Adjuvant-induced arthritis promotes vascular hyporesponsiveness to phenylephrine through a nitric oxide-related mechanism.

Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced arthritis (AIA), around the 15th day post-induction. Therefore, the present study aimed to verify the effects of AIA on hyporesponsiveness to phenylephrine in rat aortas. AIA was induced by intradermal injection of Mycobacterium tuberculosis (3.8 mg/dL) in the right hind paw of male Wistar rats (n=27). Functional experiments in isolated aortas were carried out 15 days after AIA induction. Morphometric and stereological analyses of the aortas were also performed 36 days after the induction of AIA. AIA did not promote structural modifications in the aortas at any of the time points studied. AIA reduced phenylephrine-induced contraction in endothelium-intact aortas, but not in endothelium-denuded aortas. However, AIA did not change KCl-induced contraction in either endothelium-intact or denuded aortas. L-NAME (non-selective NOS inhibitor), 1400W (selective iNOS inhibitor), and ODQ (guanylyl cyclase inhibitor) reversed AIA-induced hyporesponsiveness to phenylephrine in intact aortas. 7-NI (selective nNOS inhibitor) increased the contraction induced by phenylephrine in aortas from AIA rats. In summary, the hyporesponsiveness to phenylephrine induced by AIA was endothelium-dependent and mediated by iNOS-derived NO through activation of the NO-guanylyl cyclase pathway.

Randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: A study protocol.

BACKGROUND: When clinicians need to administer a vasopressor infusion, they are faced with the choice of administration via either peripheral intravenous catheter (PIVC) or central venous catheter (CVC). Vasopressor infusions have traditionally been administered via central venous catheters (CVC) rather than Peripheral Intra Venous Catheters (PIVC), primarily due to concerns of extravasation and resultant tissue injury. This practice is not guided by contemporary randomised controlled trial (RCT) evidence. Observational data suggests safety of vasopressor infusion via PIVC. To address this evidence gap, we have designed the "Vasopressors Infused via Peripheral or Central Access" (VIPCA) RCT. METHODS: The VIPCA trial is a single-centre, feasibility, parallel-group RCT. Eligible critically ill patients requiring a vasopressor infusion will be identified by emergency department (ED) or intensive care unit (ICU) staff and randomised to receive vasopressor infusion via either PIVC or CVC. Primary outcome is feasibility, a composite of recruitment rate, proportion of eligible patients randomised, protocol fidelity, retention and missing data. Primary clinical outcome is days alive and out of hospital up to day-30. Secondary outcomes will include safety and other clinical outcomes, and process and cost measures. Specific aspects of safety related to vasopressor infusions such as extravasation, leakage, device failure, tissue injury and infection will be assessed. DISCUSSION: VIPCA is a feasibility RCT whose outcomes will inform the feasibility and design of a multicentre Phase-3 trial comparing routes of vasopressor delivery. The exploratory economic analysis will provide input data for the full health economic analysis which will accompany any future Phase-3 RCT.

Comparative efficacy of volume expansion, inotropes and vasopressors in preterm neonates with probable transitional circulatory instability in the first week of life: a systematic review and network meta-analysis.

BACKGROUND: There exists limited agreement on the recommendations for the treatment of transitional circulatory instability (TCI) in preterm neonates OBJECTIVE: To compare the efficacy of various interventions used to treat TCI METHODS: Medline and Embase were searched from inception to 21st July 2023. Two authors extracted the data independently. A Bayesian random effects network meta-analysis was used. Recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. INTERVENTIONS: Dopamine, dobutamine, epinephrine, hydrocortisone, vasopressin, milrinone, volume and placebo. MAIN OUTCOME MEASURES: Mortality, major brain injury (MBI) (intraventricular haemorrhage > grade 2 or cystic periventricular leukomalacia), necrotising enterocolitis (NEC) ≥stage 2 and treatment response (as defined by the author). RESULTS: 15 Randomized Controlled Trials (RCTs) were included from the 1365 titles and abstracts screened. Clinical benefit or harm could not be ruled out for the critical outcome of mortality. For the outcome of MBI, epinephrine possibly decreased the risk when compared to dobutamine and milrinone (very low certainty). Epinephrine was possibly associated with a lesser risk of NEC when compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Dopamine was possibly associated with a lesser risk of NEC when compared with dobutamine (very low certainty). Vasopressin possibly decreased the risk of NEC compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Clinical benefit or harm could not be ruled out for the outcome response to treatment. CONCLUSIONS: Epinephrine may be used as the first-line drug in preterm neonates with TCI, the evidence certainty being very low. We suggest future trials evaluating the management of TCI with an emphasis on objective criteria to define it.

