who received NE within versus after the first 24 h of admission were conducted. ResultsThree hundred fifty-first trauma patients were included, with 217 (62%) surviving. Patients who died received an average maximum dose of 16.7 mcg/min compared to 9.1 mcg/min in survivors (P = 0.0003). Mortality rate increased with dosage (P < 0.0001), with doses greater than 20 mcg/min having 79% mortality. Those who received NE within the first 24 h had an inflection point in mortality at 16 mcg/min (Youden = 0.45) (OR 1.06; 95% CI 1.03-1.10). For patients who received NE after the first 24 h, an inflection point in mortality was at 10 mcg/min (Youden = 0.34) (OR 1.09; 95% CI 1.04-1.14). ConclusionsHigher maximum doses of NE were associated with increased mortality. Patients initiated on NE more than 24 h into their admission displayed an inflection point at a lower dose than those initiated later. This suggests that trauma patients initiated on NE after 24 h from injury may have a dire prognosis.

A rat model of septic shock using live Escherichia coli and response to Noradrenaline

Objectives: Popular animal models of septic shock involve injections of endotoxin (bacterial lipopolysaccharide). Other methods that induce sepsis are often time-consuming and require long-term monitoring facilities. Further, individual models using different bacterial strains can deepen our understanding of sepsis pathophysiology. Hence, our objective was to develop an acute and functional Wistar rat model of septic shock using live strains of Escherichia coli and then administer Noradrenaline, a known sympathomimetic drug, to study if the response is along expected lines. Materials and Methods: After random allocation to one of three groups (Group 1 – E. coli alone, n=7; Group 2 – E. coli followed by Noradrenaline, n = 7 and Group 3 – control (n = 4), which received saline injections), Wistar rats were anesthetised and intra-arterial pressure was recorded from carotid artery catheter. Live E. coli suspended in normal saline (5 Mcfarland concentration; dose – 650 uL/100 g body weight) was injected through the tail vein to induce sepsis. When mean arterial pressure dropped to 50% of its value before E. coli injection, Noradrenaline was injected in Group 2. Results: The average time (t1, n = 14) for the septic shock to set in was about 1.94 ± 0.97 h. Six out of seven rats (Group 1) died within 60 min without intervention. The addition of Noradrenaline after hypotension in Group 2 prolonged the time to death significantly by about 170 min. Conclusion: The rat septic shock model using E. coli described in the study is an acute, stable, and functional model to study various aspects of septic shock. Administration of Noradrenaline prolonged the animal’s life in septic shock as expected. Future studies using other common sepsis agents encountered in clinics can be undertaken similarly.

Aqueous extracts of Urtica dioica (stinging nettle) leaf contain a P2-purinoceptor antagonist-Implications for male fertility.

Stinging nettle root and leaf extracts were tested for their effect on prostatic smooth muscle contractility. Root extract did not affect electrical field stimulation induced-nerve mediated contractions of isolated rat prostates. On the other hand, leaf extract attenuated electrical field stimulation-induced contractions at all frequencies. Similarly, contractions elicited by exogenous administration of ATP and αβ-methylene ATP were inhibited by leaf extract, whereas contractions elicited by exogenous administration of noradrenaline or acetylcholine were unaffected. The active component was present within the aqueous phase of the leaf extract. In mouse mating studies, stinging nettle leaf extract (50 mg p.o. daily) reduced male fertility by 53% compared to vehicle-treated male mice. Cardiovascular parameters were unaffected by administration of stinging nettle leaf extract (p ≥ 0.057). Treated mice exhibited normal mating behaviour. Bladder and testes weighed less in stinging nettle leaf extract treated mice. All other organs and total body weight were unaffected. It is concluded that stinging nettle leaf extract reduces contractility of genitourinary smooth muscle by acting as an antagonist at postjunctional P2X1-purinoceptors. These data indicates that blocking sperm transport through pharmacological blockade of P2X1-purinoceptors via oral administration is consistent with an effective and convenient biological strategy male contraception.

First-Line Vasopressor Use in Septic Shock and Route of Administration: An Epidemiologic Study.

