Administration Of Norepinephrine Research Articles

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)

COST EFFECTIVENESS OF USING TERLIPRESSIN TO TREAT HEPATORENAL SYNDROME.

Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

Normothermic blood polarizing versus depolarizing cardioplegia in a porcine model of cardiopulmonary bypass.

OBJECTIVESWe have previously demonstrated beneficial cardiac protection with hypothermic polarizing cardioplegia compared to a hyperkalemic depolarizing cardioplegia. In this study, a porcine model of cardiopulmonary bypass was used to compare the protective effects of normothermic blood-based polarizing and depolarizing cardioplegia during cardiac arrest.METHODSThirteen pigs were randomized to receive either normothermic polarizing (n = 8) or depolarizing (n = 5) blood-based cardioplegia. After initiation of cardiopulmonary bypass, normothermic arrest (34°C, 60 min) was followed by 60 min of on-pump and 90 min of off-pump reperfusion. Primary outcome was myocardial injury measured as arterial myocardial creatine kinase concentration. Secondary outcome was haemodynamic function and the energy state of the hearts.RESULTSDuring reperfusion, release of myocardial creatine kinase was comparable between groups (P = 0.36). In addition, most haemodynamic parameters showed comparable results between groups, but stroke volume (P = 0.03) was significantly lower in the polarizing group. Adenosine triphosphate levels were significantly (18.41 ± 3.86 vs 22.97 ± 2.73 nmol/mg; P = 0.03) lower in polarizing hearts, and the requirement for noradrenaline administration (P = 0.002) and temporary pacing (6 vs 0; P = 0.02) during reperfusion were significantly higher in polarizing hearts.CONCLUSIONSUnder normothermic conditions, polarizing blood cardioplegia was associated with similar myocardial injury to depolarizing blood cardioplegia. Reduced haemodynamic and metabolic outcome and a higher need for temporary pacing with polarized arrest may be associated with the blood-based dilution of this solution.

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.

Renal Microcirculation and Function in a Pig Model of Hemorrhagic Shock Resuscitation with Norepinephrine.

Rationale: Norepinephrine (NE) is commonly used in combination with fluid during resuscitation of hemorrhagic shock, but its impact on kidney microcirculation, oxygenation, and function is still unknown in this setting. Objectives: During hemorrhagic shock resuscitation, does a combination of fluid and NE affect kidney oxygenation tension, kidney microcirculatory perfusion, and 48-hour kidney function, as compared with fluid alone? Methods: Hemorrhagic shock was induced in 24 pigs, and 8 pigs were included as a sham group. Resuscitation of hemorrhagic shock was performed, using a closed-loop device, either by fluid alone (0.9% NaCl; fluid group) or associated with the administration of NE at two doses (moderate dose: mean rate of 0.64 μg ⋅ kg-1 ⋅ min-1; high dose: mean rate of 1.57 μg ⋅ kg-1 ⋅ min-1) to obtain a target systolic arterial pressure of 80to 90 mm Hg. Resuscitation was followed by transfusion of the withdrawn blood. Measurements and Main Results: The amount of fluid required to reach the target systolic arterial pressure was lower in the NE groups than in the fluid group, with subsequently less hemodilution. NE restored kidney microcirculation, oxygenation, and function in a manner comparable to that achieved with fluid resuscitation alone. There were no histologic differences between animals resuscitated with fluid and those resuscitated with NE. Conclusions: In pigs with hemorrhagic shock, resuscitation with a combination of NE and fluid restored kidney microcirculation and oxygenation, as well as renal function, in a manner comparable to fluid resuscitation alone and without differences between the two NE doses. NE administration led to a fluid volume-sparing effect with subsequently less hemodilution.