Vascular Response of Triiodothyronine on Isolated Aortic Rings: Contribution of Redox Mechanisms. / Resposta Vascular da Triiodotironina sobre Anéis de Aortas Isoladas: Contribuição de Mecanismos Redox.

BACKGROUND: Vascular dysfunction constitutes the etiology of many diseases, such as myocardial infarction and hypertension, with the disruption of redox homeostasis playing a role in the imbalance of the vasomotor control mechanism. Our group previously has shown that thyroid hormones exert protective effects on the aortic tissue of infarcted rats by improving angiogenesis signaling. OBJECTIVE: Investigate the role of triiodothyronine (T3) on vascular response, exploring its effects on isolated aortas and whether there is an involvement of vascular redox mechanisms. METHODS: Isolated aortic rings (intact- and denuded-endothelium) precontracted with phenylephrine were incubated with T3 (10-8, 10-7, 10-6, 10-5, and 10-4 M), and tension was recorded using a force-displacement transducer coupled with an acquisition system. To assess the involvement of oxidative stress, aortic rings were preincubated with T3 and subsequently submitted to an in vitro reactive oxygen species (ROS) generation system. The level of significance adopted in the statistical analysis was 5%. RESULTS: T3 (10-4 M) promoted vasorelaxation of phenylephrine precontracted aortic rings in both intact- and denuded-endothelium conditions. Aortic rings preincubated in the presence of T3 (10-4 M) also showed decreased vasoconstriction elicited by phenylephrine (1 µM) in intact-endothelium preparations. Moreover, T3 (10-4 M) vasorelaxation effect persisted in aortic rings preincubated with NG-nitro-L-arginine methylester (L-NAME, 10 µM), a nonspecific NO synthase (NOS) inhibitor. Finally, T3 (10-4 M) exhibited, in vitro, an antioxidant role by reducing NADPH oxidase activity and increasing SOD activity in the aorta's homogenates. CONCLUSION: T3 exerts dependent- and independent-endothelium vasodilation effects, which may be related to its role in maintaining redox homeostasis.

FUNDAMENTO: A disfunção vascular constitui a etiologia de diversas doenças, incluindo infarto do miocárdio e hipertensão, diante da ruptura da homeostase oxi-redutiva ("redox"), desempenhando um papel no desequilíbrio do mecanismo de controle vasomotor. Nosso grupo demonstrou anteriormente que os hormônios tireoidianos melhoram a sinalização da angiogênese, exercendo efeitos protetores sobre o tecido aórtico de ratos infartados. OBJETIVOS: Investigar o papel da triiodotironina (T3) na resposta vascular, explorando seus efeitos em aortas isoladas e a presença de mecanismos redox vasculares. MÉTODOS: Anéis aórticos isolados (endotélio intacto e desnudado) pré-contraídos com fenilefrina foram incubados com T3 (10-8, 10-7, 10-6, 10-5 e 10-4 M) e a tensão foi registrada usando um transdutor de deslocamento de força acoplado a um sistema de coleta. Para avaliar o envolvimento do estresse oxidativo, os anéis aórticos foram pré-incubados com T3 e posteriormente submetidos a um sistema de geração de espécies reativas de oxigênio (ROS) in vitro. O nível de significância adotado na análise estatística foi de 5%. RESULTADOS: A T3 (10-4 M) promoveu o vasorrelaxamento dos anéis aórticos pré-contraídos com fenilefrina em endotélio intacto e desnudado. Os anéis aórticos pré-incubados na presença de T3 (10-4 M) também mostraram diminuição da vasoconstrição provocada pela fenilefrina (1 µM) em preparações de endotélio intacto. Além disso, o efeito vasorrelaxante da T3 (10-4 M) persistiu em anéis aórticos pré-incubados com éster metílico de NG-nitro-L-arginina (L-NAME, 10 µM), um inibidor inespecífico da NO sintase (NOS). Por fim, a T3 (10-4 M) exibiu, in vitro, um papel antioxidante ao reduzir a atividade da NADPH oxidase e aumentar a atividade da SOD nos homogenatos aórticos. CONCLUSÃO: A T3 exerce efeitos dependentes e independentes de endotélio, o que pode estar relacionado ao seu papel na manutenção da homeostase redox.

