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.

Use of hydroxocobalamin to treat intraoperative vasoplegic syndrome refractory to vasopressors and methylene blue during liver transplantation.

INTRODUCTION: For patients with catecholamine-resistant vasoplegic syndrome (VS) during liver transplantation (LT), treatment with methylene blue (MB) and/or hydroxocobalamin (B12) has been an acceptable therapy. However, data on the effectiveness of B12 is limited to case reports and case series. METHODS: We retrospectively reviewed records of patients undergoing LT from January 2016 through March 2022. We identified patients with VS treated with vasopressors and MB, and abstracted hemodynamic parameters, vasopressor requirements, and B12 administration from the records. The primary aim was to describe the treatment efficacy of B12 for VS refractory to vasopressors and MB, measured as no vasopressor requirement at the conclusion of the surgery. RESULTS: One hundred one patients received intraoperative VS treatment. For the 35 (34.7%) patients with successful VS treatment, 14 received MB only and 21 received both MB and B12. Of the 21 patients with VS resolution after receiving both MB and B12, 17 (89.5%) showed immediate, but transient, hemodynamic improvements at the time of MB administration and later showed sustained response to B12. CONCLUSION: Immediate but transient hemodynamic response to MB in VS patients during LT supports the diagnosis of VS and should prompt B12 administration for sustained treatment response.

Adverse Clinical Effects Associated With Non-catecholamine Pharmacologic Agents for Treatment of Vasoplegic Syndrome in Adult Cardiac Surgery.

Vasoplegic syndrome is a relatively common complication that can happen during and after major adult cardiac surgery. It is associated with a higher rate of complications, including postoperative renal failure, longer duration of mechanical ventilation, and intensive care unit stay, as well as increased mortality. The underlying pathophysiology of vasoplegic syndrome is that of profound vascular hyporesponsiveness, and involves a complex interplay among inflammatory cytokines, cellular surface receptors, and nitric oxide (NO) production. The pharmacotherapy approaches for the treatment of vasoplegia include medications that increase vascular smooth muscle contraction via increasing cytosolic calcium in myocytes, reduce the vascular effects of NO and inflammation, and increase the biosynthesis of and vascular response to norepinephrine. Clinical trials have demonstrated the clinical efficacy of non-catecholamine pharmacologic agents in the treatment of vasoplegic syndrome. With an increase in their use today, it is important for clinicians to understand the adverse clinical outcomes and patient risk profiles associated with these agents, which will allow better-tailored medical therapy.

Hemodynamic Management Strategies in Pediatric Septic Shock: Ten Concepts for the Bedside Practitioner.

The three pathophysiologic contributors to septic shock include varying combinations of hypovolemia (relative > absolute), decreased vascular tone or vasoplegia, and myocardial dysfunction. The three pillars of hemodynamic support include fluid boluses, vasopressors with or without inotrope infusions. The three end-points of hemodynamic resuscitation include an adequate cardiac output (CO), adequate mean arterial pressure (MAP) and diastolic blood pressure (DBP) for organ perfusion, and avoiding congestion (worse filling) parameters. Only 33-50% of septic patients show post-fluid bolus CO improvements; this may be sustained in ≥10% on account of sepsis-mediated glycocalyx injury. A pragmatic approach is to administer a small bolus (10 mL/kg over 20-30 min) and judge the response based on clinical perfusion markers, pressure elements, and congestive features. Vasoplegia marked by low DBP is a major contributor to hypotension in septic shock. Hence, a strategy of restricted fluid bolus with early low-dose norepinephrine (NE) (0.05-0.1 µg/kg/min) can be helpful. NE may also be useful in septic myocardial dysfunction (SMD) as an initial agent to maintain adequate coronary perfusion and DBP while minimizing tachycardia and providing inotropy. Severe SMD may benefit from additional inotropy (epinephrine/dobutamine). Except vasopressin, most vasoactive drugs may safely be administered via a peripheral route. The lowest MAP (5th centile for age) may be an acceptable target, provided end-organ perfusion is satisfactory. A clinical individualized approach combining the history, serial physical examination, laboratory analyses, available monitoring tools, and repeated assessment to individualize circulatory support may to lead to better outcomes than one-size-fits-all algorithms.

Vasopressin in vasoplegic shock in surgical patients: systematic review and meta-analysis.

