Pharmacological inhibition of CK2 by silmitasertib mitigates sepsis-induced circulatory collapse, thus improving septic outcomes in mice.

Casein kinase II (CK2) has recently emerged as a pivotal mediator in the propagation of inflammation across various diseases. Nevertheless, its role in the pathogenesis of sepsis remains unexplored. Here, we investigated the involvement of CK2 in sepsis progression and the potential beneficial effects of silmitasertib, a selective and potent CK2α inhibitor, currently under clinical trials for COVID-19 and cancer. Sepsis was induced by caecal ligation and puncture (CLP) in four-month-old C57BL/6OlaHsd mice. One hour after the CLP/Sham procedure, animals were assigned to receive silmitasertib (50 mg/kg/i.v.) or vehicle. Plasma/organs were collected at 24 h for analysis. A second set of experiments was performed for survival rate over 120 h. Septic mice developed multiorgan failure, including renal dysfunction due to hypoperfusion (reduced renal blood flow) and increased plasma levels of creatinine. Renal derangements were associated with local overactivation of CK2, and downstream activation of the NF-ĸB-iNOS-NO axis, paralleled by a systemic cytokine storm. Interestingly, all markers of injury/inflammation were mitigated following silmitasertib administration. Additionally, when compared to sham-operated mice, sepsis led to vascular hyporesponsiveness due to an aberrant systemic and local release of NO. Silmitasertib restored sepsis-induced vascular abnormalities. Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis.

Successful use of methylene blue for catecholamine-refractory vasoplegic shock due to metformin intoxication: A case report and literature review.

Background: Severe metformin intoxication can lead to lactic acidosis and vasoplegic shock, for which the optimal management strategy remains uncertain, especially in cases of severe circulatory collapse. Case Presentation: A 45-year-old diabetic woman on metformin therapy presented with impaired consciousness and seizures. She had experienced a cardiac arrest and undergone extracorporeal cardiopulmonary resuscitation. Blood gas analysis showed severe lactic acidosis. A 71-g metformin packet was found at the patient's home, suggesting an overdose. Despite extracorporeal support and blood purification, severe lactic acidosis and hypotension persisted. Methylene blue was administered 32 h from the onset, which improved her metabolic and circulatory status. We examined her blood sample throughout the case to check the transition of metformin blood concentration. Conclusion: Methylene blue may be beneficial for severe metformin toxicity, regardless of the blood concentration of metformin and the time since intoxication. However, further research is needed to establish its optimal use and effectiveness.

Mortality and morbidity after combined heart and liver transplantation in the failing Fontan: An updated dual center retrospective study.

INTRODUCTION: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation. METHODS: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022. RESULTS: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis. CONCLUSION: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted.

Vasoplegic syndrome during heart transplantation: A systematic review and meta-analysis.

BACKGROUND: Vasoplegic syndrome (VS) is a common occurrence during heart transplantation (HT). It currently lacks a uniform definition between transplant centers, and its pathophysiology and treatment remain enigmatic. This systematic review summarizes the available published clinical data regarding VS during HT. METHODS: We searched databases for all published reports on VS during HT. Data collected included the incidence of VS in the HT population, patient and intraoperative characteristics, and postoperative outcomes. RESULTS: Twenty-two publications were included in this review. The prevalence of VS during HT was 28.72% (95% confidence interval: 27.37%, 30.10%). Factors associated with VS included male sex, higher body mass index, hypothyroidism, pre-HT left ventricular assist device or venoarterial extracorporeal membrane oxygenation (VA-ECMO), pre-HT calcium channel blocker or amiodarone usage, longer cardiopulmonary bypass time, and higher blood product transfusion requirement. Patients who developed VS were more likely to require postoperative VA-ECMO support, renal replacement therapy, reoperation for bleeding, longer mechanical ventilation, and a greater 30-day and 1-year mortality. CONCLUSIONS: The results of our systematic review are an initial step for providing clinicians with data that can help identify high-risk patients and avenues for potential risk mitigation. Establishing guidelines that officially define VS will aid in the precise diagnosis of these patients during HT and guide treatment. Future studies of treatment strategies for refractory VS are needed in this high-risk patient population.

Vascular Reactivity Index as an Effective Predictor of Mortality in Patients With Septic Shock: A Retrospective Study.