Endobronchial Phenylephrine in Airway Bleeding During Bronchoscopy Does not Cause Hypertension: A Retrospective Observational Study.

BACKGROUND: Bleeding is a known complication during bronchoscopy, with increased incidence in patients undergoing a more invasive procedure. Phenylephrine is a potent vasoconstrictor that can control airway bleeding when applied topically and has been used as an alternative to epinephrine. The clinical effects of endobronchial phenylephrine on systemic vasoconstriction have not been clearly evaluated. Here, we compared the effects of endobronchial phenylephrine versus cold saline on systemic blood pressure. METHODS: In all, 160 patients who underwent bronchoscopy and received either endobronchial phenylephrine or cold saline from July 1, 2017 to June 30, 2022 were included in this retrospective observational study. Intra-procedural blood pressure absolute and percent changes were measured and compared between the 2 groups. RESULTS: There were no observed statistical differences in blood pressure changes between groups. The median absolute change between the median and the maximum intra-procedural systolic blood pressure in the cold saline group was 29 mm Hg (IQR 19 to 41) compared with 31.8 mm Hg (IQR 18 to 45.5) in the phenylephrine group. The corresponding median percent changes in SBP were 33.6 % (IQR 18.8 to 39.4) and 28% (IQR 16.8 to 43.5) for the cold saline and phenylephrine groups, respectively. Similarly, there were no statistically significant differences in diastolic and mean arterial blood pressure changes between both groups. CONCLUSIONS: We found no significant differences in median intra-procedural systemic blood pressure changes comparing patients who received endobronchial cold saline to those receiving phenylephrine. Overall, this argues for the vascular and systemic safety of phenylephrine for airway bleeding as a reasonable alternative to epinephrine.

Intravital Microscopy Evidence That Methylene Blue Should Be a Vasopressor-Sparing Agent in Sepsis Vasoplegia.

Microvasculature failure is expected in sepsis and at higher amine concentrations. Therefore, special attention focused individually on microcirculation is needed. Here, we present that methylene blue can prevent leukocytes from adhering to the endothelium in a rat model of lipopolysaccharide-induced endotoxemia. As hypothesis evidence, an intravital microscopy image is presented.

Understanding How Clinicians Personalize Fluid and Vasopressor Decisions in Early Sepsis Management.