Rationale: Norepinephrine is a first-line agent for the treatment of hypotension in septic shock. However, its frequency of use and potential barriers to its use are unclear. Objectives: To evaluate the frequency of use of norepinephrine in septic shock, to identify potential barriers to its use, and to evaluate trends in use of vasopressors over time. Methods: We conducted a retrospective population-based cohort study of patients with septic shock in Alberta, Canada, between July 1, 2012, and December 31, 2018. The primary outcome was receipt of a first-line vasopressor other than norepinephrine ("nonnorepinephrine vasopressor"). Predictors of receiving a nonnorepinephrine vasopressor were assessed using a multivariable-adjusted, multilevel logistic regression model with intensive care unit as a random effect. Results: Among 6,343 patients with septic shock, the proportion of patients receiving nonnorepinephrine vasopressors as first-line treatment decreased steadily from 11.5% in 2012 to 3.0% in 2018. Two factors most strongly associated with their receipt were having peripheral intravenous access only (adjusted odds ratio [aOR], 6.15; 95% confidence interval [CI], 4.58-8.26; P < 0.001) and year of admission (aOR, 0.74 per year after 2012; 95% CI, 0.69-0.80; P < 0.001). Other factors that had associations after adjustment included admission to a nonteaching hospital (aOR, 2.19; 95% CI, 1.23-3.89; P = 0.007), admission to a coronary care unit (aOR, 2.56; 95% CI, 1.001-6.54; P = 0.05), Sequential Organ Failure Assessment score (aOR, 0.92 per unit increase; 95% CI, 0.88-0.96; P < 0.001), and heart rate (aOR, 0.92 per 10-beat per minute increase; 95% CI, 0.87-0.97; P = 0.002). Conclusions: In a large cohort of patients in Alberta, Canada, we found a steady decrease in use of first-line vasopressors other than norepinephrine in septic shock. The strongest factor associated with their use was the presence of only peripheral venous access, suggesting that this may still be considered a barrier to administration of norepinephrine.

Effect of sarpogrelate treatment on 5-HT modulation of vascular sympathetic innervation and platelet activity in diabetic rats

This study aimed to investigate whether the 5-HT2 receptor blockade alters the 5-HT effect on vascular sympathetic neurotransmission and platelet activation in type 1 diabetes. 28-day diabetes was obtained by alloxan (150 mg/kg; s.c.) in male Wistar rats, administering sarpogrelate (5-HT2 blocker; 30 mg/kg/day; p.o.) for 14 days. Blood glucose and body weight were monitored for 28 days. After 4 weeks of diabetes induction, food and drink intake, urine, plasma-platelet 5-HT, and platelet activation were determined in normoglycemic, non-treated diabetic and sarpogrelate-treated diabetic rats. Another set of diabetic rats were pithed to run the vascular sympathetic stimulation or exogenous noradrenaline administration, examining the induced vasoconstrictor responses. Sarpogrelate treatment significantly reduced drink intake and urine, whereas BW gain, hyperglycemia, and food intake were not modified in diabetic rats. The platelet activation and plasma 5-HT concentration were decreased (increasing the stored 5-HT platelet) by 5-HT2 blockade in diabetic animals. The sympathetic-induced vasoconstrictions were higher in non-treated than in sarpogrelate-treated diabetic rats. 5-HT inhibited these vasopressor responses, reproduced exclusively by the 5-HT1/5/7 receptor agonist, 5-CT. The 5-CT-produced inhibition was partly reversed by 5-HT1D or 5-HT7 antagonists (LY310762 or SB-258719, respectively), and totally annulled by the mixture of LY310762+SB‐258719. Noradrenaline-caused vasoconstrictions were also decreased by 5-CT. In conclusion, our results reveal that 14-day sarpogrelate treatment improves polydipsia and polyuria, reduces platelet hyperactivation, plasma 5-HT and the vascular sympathetic tone, and changes 5-HT receptors inhibiting noradrenergic drive in diabetic rats: pre and/or postjunctional 5-HT1D/7 are involved in the sympatho-inhibition.

165-OR: Norepinephrine Acts on Glutamatergic Neurons in the Ventromedial Hypothalamus to Stimulate the Release of Counterregulatory Hormones

Release of glutamate in the ventromedial hypothalamus (VMH) is important for stimulating the counterregulatory hormone responses to hypoglycemia. It is currently not known whether VMH glutamatergic neurotransmission is influenced by adrenergic inputs. To address this question, we examined whether ß2-adrenergic receptors are expressed on VMH glutamatergic neurons using immunohistochemistry. Coronal brain sections collected from Sprague Dawley (SD) rats showed fairly extensive co-localization of Vglut2 (a marker of glutamatergic neurons) and ß2-adrenergic receptors. We then used local microinjection in combination with microdialysis to examine whether norepinephrine administration into the VMH stimulated the release of neurotransmitter glutamate and the counterregulatory hormones in the absence of hypoglycemia. About 7-8 rats were randomly allocated to one of two treatment groups: Controls, which received an infusion of artificial extracellular fluid, or the NE group, which received an infusion of 400 nM of norepinephrine. Our results indicate that NE administration into the VMH caused a marked increase in glutamate that was accompanied by an ∼3-fold increase in both plasma glucagon and epinephrine release (P&amp;lt;0.vs. Control) . Our data suggests that NE enhances the release of neurotransmitter glutamate in the VMH that in turn, may stimulate the release of counterregulatory hormones. Disclosure D.A.Appadurai: None. O.Chan: None. Funding NIH (DK099315)