BACKGROUND: Sepsis is a serious complication that occurs after trauma, burns, and infections, and it is an important cause of death in intensive care unit (ICU) patients. Despite many new measures being proposed for sepsis treatment, its mortality rate remains high; sepsis has become a serious threat to human health, and there is an urgent need to carry out in-depth clinical research related to sepsis. In recent years, it has been found that septic shock-induced vasoplegia is a result of vascular hyporesponsiveness to vasopressors. Therefore, this study intended to establish an objective formula related to vasoplegia that can be used to assess the prognosis of patients and guide clinical treatment. MATERIALS AND METHODS: A retrospective cohort study was conducted using data from 106 septic shock patients admitted to the ICU of Jining No. 1 People's Hospital from January 2020 to December 2022. The patients were divided into mortality and survival groups based on 28-day survival, and hemodynamics were monitored by the pulse index continuous cardiac output system. The dose and duration of vasopressors, major hemodynamic parameters, lactic acid (Lac) levels, and Sequential Organ Failure Assessment scores were recorded within 48 h of hospital admission. Multifactorial logistic regression was used to analyze the independent risk factors affecting the prognosis of patients, and the predictive value of the vascular response index (VRI) was analyzed by the receiver operating characteristic (ROC) curve. RESULTS: The differences between the survival and mortality groups in terms of age, sex ratio, body weight, ICU length of stay, distribution of infection sites, underlying disease conditions, baseline Lac levels, and some hemodynamic parameters were not statistically significant (P > .05). The results of multifactorial logistic regression showed that the admission Acute Physiology and Chronic Health Evaluation II score, Lac level at 24 h of treatment, maximal vasoactive inotropic score at 24 h (VISmax24), maximal vasoactive inotropic score at 48 h (VISmax48), and VRI were independent risk factors affecting 28-day mortality. Within 48 h of receiving vasopressor therapy, the VRI was lower in the mortality group than in the survival group. The area under the ROC curve for the VRI was 0.86, and the best cutoff value of the VRI for predicting 28-day mortality was 32.50 (YI = 0.80), with a sensitivity of 0.90, a specificity of 0.90, and a better prediction of mortality than the other indicators. CONCLUSIONS: The VRI is a good predictor of mortality in patients with septic shock, and a lower VRI indicates more severe vasoplegia, poorer prognosis, and higher mortality in patients with septic shock.

The Use of Methylene Blue in Conjunction With Hydroxocobalamin and Multiple Pressors to Treat Severe Vasoplegia in a Patient Due to Calcium Channel Blocker Toxicity: A Case Report.

Vasoplegia, the demonstration of persistently low systemic vascular resistance (SVR) and resistant hypotension in the presence of a normal cardiac index despite aggressive resuscitation attempts, is a serious clinical diagnosis that requires prompt treatment to prevent patient morbidity and mortality. Currently, treatment of vasoplegia involves treatment with vasopressors such as vasopressin, norepinephrine, and hydroxocobalamin. However, some evidence suggests that in addition to this treatment regimen, the addition of methylene blue may result in a reduction in overall norepinephrine equivalent vasopressor requirements, increased mean arterial pressure, and an improved clinical course. Here, we report the case of a 64-year-old male patient who presented to the ED after being found unresponsive and covered in emesis at home. The patient's presentation was complicated by worsening dyspnea, hypotension, and hemodynamic instability, requiring intubation and admission to the ICU for management of undifferentiated shock of unclear etiology and acute respiratory failure. Urine studies were consistent with a diagnosis of vasoplegia due to dihydropyridine calcium channel blocker toxicity, which was confirmed by pill counting of his home medications in the setting of recent paranoia and depression. The patient was treated aggressively with vasopressors, including vasopressin, phenylephrine, and epinephrine, as well as a combination of hydroxocobalamin and methylene blue. He was also started on a calcium and insulin drip. Upon initiation of non-catecholamine agents for vasoplegia, his clinical course quickly improved, and he was weaned from all vasopressors. He regained hemodynamic stability, was successfully extubated, evaluated by psychiatry, and discharged from the hospital in a stable condition on day 15 with the continuation of outpatient psychiatric services.

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.

Diagnosis and Management of Vasoplegia in Temporary Mechanical Circulatory Support: A Narrative Review.