Importance: Recent sepsis trials suggest that fluid-liberal vs fluid-restrictive resuscitation has similar outcomes. These trials used generalized approaches to resuscitation, and little is known about how clinicians personalize fluid and vasopressor administration in practice. Objective: To understand how clinicians personalize decisions about resuscitation in practice. Design, Setting, and Participants: This survey study of US clinicians in the Society of Critical Care Medicine membership roster was conducted from November 2022 to January 2023. Surveys contained 10 vignettes of patients with sepsis where pertinent clinical factors (eg, fluid received and volume status) were randomized. Respondents selected the next steps in management. Data analysis was conducted from February to September 2023. Exposure: Online Qualtrics clinical vignette survey. Main Outcomes and Measures: Using multivariable logistic regression, the associations of clinical factors with decisions about fluid administration, vasopressor initiation, and vasopressor route were tested. Results are presented as adjusted proportions with 95% CIs. Results: Among 11 203 invited clinicians, 550 (4.9%; 261 men [47.5%] and 192 women [34.9%]; 173 with >15 years of practice [31.5%]) completed at least 1 vignette and were included. A majority were physicians (337 respondents [61.3%]) and critical care trained (369 respondents [67.1%]). Fluid volume already received by a patient was associated with resuscitation decisions. After 1 L of fluid, an adjusted 82.5% (95% CI, 80.2%-84.8%) of respondents prescribed additional fluid and an adjusted 55.0% (95% CI, 51.9%-58.1%) initiated vasopressors. After 5 L of fluid, an adjusted 17.5% (95% CI, 15.1%-19.9%) of respondents prescribed more fluid while an adjusted 92.7% (95% CI, 91.1%-94.3%) initiated vasopressors. More respondents prescribed fluid when the patient examination found dry vs wet (ie, overloaded) volume status (adjusted proportion, 66.9% [95% CI, 62.5%-71.2%] vs adjusted proportion, 26.5% [95% CI, 22.3%-30.6%]). Medical history, respiratory status, lactate trend, and acute kidney injury had small associations with fluid and vasopressor decisions. In 1023 of 1127 vignettes (90.8%) where the patient did not have central access, respondents were willing to start vasopressors through a peripheral intravenous catheter. In cases where patients were already receiving peripheral norepinephrine, respondents were more likely to place a central line at higher norepinephrine doses of 0.5 µg/kg/min (adjusted proportion, 78.0%; 95% CI, 74.7%-81.2%) vs 0.08 µg/kg/min (adjusted proportion, 25.2%; 95% CI, 21.8%-28.5%) and after 24 hours (adjusted proportion, 59.5%; 95% CI, 56.6%-62.5%) vs 8 hours (adjusted proportion, 47.1%; 95% CI, 44.0%-50.1%). Conclusions and Relevance: These findings suggest that fluid volume received is the predominant factor associated with ongoing fluid and vasopressor decisions, outweighing many other clinical factors. Peripheral vasopressor use is common. Future studies aimed at personalizing resuscitation must account for fluid volumes and should incorporate specific tools to help clinicians personalize resuscitation.

Management of hepatorenal syndrome and associated outcomes: a systematic reviews.

BACKGROUND: Hepatorenal syndrome (HRS), a multiorgan condition of acute kidney injury, is seen in advanced liver disease. This study aims to evaluate the current treatment for HRS. METHODS: The authors searched PubMed, Scopus and Google Scholar literature. After quality assessment, 31 studies were included in this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology and the population, intervention, comparison and outcome scheme were used. We included human-controlled trials that evaluate the current treatment for HRS. Two authors independently screened articles for inclusion, extracted data and assessed the quality of included studies. RESULTS: This study investigated the studies conducted on the effects of different treatments on follow-up of HRS patients. We gathered 440 articles, so 31 articles remained in our study. Of which 24 articles were conducted on terlipressin versus placebo or other treatments (midodrine/octreotide, norepinephrine, etc) that showed the higher rate of HRS reversal was detected for terlipressin in 17 studies (10 of them were significant), 2 studies achieved an insignificant lower rate of the model for end-stage liver disease score for terlipressin, 15 studies showed a decreased mortality rate in the terlipressin group (4 of them were significant). CONCLUSION: This review showed that terlipressin has a significantly higher reversal rate of HRS than the other treatments. Even the results showed that terlipressin is more efficient than midodrine/octreotide and norepinephrine as a previous medication, in reverse HRS, increasing patient survival.

Limb Necrosis in the Setting of Vasopressor Use.