PURPOSE: Vasoplegia, or vasoplegic shock, is a syndrome whose main characteristic is reducing blood pressure in the presence of a standard or high cardiac output. For the treatment, vasopressors are recommended, and the most used is norepinephrine. However, new drugs have been evaluated, and conflicting results exist in the literature. METHODS: This is a systematic review of the literature with meta-analysis, written according to the recommendations of the PRISMA report. The SCOPUS, PubMed, and ScienceDirect databases were used to select the scientific articles included in the study. Searches were conducted in December 2022 using the terms "vasopressin," "norepinephrine," "vasoplegic shock," "postoperative," and "surgery." Meta-analysis was performed using Review Manager (RevMan) 5.4. The endpoint associated with the study was efficiency in treating vasoplegic shock and reduced risk of death. RESULTS: In total, 2,090 articles were retrieved; after applying the inclusion and exclusion criteria, ten studies were selected to compose the present review. We found no significant difference when assessing the outcome mortality comparing vasopressin versus norepinephrine (odds ratio = 1.60; confidence interval 0.47-5.50), nor when comparing studies on vasopressin versus placebo. When we analyzed the length of hospital stay compared to the use of vasopressin and norepinephrine, we identified a shorter length of hospital stay in cases that used vasopressin; however, the meta-analysis did not demonstrate statistical significance. CONCLUSIONS: Considering the outcomes included in our study, it is worth noting that most studies showed that using vasopressin was safe and can be considered in managing postoperative vasoplegic shock.

Anticholinergic Toxidrome as a Possible Explanation for Methylene Blue Toxicity.

BACKGROUND Methylene blue has multiple uses in medicine. It is generally used to treat refractory vasoplegia and methemoglobin toxicity, and can be used as a dye to localize the parathyroid glands intra-operatively. In refractory vasoplegia, methylene blue inhibits endothelial nitric oxide and guanylate cyclase, causing vasoconstriction and potentially stabilizing blood pressure. Multiple complications have been associated with the use of methylene blue. These are related to either the sole effect of methylene blue or the combined effect of methylene blue and certain antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). To the best of our knowledge, in the setting of post-cardiac surgery vasoplegia, there have been no reports of the neurological toxicity of methylene blue in the absence of SSRI use. In this case report, we describe the anticholinergic manifestations associated with the use of methylene blue in post-cardiac surgery vasoplegia. CASE REPORT A male patient in his mid-sixties with severe mitral regurgitation underwent elective mitral valve replacement. Postoperatively, he was hypotensive and required a high dose of vasopressors. Methylene blue was administered to treat refractory vasoplegia. The patient became anuric and febrile, with bilateral mydriasis. Internal cooling and continuous renal replacement therapy were initiated, and symptoms rapidly resolved. The patient was discharged after prolonged hospitalization with a permanent catheter for hemodialysis. CONCLUSIONS Anticholinergic toxidrome may explain the neurological adverse effects associated with high doses of methylene blue. Physicians should be cautious when using methylene blue in combination with other anticholinergic drugs and in conditions of renal failure. The development of methylene blue toxicity warrants the urgent discontinuation of the agent and early drug elimination.

Intraoperative Versus Postoperative Hydroxocobalamin for Vasoplegic Shock in Cardiothoracic Surgery.

OBJECTIVES: Hydroxocobalamin inhibits nitric oxide pathways contributing to vasoplegic shock in patients undergoing cardiopulmonary bypass (CPB). The objective of this study was to evaluate the effect of intraoperative versus postoperative application of hydroxocobalamin for vasoplegic shock in patients undergoing CPB. DESIGN: This was a historic cohort study. SETTING: The study was conducted at a quaternary academic cardiovascular surgery program. PARTICIPANTS: Adults undergoing cardiac surgery using CPB were participants in the study. INTERVENTIONS: Hydroxocobalamin (5 g) intravenously over 15 minutes. MEASUREMENTS AND MAIN RESULTS: The treatment groups were assigned based on the receipt location of hydroxocobalamin (ie, intensive care unit [ICU] versus operating room [OR]). The primary outcome was vasopressor-free days in the first 14 days after CPB. Of the 112 patients included, 37 patients received hydroxocobalamin in the OR and 75 in the ICU. Patients in the OR group were younger than those in the ICU group (57.5 v 63.9 years, p = 0.007), with statistically similar American Society of Anesthesiologists scores. The mean CPB duration was 3.4 hours in the OR group and 2.9 hours in the ICU group (p = 0.09). In both groups, the norepinephrine-equivalent dose of vasopressors at hydroxocobalamin was 0.27 µg/kg/min. Days alive and free of vasopressors were not different between the OR and ICU groups (estimated difference 0.48 [95% CI -1.76-2.72], p = 0.67). The odds of postoperative renal failure, mesenteric ischemia, ICU, hospital length of stay, and in-hospital mortality were also similar between groups. CONCLUSIONS: A difference in vasopressor-free days after CPB was not found between patients who received hydroxocobalamin intraoperatively versus postoperatively for vasoplegic shock.