Refractory vasodilatory shock, or vasoplegia, is a pathophysiologic state observed in the intensive care unit and operating room in patients with a variety of primary diagnoses. Definitions of vasoplegia vary by source but are qualitatively defined clinically as a normal or high cardiac index and low systemic vascular resistance causing hypotension despite high-dose vasopressors in the setting of euvolemia. This definition can be difficult to apply to patients undergoing mechanical circulatory support (MCS). A large body of mostly retrospective literature exists on vasoplegia in the non-MCS population, but the increased use of temporary MCS justifies an examination of vasoplegia in this population. MCS, particularly extracorporeal membrane oxygenation, adds complexity to the diagnosis and management of vasoplegia due to challenges in determining cardiac output (or total blood flow), lack of clarity on appropriate dosing of noncatecholamine interventions, increased thrombosis risk, the difficulty in determining the endpoints of adequate volume resuscitation, and the unclear effects of rescue agents (methylene blue, hydroxocobalamin, and angiotensin II) on MCS device monitoring and function. Care teams must combine data from invasive and noninvasive sources to diagnose vasoplegia in this population. In this narrative review, the available literature is surveyed to provide guidance on the diagnosis and management of vasoplegia in the temporary MCS population, with a focus on noncatecholamine treatments and special considerations for patients supported by extracorporeal membrane oxygenation, transvalvular heart pumps, and other ventricular assist devices.

Mini Aortic Valve Replacement Converted to Bentall Procedure Secondary to Chronic Type A Aortic Dissection.

In our case, a 46-year-old female with severe aortic insufficiency presented for minimally invasive aortic valve replacement. The patient was taken to the operating room, where transesophageal echocardiography showed severe aortic regurgitation with prolapse of the non-coronary cusp. The patient was placed on a cardiopulmonary bypass machine with peripheral cannulation. The aorta was cross-clamped, and an aortotomy was made. Despite multiple attempts, the left main coronary ostium was not visible. A sternotomy was quickly performed, and a newly discovered chronic type A dissection, obscuring the left main coronary artery, was found. Seventeen minutes after the cross-clamp was placed, the left main was transected, and cardioplegia was delivered. The patient then underwent a Bentall procedure with an aortic valve and root replacement.

FLAVOUR Study: FLow profiles And postoperative VasOplegia after continUous-flow left ventriculaR assist device implantation.

This study aims to associate the incidence of postoperative vasoplegia and short-term survival to the implantation of various left ventricular assist devices differing in hemocompatibility and flow profiles. The overall incidence of vasoplegia was 25.3% (73/289 patients) and 30.3% (37/122), 25.0% (18/72), and 18.9% (18/95) in the axial flow (AXF), centrifugal flow (CF), and centrifugal flow with artificial pulse (CFAP) group, respectively. Vasoplegia was associated with longer intensive care (ICU) and hospital length of stay (LOS) and mortality. ICU and in-hospital LOS and 1-year mortality were the lowest in the CFAP group. Post hoc analysis resulted in a p-value of 0.43 between AXF and CF; 0.35 between CF and CFAP; and 0.06 between AXF and CFAP. Although there is a trend in diminished incidence of vasoplegia, pooled logistic regression using flow profile and variables that remained after feature selection showed that flow profile was not an independent predictor for postoperative vasoplegia.

Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.

Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.

Angiotensin-II for vasoplegia following cardiac surgery.

INTRODUCTION: The objective of this study was to describe the implementation and outcomes of a protocol outlining angiotensin-II utilization for vasoplegia following cardiac surgery. METHODS: This was a retrospective chart review at a single-center university hospital. Included patients received angiotensin-II for vasoplegia refractory to standard interventions, including norepinephrine 20 mcg/min and vasopressin 0.04 units/min, following cardiac surgery between April 2021 and April 2022. RESULTS: 30 patients received angiotensin-II for refractory vasoplegia. Adjunctive agents at angiotensin-II initiation included corticosteroids (26 patients; 87%), epinephrine (26 patients; 87%), dobutamine (17 patients; 57%), dopamine (9 patients; 30%), milrinone (2 patients; 7%), and hydroxocobalamin (4 patients; 13%). At 3 hours, the median mean arterial pressure increased from baseline (70 vs 61.5 mmHg, p = .0006). Median norepinephrine doses at angiotensin-II initiation, 1 hour, 3 hours, and angiotensin-II discontinuation were 0.22, 0.16 (p = .0023), 0.10 (p < .0001), and 0.07 (p < .0001) mcg/kg/min. Median dobutamine doses decreased throughout angiotensin-II infusion from eight to six mcg/kg/min (p = .0313). Other vasoactive medication doses were unchanged. Three patients (10%) subsequently received hydroxocobalamin. Thirteen (43.3%) and five (16.7%) patients experienced mortality by day 28 and venous or arterial thrombosis events, respectively. CONCLUSIONS: The administration of angiotensin-II to vasoplegic patients following cardiac surgery was associated with increased mean arterial pressure, reduced norepinephrine dosages, and reduced dobutamine dosages.