BACKGROUND: It remains poorly understood why only some hemodynamically unstable patients who receive aggressive treatment with vasopressor medications develop limb necrosis. OBJECTIVE: To determine the incidence of limb necrosis and the factors associated with it following high-dose vasopressor therapy. METHODS: A retrospective case-control medical records review was performed of patients aged 18 to 89 years who received vasopressor therapy between 2012 and 2021 in a single academic medical center. The study population was stratified by the development of limb necrosis following vasopressor use. Patients who experienced necrosis were compared with age- and sex-matched controls who did not experience necrosis. Demographic information, comorbidities, and medication details were recorded. RESULTS: The incidence of limb necrosis following vasopressor administration was 0.25%. Neither baseline demographics nor medical comorbidities differed significantly between groups. Necrosis was present in the same limb as the arterial catheter most often for femoral catheters. The vasopressor dose administered was significantly higher in the necrosis group than in the control group for ephedrine (P = .02) but not for the other agents. The duration of therapy was significantly longer in the necrosis group than in the control group for norepinephrine (P = .001), epinephrine (P = .04), and ephedrine (P = .01). The duration of vasopressin administration did not differ significantly between groups. CONCLUSION: The findings of this study suggest that medication-specific factors, rather than patient and disease characteristics, should guide clinical management of necrosis in the setting of vasopressor administration.

Hepatorenal Syndrome Type 1: Diagnosis and Treatment.

Hepatorenal syndrome (HRS) is a feared complication in patients with advanced cirrhosis and is associated with significant morbidity and mortality. While recognized as a distinct physiologic condition for well over one hundred years, a lack of objective diagnostic tests has made the diagnosis one of exclusion. Since 1979, multiple sets of diagnostic criteria have been proposed. Though varying in detail, the principal intent of these criteria is to identify patients with severe, functional acute kidney injury that is unresponsive to volume resuscitation and exclude those with structural injury. However, accurate differential diagnosis remains challenging. Recently, multiple urinary biomarkers of kidney injury, including neutrophil gelatinase-associated lipocalin, have been studied as a means of objectively phenotyping etiologies of acute kidney injury in patients with cirrhosis. Along with markers reflecting tubular functional integrity, including the fractional excretion of sodium, injury markers will likely be incorporated into future diagnostic criteria. Making an accurate diagnosis is critical, as therapeutic options exist for HRS but must be given in a timely manner and only to those patients likely to benefit. Terlipressin, an analog of vasopressin, is the first line of therapy for HRS in much of the world and has recently been approved for use in the United States. Significant questions remain regarding the optimal dosing strategy, metrics for titration, and the potential role of point-of-care ultrasound to help guide concurrent albumin administration.

Exploration of factors affecting hemodynamic stability following pheochromocytoma resection - cohort study.

Purpose: Surgery is the only way to cure pheochromocytoma; however, postoperative hemodynamic instability is one of the main causes of serious complications and even death. This study's findings provide some guidance for improved clinical management. Patients and methods: This study was to investigate the factors leading to postoperative hemodynamic instability in the postoperative pathology indicated pheochromocytoma from May 2016 to May 2022. They were divided into two groups according to whether vasoactive drugs were used for a median number of days or more postoperatively. The factors affecting the postoperative hemodynamics in the perioperative period (preoperative, intraoperative, and postoperative) were then evaluated. Results: The median number of days requiring vasoactive drug support postoperatively was three in 234 patients, while 118 (50.4%) patients required vasoactive drug support for three days or more postoperatively. The results of the multivariate analysis indicated more preoperative colloid use (odds ratio [OR]=1.834, confidence interval [CI]:1.265-2.659, P=0.001), intraoperative use of vasoactive drug (OR=4.174, CI:1.882-9.258, P<0.001), and more postoperative crystalloid solution input per unit of body weight per day (ml/kg/d) (OR=1.087, CI:1.062-1.112, P<0.001) were risk factors for predicting postoperative hemodynamic instability. The optimal cutoff point of postoperative crystalloid use were 42.37 ml/kg/d. Conclusion: Hemodynamic instability is a key issue for consideration in the perioperative period of pheochromocytoma. The amount of preoperative colloid use, the need for intraoperative vasoactive drugs, and postoperative crystalloid solution are risk factors for predicting postoperative hemodynamic instability (registration number: ChiCT2300071166).