Incidence of Intraoperative Vasoplegic Syndrome in Lung Transplantation.

OBJECTIVES: Severe hypotension and low systemic vascular resistance in the setting of adequate cardiac output, known as "vasoplegic syndrome" (VS), is a physiologic disturbance reported in 9% to 44% of cardiac surgery patients. Although this phenomenon is well-documented in cardiac surgery, there are few studies on its occurrence in lung transplantation. The goal of this study was to characterize the incidence of VS in lung transplantation, as well as identify associated risk factors and outcomes. DESIGN: Retrospective study of single and bilateral lung transplants from April 2013 to September 2021. SETTING: The study was conducted at an academic hospital. PARTICIPANTS: Patients ≥18 years of age who underwent lung transplantation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors defined VS as mean arterial pressure <65 mmHg, cardiac index ≥2.2 L/min/m2, and ≥30 minutes of vasopressor administration after organ reperfusion. The association between VS and risk factors or outcomes was assessed using t tests, Mann-Whitney U, and chi-square tests. The authors ran multivariate logistic regression models to determine factors independently associated with VS. The incidence of VS was 13.9% (CI 10.4%-18.4%). In the multivariate model, male sex (odds ratio 2.85, CI 1.07-7.58, p = 0.04) and cystic fibrosis (odds ratio 5.76, CI 1.43-23.09, p = 0.01) were associated with VS. CONCLUSIONS: The incidence of VS in lung transplantation is comparable to that of cardiac surgery. Interestingly, male sex and cystic fibrosis are strong risk factors. Identifying lung transplant recipients at increased risk of VS may be crucial to anticipating intraoperative complications.

Vasoplegia: A Review.

Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled vasodilation. Vasoplegia may occur due to various conditions, including cardiac failure, sepsis, and post-cardiac surgery. In the cardiac cohort, multiple risk factors for vasoplegia have been identified. Several factors contribute to the pathophysiology of this condition, and various mechanisms have been proposed, including nitric oxide, adenosine, prostanoids, endothelins, the renin-angiotensin-aldosterone system, and hydrogen sulfide. Early identification and prompt management of vasoplegia is crucial to prevent development of shock. This review expands upon the different vasopressors used in management of vasoplegia, including catecholamines such as norepinephrine, dopamine, epinephrine, phenylephrine, and other agents including vasopressin, methylene blue, angiotensin II, hydroxocobalamin, vitamin C, thiamine, and corticosteroids (ie, hydrocortisone). It also emphasizes the importance of conducting further research and making advancements in treatment regimens for vasoplegia.

Intravenous vitamin C for vasoplegia: A double-blinded randomised clinical trial (VALENCIA trial).

PURPOSE: To determine whether intravenous vitamin C compared with placebo, reduces vasopressor requirements in patients with vasoplegic shock. METHODS: Double-blinded, randomised clinical trial (RCT) conducted in two intensive care units in Perth, Australia. Vasopressor requirements at enrolment needed to be >10 µg/min noradrenaline after hypovolaemia was clinically excluded. Patients received either intravenous 1.5 g sodium ascorbate in 100 ml normal saline every 6 h for 5 days, or placebo (100 ml normal saline). The primary outcome was duration of vasopressor usage in hours. Secondary outcomes were ICU and hospital length of stay, and 28-day, ICU and hospital mortality. RESULTS: Of the 71 patients randomised (35 vitamin C, 36 placebo group), the median vasopressor duration was 44 h [95% CI, 37-54 h] and 55 h [95% CI, 33-66 h]) in the vitamin C and placebo groups (p = 0.057). ICU and hospital length of stay, mortality outcomes were similar between groups. CONCLUSIONS: In this RCT of patients with vasoplegic shock of at least moderate severity, the use of IV vitamin C compared with placebo did not significantly reduce the duration of vasopressors. TRIAL REGISTRATION: Prospective registration - trial number ACTRN12617001392358.