Prehospital norepinephrine administration reduces 30-day mortality among septic shock patients

BackgroundDespite differences in time of sepsis recognition, recent studies support that early initiation of norepinephrine in patients with septic shock (SS) improves outcome without an increase in adverse effects. This study aims to investigate the relationship between 30-day mortality in patients with SS and prehospital norepinephrine infusion in order to reach a mean blood pressure (MAP) > 65 mmHg at the end of the prehospital stage.MethodsFrom April 06th, 2016 to December 31th, 2020, patients with SS requiring prehospital Mobile Intensive Care Unit intervention (MICU) were retrospectively analysed. To consider cofounders, the propensity score method was used to assess the relationship between prehospital norepinephrine administration in order to reach a MAP > 65 mmHg at the end of the prehospital stage and 30-day mortality.ResultsFour hundred and seventy-eight patients were retrospectively analysed, among which 309 patients (65%) were male. The mean age was 69 ± 15 years. Pulmonary, digestive, and urinary infections were suspected among 44%, 24% and 17% patients, respectively. One third of patients (n = 143) received prehospital norepinephrine administration with a median dose of 1.0 [0.5–2.0] mg h−1, among which 84 (69%) were alive and 38 (31%) were deceased on day 30 after hospital-admission. 30-day overall mortality was 30%. Cox regression analysis after the propensity score showed a significant association between prehospital norepinephrine administration and 30-day mortality, with an adjusted hazard ratio of 0.42 [0.25–0.70], p < 10–3. Multivariate logistic regression of IPTW retrieved a significant decrease of 30-day mortality among the prehospital norepinephrine group: ORa = 0.75 [0.70–0.79], p < 10–3.ConclusionIn this study, we report that prehospital norepinephrine infusion in order to reach a MAP > 65 mmHg at the end of the prehospital stage is associated with a decrease in 30-day mortality in patients with SS cared for by a MICU in the prehospital setting. Further prospective studies are needed to confirm that very early norepinephrine infusion decreases septic shock mortality.

Genetic, antimicrobial resistance profile andmortality rates of Acinetobacter baumanniiinfection in Brazil: A systematic reviewMirian.

The increase of multidrug-resistant bacteria - including Acinetobacter baumannii (A. baumannii) - has been reported globally. The aim of this systematic review was to determine the risk factors of A. baumannii infection, its resistance profile, reservoirs and mortality rates in Brazil. Data from over 3,000 patients were included. Results suggested that A. baumannii is widely transmitted in Brazil and the endemic clones ST1, ST15, ST 25, ST79, ST162 and ST730 were the most reported; also, blaOXA23, blaOXA51 and blaOXA143 were common resistant genes. The risk factors for A. baumannii infection included the procedure of using invasive devices, previous antibiotic therapy, hemodialysis, comorbidities and higher scores on the Sequential Organ Failure Assessment (SOFA). Two out of five studies identified multidrug resistant A. baumannii to polymyxin. Mortality rates varied between 43.7% to 81%, except for the ST25 strain in which there was a 100% mortality rate. Mortality was associated with sepsis, respiratory infection, septic shock, old age (>60 years) and administration of norepinephrine. Nonetheless, this review highlights the need for more data on A. baumannii infection across Brazil to support public policies aiming to control and prevent the dissemination of this bacteria.

Milrinone vs norepinephrine administration in preventing delayed cerebral ischaemia in cerebral vasospasm: a systematic review

Background: Subarachnoid haemorrhage is a form of stroke, classified as traumatic or aneurysmal in origin. Subarachnoid haemorrhage from aneurysmal rupture can cause significant side effects—most frequently, cerebral vasospasm, which increases the risk of developing delayed cerebral ischaemia. Medical and endovascular interventions differ between institutions and regions. However, the most common intervention is medication management with milrinone and norepinephrine. Aims: This systematic review determines the effectiveness of milrinone versus norepinephrine administration in preventing delayed cerebral ischaemia in aneurysmal subarachnoid haemorrhage patients with cerebral vasospasm. Methods: Critical appraisal of 13 studies, consisting of randomised controlled trials, prospective/retrospective case series and reports and cross setional studies, was conducted. Findings: There was considerable variation in dosing and co-interventions for both milrinone and norepinephrine administration. Some 11 studies agreed milrinone was more beneficial in increasing cerebral blood flow than norepinephrine. For milrinone, good functional outcomes were identified in 60–100% of assessed populations, compared to 44–64% with norephinephrine. For both medications poor outcomes related to an increased severity of haemorrhage. Adverse effects following milrinone administration were seen in three studies, but were deemed negligible compared to treatment benefit. Only one norepinephrine study reported severe adverse events. Conclusions: Milrinone appears to be more beneficial than norepinephrine in preventing delayed cerebral ischaemia, improving functional outcomes and causing less adverse effects. Owing to the low quality of evidence supporting milrinone use in subarachnoid haemorrhgae, further research is needed.