Evaluation of the early use of norepinephrine in major abdominal surgery on medical and surgical postoperative complications: study protocol for a randomised controlled trial (EPON STUDY).

BACKGROUND: Post-induction anaesthesia often promotes intraoperative hypotension (IOH) that can worsen postoperative outcomes. This study aims to assess the benefit of norepinephrine versus ephedrine at the induction of anaesthesia to prevent postoperative complications following major abdominal surgery by preventing IOH. METHODS AND ANALYSIS: The EPON STUDY is a prospective single-centre randomised controlled trial with the planned inclusion of 500 patients scheduled for major abdominal surgery at the Amiens University Hospital. The inclusion criteria are patients aged over 50 years weighing more than 50 kg with an American Society of Anesthesiologists physical status score of ≥2 undergoing major abdominal surgery under general anaesthesia. Patients are allocated either to the intervention group (n=250) or the standard group (n=250). In the intervention group, the prevention of post-induction IOH is performed with norepinephrine (dilution to 0.016 mg/mL) using an electric syringe pump at a rate of 0.48 mg/h (30 mL/h) from the start of anaesthesia and then titrated to achieve the haemodynamic target. In the control group, the prevention of post-induction IOH is performed with manual titration of ephedrine, with a maximal dose of 30 mg, followed by perfusion with norepinephrine. In both groups, the haemodynamic target to maintain is a mean arterial pressure (MAP) of 65 mm Hg or 70 mm Hg for patients with a medical history of hypertension. An intention-to-treat analysis will be performed. The primary outcome is the Clavien-Dindo score assessed up to 30 days postoperatively. The secondary endpoints are the length of hospital stay and length of stay in an intensive care unit/postoperative care unit; postoperative renal function; postoperative cardiovascular, respiratory, neurological, haematological and infectious complications at 1 month; and volume of intraoperative vascular filling and mortality at 1 month. ETHICS AND DISSEMINATION: Ethical approval was obtained from the committee of protection of the persons of Ile de France in May 2021 (number 21 05 41). The authors will be involved in disseminating the research findings (through attending conferences and co-authoring papers). The results of the study will be disseminated via peer-reviewed publications and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT05276596.

A retrospective, multi-agency 'target trial emulation' for the comparison of post-resuscitation epinephrine to norepinephrine.

INTRODUCTION: Epinephrine and norepinephrine are the two most commonly used prehospital vasopressors in the United States. Prior studies have suggested that use of a post-ROSC epinephrine infusion may be associated with increased rearrest and mortality in comparison to use of norepinephrine. We used target trial emulation methodology to compare the rates of rearrest and mortality between the groups of OHCA patients receiving these vasopressors in the prehospital setting. METHODS: Adult (18-80 years of age) non-traumatic OHCA patients in the 2018-2022 ESO Data Collaborative datasets with a documented post-ROSC norepinephrine or epinephrine infusion were included in this study. Logistic regression modeling was used to evaluate the association between vasopressor agent and outcome using two sets of covariables. The first set of covariables included standard Utstein factors, the dispatch to ROSC interval, the ROSC to vasopressor interval, and the follow-up interval. The second set added prehospital systolic blood pressure and SpO2 values. Kaplan-Meier time-to-event analysis was also conducted and the vasopressor groups were compared using a multivariable Cox regression model. RESULTS: Overall, 1,893 patients treated by 309 EMS agencies were eligible for analysis. 1,010 (53.4%) received an epinephrine infusion and 883 (46.7%) received a norepinephrine infusion as their initial vasopressor. Adjusted analyses did not discover an association between vasopressor agent and rearrest (aOR: 0.93 [0.72, 1.21]) or mortality (aOR: 1.00 [0.59, 1.69]). CONCLUSIONS: In this multi-agency target trial emulation, the use of a post-resuscitation epinephrine infusion was not associated with increased odds of rearrest in comparison to the use of a norepinephrine infusion.