Hydroxocobalamin for Vasodilatory Hypotension in Shock: A Systematic Review With Meta-Analysis for Comparison to Methylene Blue.

Hydroxocobalamin inhibits nitric oxide-mediated vasodilation, and has been used in settings of refractory shock. However, its effectiveness and role in treating hypotension remain unclear. The authors systematically searched Ovid Medline, Embase, EBM Reviews, Scopus, and Web of Science Core Collection for clinical studies reporting on adult persons who received hydroxocobalamin for vasodilatory shock. A meta-analysis was performed with random-effects models comparing the hemodynamic effects of hydroxocobalamin to methylene blue. The Risk of Bias in Nonrandomized Studies of Interventions tool was used to assess the risk of bias. A total of 24 studies were identified and comprised mainly of case reports (n = 12), case series (n = 9), and 3 cohort studies. Hydroxocobalamin was applied mainly for cardiac surgery vasoplegia, but also was reported in the settings of liver transplantation, septic shock, drug-induced hypotension, and noncardiac postoperative vasoplegia. In the pooled analysis, hydroxocobalamin was associated with a higher mean arterial pressure (MAP) at 1 hour than methylene blue (mean difference 7.80, 95% CI 2.63-12.98). There were no significant differences in change in MAP (mean difference -4.57, 95% CI -16.05 to 6.91) or vasopressor dosage (mean difference -0.03, 95% CI -0.12 to 0.06) at 1 hour compared to baseline between hydroxocobalamin and methylene blue. Mortality was also similar (odds ratio 0.92, 95% CI 0.42-2.03). The evidence supporting the use of hydroxocobalamin for shock is limited to anecdotal reports and a few cohort studies. Hydroxocobalamin appears to positively affect hemodynamics in shock, albeit similar to methylene blue.

Postoperative vasoplegia in lung transplantation: incidence and relation to outcome in a single-centre retrospective study.

BACKGROUND: The incidence and clinical importance of vasoplegia after lung transplantation remains poorly studied. We describe the incidence of vasoplegia and its association with complications after lung transplantation. METHODS: Perioperative data of 279 lung transplant recipients operated on from 2015 to 2020 in a UK hospital were analysed retrospectively. RESULTS: Vasoplegia occurred in 41.6% of patients after lung transplantation (mild, 31.0%; moderate, 55.2%; severe, 13.8%). Compared with non-vasoplegic patients, vasoplegic patients had a higher incidence of any acute kidney injury, defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria (78.5% vs 65%, P=0.015), renal replacement therapy (47.4% vs 24.5%, P<0.001), and delayed chest closure (18.4% vs 9.2%, P=0.025); were ventilated longer (70 [32-368] vs 34 [19-105] h, P<0.001); and stayed longer in the ICU (12.9 [5-30] vs 6.8 [3-20] days, P<0.001). Mortality at 30 days and 1 yr was higher in patients with vasoplegia (11.2% vs 5.5% and 20.7% vs 11.7%, P=0.039, respectively). Severe vasoplegia represented a predictor of longer-term mortality (hazard ratio=1.65, P=0.008). Underlying infectious disease, increased BMI, higher preoperative pulmonary artery systolic pressure and bilirubin levels, lower glomerular filtration rate, and increased fresh frozen plasma transfusion were predictors of vasoplegia severity. Neutrophilia, leucocytosis, and increased C-reactive protein were associated with vasoplegia, but release of the neutrophil activation markers myeloperoxidase and heparin-binding protein was similar between groups. CONCLUSIONS: Influenced by preoperative status as well as procedural factors and inflammatory response, vasoplegia is a common and critical condition after lung transplantation with worse short-term outcomes and long-term survival.

A norepinephrine weaning strategy using dynamic arterial elastance is associated with reduction of acute kidney injury in patients with vasoplegia after cardiac surgery: A post-hoc analysis of the randomized SNEAD study.