Adrenergic Control of Primo Tissue Size in Rats.

Hyperplastic morphological changes associated with erythropoiesis have been reported in the primo vascular system (PVS) tissue on the surface of abdominal organs in rats with heart failure (HF) or hemolytic anemia (HA). Objectives: Since adrenergic activity is commonly activated in both HF and HA, we investigated whether adrenergic signaling mediates the abovementioned morphological changes. We compared the effects of adrenolytic treatments (exercise training and 6-hydroxydopamine) on the gross morphology of the PVS tissues isolated from organ surfaces in HF or HA rats. HF and HA were induced by ligating the left coronary artery and injecting phenylhydrazine, respectively. We further compared the effects of norepinephrine and norepinephrine plus α- or β-adrenoceptor blockers. The number of samples per rat, PN size, and proportion of red-colored samples in the PVS tissue increased in the HF and HA rats. These changes were reversed by adrenolytic treatments. Interestingly, 6-hydroxydopamine also reversed phenylhydrazineinduced hemolytic changes in erythrocytes. Subcutaneous administration of norepinephrine (3 mg/kg/d) increased the sampling frequency per rat and the PN size, but these effects were blunted at a higher dose (10 mg/kg/d). Norepinephrine administration had little effect on the proportion of red-colored tissues. Norepinephrine-induced morphological changes were completely blocked by a β-adrenoceptor antagonist (propranolol) but increased slightly by an α-adrenoceptor antagonist (phentolamine). Adrenergic signaling controls hyperplastic changes in the organ surface PVS in rats. These findings may explain the morphological dynamics of the PVS tissues proposed by Bong Han Kim and further clarify the pathophysiological roles of the PVS.

Comparison of phenylephrine and norepinephrine for treatment of spinal hypotension during elective cesarean delivery- A randomised, double-blind study.

Hypotension following subarachnoid block for cesarean delivery (CD) is common. We compared the effect of bolus administration of norepinephrine and phenylephrine on umbilical artery pH (primary objective) and their efficacy for the treatment of maternal hypotension (secondary objective) in term parturients undergoing elective CD under spinal anesthesia. In a randomized, double-blinded study, parturients received 1 mL boluses of either phenylephrine 100 μg/mL (group phenylephrine; n = 45) or norepinephrine 7.5 μg/mL (group norepinephrine; n = 45) whenever maternal systolic blood pressure decreased to ≤80% of baseline. Maternal hemodynamic changes, vasopressor, and atropine requirement and neonatal outcome (umbilical cord blood gas analysis, Apgar scores, neonatal neurobehavioral response) were assessed. The Apgar scores and umbilical cord blood gas analysis were comparable between groups. The neurobehavioral scale score was significantly higher in group NE compared with that in group PE at 24 h and 48 h; P = 0.007 and 0.002, respectively. The number of vasopressor doses and time to the first vasopressor requirement for maintaining systolic pressure >80% of baseline was comparable in both groups. Incidence of bradycardia (P = 0.009), reactive hypertension (P = 0.003), and dose requirement of atropine (P = 0.005) was higher in group PE compared with group NE. In term normotensive parturients who received bolus norepinephrine 7.5 μg or phenylephrine 100 μg for the treatment of post-spinal hypotension during CD, neonatal umbilical cord blood gas analysis and Apgar scores were comparable. Norepinephrine use was associated with a lower incidence of maternal bradycardia and reactive hypertension compared with phenylephrine.