Vasopressin in Sepsis and Other Shock States: State of the Art.

This review of the use of vasopressin aims to be comprehensive and highly practical, based on the available scientific evidence and our extensive clinical experience with the drug. It summarizes controversies about vasopressin use in septic shock and other vasodilatory states. Vasopressin is a natural hormone with powerful vasoconstrictive effects and is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Septic shock is defined by the need for vasopressors to correct hypotension and lactic acidosis secondary to infection, with a high mortality rate. The Surviving Sepsis Campaign guidelines recommend vasopressin as a second-line vasopressor, added to norepinephrine. However, these guidelines do not address specific debates surrounding the use of vasopressin in real-world clinical practice.

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.

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.

The Effect of Fluid Pre-loading on Vital Signs and Hemodynamic Parameters in a Porcine Model of Lipopolysaccharide-Induced Endotoxemia.

Background Animal models of distributive hypotension and resuscitation allow the assessment of hemodynamic monitoring modalities and resuscitation strategies. The fluid-first paradigm for resuscitation is currently being challenged with clinical trials. In this investigation, venous return and perfusion are assessed, and full hemodynamics are characterized, in a porcine model of endotoxemic hypotension with and without fluid pre-loading. Methods Two groups of six pigs had the induction of standardized endotoxemic hypotension ("critical hypotension"). Group 1 underwent four 10 cc/kg crystalloid boluses, and Group 2 was not fluid pre-resuscitated. Both groups underwent progressive norepinephrine (NE) up-titration to 0.25 mcg/kg/minute over 30 minutes. Vital signs, central parameters, and laboratory values were obtained at baseline, "critical hypotension," after each bolus and during NE administration. Results Endotoxemia decreased the systemic vascular resistance (SVR) in Group 1 (1031±106 dyn/s/cm-5 versus 738±258 dyn/s/cm-5; P=0.03) and Group 2 (1121±196 dyn/s/cm-5 versus 759±342 dyn/s/cm-5; P=0.003). In Group 1, the four fluid boluses decreased heart rate (HR), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) (P<0.05). No changes were observed in blood pressure, cardiac output (CO), or lactate. NE up-titration increased HR in Group 1 and decreased CVP in both groups. Higher final CVP (11 {3} versus 4 {4} mmHg; P=0.01) and PCWP (5 {1} versus 2 {2} mmHg; P=0.005) values were observed in Group 1 relative to Group 2, reflecting increased venous return. Conclusions Porcine endotoxemic hypotension and resuscitation were robustly characterized. In this model, fluid loading improved venous return with NE, though perfusion (CO) was preserved by increased NE-induced chronotropy.

Can Use of Intravenous Methylene Blue Improve the Hemodynamics and Outcome of the Patients with Refractory Septic Shock? An Observational Study.