STUDY OBJECTIVE: To evaluate the impact of a dynamic arterial elastance guided norepinephrine weaning strategy on the occurrence of acute kidney injury (AKI) in patients with vasoplegia after cardiac surgery. DESIGN: A post-hoc analysis of a monocentric randomized controlled trial. SETTING: A tertiary care hospital in France. PARTICIPANTS: Vasoplegic cardiac surgical patients treated with norepinephrine. INTERVENTION: Patients were randomized to an algorithm-based norepinephrine weaning intervention (dynamic arterial elastance) group or a control group. MEASUREMENTS: The primary endpoint was the number of patients with AKI defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The secondary endpoint were major adverse cardiac post-operative events (new onset of atrial fibrillation or flutter, low cardiac output syndrome, and in-hospital death). End points were evaluated during the first seven post-operative days. RESULTS: 118 patients were analyzed. In the overall study population, the mean age was 70 (62-76) years, 65% were male and the median EuroSCORE was 7 (5-10). Overall, 46 (39%) patients developed AKI (30 KDIGO 1, 8 KDIGO 2, 8 KDIGO 3), and 6 patients required renal replacement therapy. The incidence of AKI was significantly lower in the intervention group than in the control group (16 patients (27%) vs 30 patients (51%), p = 0.12). Higher dose and longer duration of norepinephrine were associated with AKI severity. CONCLUSION: Decreasing norepinephrine exposure by using a dynamic arterial elastance guided norepinephrine weaning strategy was associated with a reduced incidence of acute kidney injury in patients with vasoplegia after cardiac surgery. Further prospective multicentric studies are needed to confirm these results.

Use of methylene blue to treat vasoplegia syndrome in cystic fibrosis patients undergoing lung transplantation: A case series.

Background: Several studies have demonstrated the utility of methylene blue (MB) to treat vasoplegic syndrome (VS), but some have cautioned against its routine use in lung transplantation with only two cases described in prominent literature. Cystic fibrosis patients commonly have chronic infections which predispose them to a systemic inflammatory syndrome-like vasoplegic response during lung transplantation. We present 13 cystic fibrosis patients who underwent lung transplantation and received MB for vasoplegic syndrome while on cardiopulmonary bypass, with or without inhaled pulmonary vasodilator therapy. Methods: Single-center, retrospective, case series analysis of cystic fibrosis patients who underwent lung transplant and received MB for vasoplegia. We defined the primary outcome as 30-day mortality, and secondary outcomes as primary graft failure, 1-year mortality, postoperative complications, and hemodynamic response to MB. Results: MB was associated with a significant increase in mean arterial pressure (MAP) (P < 0.001) in all patients, and 84.6% (11/13) of the patients had either a decrease or no change in vasopressor requirement. No patients developed acute primary graft dysfunction and there was 100% 30-day and 1-year survival. One patient required Extracorporeal membrane oxygenation (ECMO) for hypoxemia and 69% (9/13) of the patients had evidence of postoperative right ventricular dysfunction, but no patients required a right ventricular assist device. Conclusion: This case series demonstrates the effectiveness of MB in treating vasoplegia in cystic fibrosis patients during lung transplantation, without evidence of primary graft dysfunction, 30-day or 1-year mortality. The safety of MB regarding hypoxemia and increased pulmonary vascular resistance requires further investigation.

MiRNA-30d and miR-770-5p as potential clinical risk predictors of Vasoplegic Syndrome in Patients undergoing on-pump coronary artery bypass grafting.

The aims of this study were to perform pre-surgery miRNA profiling of patients who develop Vasoplegic syndrome (VS) after coronary artery bypass grafting (CABG) and identify those miRNAs that could be used as VS prognostic tools and biomarkers. The levels of 754 microRNAs (miRNAs) were measured in whole blood samples from a cohort of patients collected right before the coronary artery bypass grafting (CABG) surgery. We compared the miRNA levels of those who developed VS (VASO group) with those who did not (NONVASO group) after surgery. Six miRNAs (hsa-miR-548c-3p, -199b-5p, -383-5p -571 -183-3p, -30d-5p) were increased and two (hsa-1236-3p, and hsa-miR770-5p) were decreased in blood of VASO compared to NONVASO groups. Receiver Operating Characteristic (ROC) curve analysis revealed that a combination of the miRNAs, hsa-miR-30d-5p and hsa-miR-770-5p can be used as VS predictors (AUC = 0.9615, p < 0.0001). The computational and functional analyses were performed to gain insights into the potential role of these dysregulated miRNAs in VS and have identified the "Apelin Liver Signaling Pathway" as the canonical pathway containing the most target genes regulated by these miRNAs. The expression of the combined miRNAs hsa-miR-30d and hsa-miR-770-5p allowed the ability to distinguish between patients who could and could not develop VS, representing a potential predictive biomarker of VS.