Impaired physiological thermoregulation in postweaning obese female LA/Ntul//-cp (corpulent) rats

Groups of lean and obese female lean, and obese LA/Ntul//cp (corpulent) rats were subjected to measures of thermic responses to feeding, noradrenaline administration, and responses to 14 hours of cold exposure to access their capacity for thermoregulation beginning at 6 to 8 weeks of age. Body weights and adipose tissue mass were greater in the obese than the lean phenotype (p=&lt;0.05). RMR and the dose related thermic responses to norepinephrine (NE) in lean were greater than in obese. Cold exposure at 4°C resulted in decreases in rectal but not core temperature in obese rats, and the thermic responses to 45 minutes of 4°C cold exposure on VO2 were typical but were significantly greater in lean than obese animals at all points measured. Circulating thyroid hormone concentrations were similar in lean and obese rats and T3 but not T4 increased dramatically in both phenotypes following the cold exposure, consistent with phenotype- and IBAT-linked changes in T4-5’ deiodinase and thyroidal activity in this strain. These thermoregulatory changes are consistent with previous studies and may contribute to phenotype mediated aspects of energy metabolism, storage, and adipose tissue deposition and to a phenotype specific selective epigenetic propensity for the expression of obesity during the early postweaning period

Clinical Update on Vasopressors and Titration Strategies.

Clinical Update on Vasopressors and Titration Strategies.

An Economic Analysis of Critical Care Nurse Resourcing Following the Uptake of Ready-to-Administer Noradrenaline for Hypotensive Shock in Adults in England

IntroductionReady-to-administer formulations for intravenous administration of noradrenaline are now broadly recommended and predicted to reduce pressure on critical care nursing. This analysis sought to quantify the nurse resource released from national level transition.MethodsThe annual number of noradrenaline support days for hypotensive shock was determined and the administration of noradrenaline was simulated over 24 h using a decision tree. A ‘best-practice’ ready-to-administer strategy (RtA) of volumetrically pumped noradrenaline was compared to a ‘nil uptake’ strategy (AfC) of bedside prepared solution delivered either volumetrically or using a double syringe pump. A mix of noradrenaline concentrations, flow rates, product sizes, and preferences for ampoule pooling, preparation volume, and sterility were included. The consumption of nurse days and product units was then projected over 1 year for a population of adults in critical care in England.ResultsNoradrenaline was administered over 231,011 days per year across 4123 critical care beds in England. Implementing a transition from AfC to RtA strategies on this scale released 35,791 nurse days or 176 whole-time nurse equivalents at 50/50 NHS band 5 and 6, a monetised release of £11.6 million. There was an increase in drug acquisition cost of £2.1 million using the licensed commercial product Sinora®. Annual net monetary benefit was + £9.5 million, or + £65,961 per critical care unit (CCU) of 29 beds, equivalent to one nurse released per unit for patient care.ConclusionsThis modelling of ready-to-administer noradrenaline with volumetric delivery quantifies and bears out the recommendations of the Lord Carter review, the Royal Pharmaceutical Society, and the NHS Specialist Pharmacy Service in their encouragement of ready-to-administer formulations for safe and resource-effective critical care.

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

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. 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. 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. 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.

α-1 Adrenoceptor Activation in the Dorsal Raphe Nucleus Decreases Food Intake in Fasted Rats.

The dorsal raphe (DR) nucleus is involved in a myriad of physiological functions, such as the control of sleep-wake cycle, motivation, pain, energy balance, and food intake. We have previously demonstrated that in ad libitum fed rats the intra-DR administration of phenylephrine, an α-1 receptor agonist, does not affect food intake, whereas clonidine, an α-2 receptor agonist, potently stimulates food intake. These results indicated that in fed rats an increased adrenergic tonus blocked food intake, since the activation of α-2 auto-receptors, which decreases pre-synaptic release of adrenaline/noradrenaline, affected food intake. Thus, in this study we assessed whether the response to adrenergic stimuli would differ after overnight fasting, a situation of low adrenergic activity in the DR. Intra-DR administration of adrenaline and noradrenaline blocked food intake evoked by overnight fasting. Similarly, phenylephrine administration decreased hunger-induced food intake. These changes in food intake were accompanied by changes in other behaviors, such as increased immobility time and feeding duration. On the other hand, intra-DR administration of clonidine did not affect food-intake or associated behaviors. These results further support the hypothesis that in fed animals, increased adrenergic tonus in DR neurons inhibiting feeding, while in fasted rats the adrenergic tonus decreases and favors food intake. These data indicate a possible mechanism through which adrenergic input to the DRN contributes to neurobiology of feeding.