Introduction: Refractory shock, which fails to respond to conventional vasopressor therapy, is a common complication of sepsis. Methylene blue has emerged as a potential adjunctive treatment option for reversing refractory shock in sepsis. The aim of this study was to evaluate the impact of intravenous methylene blue infusion on hemodynamic improvement and mortality in patients with refractory shock. Methodology: This was an observational prospective study for the duration of six months conducted at intensive care a medical college and teaching hospital including 76 patients with a diagnosis of septic shock requiring vasopressor therapy. Intravenous (IV) methylene blue was infused as a bolus dose with 2 mg/kg dose in 20 minutes and its response to mean arterial blood pressure, decrease in vasopressor therapy, lactate level, and urine output was recorded in next 2 hours. Patients with improvement in mean arterial pressure (MAP) by 10% or decrease in vasopressor therapy in the next 2 hours were leveled as responder. The length of intensive care unit (ICU) stay, duration of mechanical ventilation, incidence of acute kidney injury (AKI), and mortality were compared between responder and non-responder. Results: A total of 76 patients with refractory shock were included in the study. With the use of IV methylene blue, 41 (53.9%) patients showed significant improvement in MAP within 2 hours (70.17 ± 8.30 vs 64.28 ± 11.84, p = 0.005). Responders were 4.019 times more likely to have vasopressor-free time within 24 hours (18.4% vs 5.3%, p = 0.020, odds ratio 4.019, 95% confidence interval, 1.180-13.682). However, there was no significant difference in terms of mortality, length of ICU stay, ventilator free days, and incidence of AKI. In the responder group, there was a significant increase in the MAP and decrease in vasopressor requirement pre- and post-infusion of methylene blue (p < 0.05). Responder had shorter vasopressor-free days as compared with non-responder (5.34 vs 6.79, p = 0.008) while the mean survival time was longer with responders (21.97 vs 15.93 days, p = 0.024). Conclusion: The use of IV methylene blue in refractory shock as an adjuvant therapy significantly improved the mean arterial blood pressure and decreased the requirement of vasopressor therapy as well as improvement in the survival time. However, there was no change in the mortality, length of ICU stay, ventilator-free days, or incidence of AKI in the patients. How to cite this article: Rajbanshi LK, Bajracharya A, Arjyal B, Devkota D. Can Use of Intravenous Methylene Blue Improve the Hemodynamics and Outcome of the Patients with Refractory Septic Shock? An Observational Study. Indian J Crit Care Med 2023;27(9):669-674.

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.

Effect of norepinephrine on the vascular waterfall and tissue perfusion in vasoplegic hypotensive patients: a prospective, observational, applied physiology study in cardiac surgery.

BACKGROUND: Norepinephrine is a commonly used drug for treating vasoplegic acute circulatory failure in ICU. The prediction of norepinephrine macro- and micro-circulatory response is complicated by its uneven receptors' distribution between the arterial and the venous structures, and by the presence of a physiological vascular waterfall (VW) that disconnects the arterial and the venous circulation in two pressure systems. The objectives of this study were to describe the VW in patients with arterial hypotension due to vasodilatory circulatory shock, and its behavior according to its response to norepinephrine infusion. METHODS: A prospective, observational, bi-centric study has included adult patients, for whom the physician decided to initiate norepinephrine during the six first hours following admission to the ICU after cardiac surgery, and unresponsive to a fluid challenge. The mean systemic pressure (MSP) and the critical closing pressure (CCP) were measured at inclusion and after norepinephrine infusion. RESULTS: Thirty patients were included. Norepinephrine increased arterial pressure and total peripheral resistances in all cohort. The cohort was dichotomized as VW responders (patients with a change of VW over the least significant change (≥ 93% increase in VW)), and as VW non-responders. In 19 (63%) of the 30 patients, VW increased from 3.47 [- 14.43;7.71] mmHg to 43.6 [25.8;48.1] mmHg, p < 0.001) with norepinephrine infusion, being classified as VW responders. The VW responders improved cardiac index (from 1.8 (0.6) L min-1 m-2 to 2.2 (0.5) L min-1 m-2, p = 0.002), capillary refill time (from to 4.2 (1.1) s to 3.1 (1) s, p = 0.006), and pCO2 gap (from 9 [7;10] mmHg to 6 [4;8] mmHg, p = 0.04). No baseline parameters were able to predict the VW response to norepinephrine. In comparison, VW non-responders did not significantly change the VW (from 5 [-5;16] mmHg to -2 [-12;15] mmHg, p = 0.17), cardiac index (from 1.6 (0.3) L min-1 m-2 to 1.8 (0.4) L min-1 m-2, p = 0.09) and capillary refill time (from 4.1 (1) s to 3.7 (1.4), p = 0.44). CONCLUSIONS: In post-cardiac surgery patients with vasoplegic arterial hypotension, the vascular waterfall is low. Norepinephrine did not systematically restore the vascular waterfall. Increase of the vascular waterfall was associated with an improvement of laboratory and clinical parameters of tissue perfusion.