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Vasoplegia, characterized by low systemic vascular resistance despite normal to high cardiac output, can result from various conditions, including cardiac surgery, and progress to vasoplegic shock if untreated. This case study involves a male in his 70s with multiple risk factors, including a left ventricular ejection fraction of 35%, who developed vasoplegia after taking lisinopril on the day of his elective coronary artery bypass graft (CABG) surgery. Despite initial management with vasopressors, the patient's condition necessitated postponing the CABG. The patient was stabilized in the ICU with a combination of vasopressin, epinephrine, norepinephrine, and hydrocortisone, and his vasoplegia was successfully treated with hydroxocobalamin, leading to significant clinical improvement. The patient later underwent a successful CABG without preoperative ACE inhibitor use. This case underscores the potential of hydroxocobalamin as an effective treatment for vasoplegia, particularly following ACE inhibitor use in cardiac surgery patients. [ABSTRACT FROM AUTHOR]

Objective: Vasoplegic shock, sometimes referred to as distributive shock, is a life-threatening clinical syndrome involving systemic vasodilation and is associated with significant morbidity and mortality in intensive care unit (ICU) patients. The most common etiology is sepsis; others include post-cardiac bypass vasoplegia and various toxidromes. Key components of management include fluid resuscitation and vasopressors to restore vascular tone. Methylene blue selectively targets inducible nitric oxide synthase, a key component of early vasodilation in response to inflammation. We investigated whether the timing of administration of methylene blue influences clinical response, as measured by subsequent vasopressor requirements, fluid resuscitation, organ system function, and mortality. Design: This study was a retrospective case series including 33 cases. Data were collected for each case, including timing of administration, vasopressor and fluid requirements, Sequential Organ Failure Assessment (SOFA) scores, and inhospital mortality. A Spearman's rank correlation was performed to assess the correlation between the timing of administration of methylene blue and improvement in relevant clinical parameters. Setting: A large metropolitan Intensive Care Unit (47 beds). Patients and participants: Included in this study were adult patients who received methylene blue in the participating ICU between 2020 and 2022 for managing vasoplegic shock. Interventions: Administration of intravenous methylene blue. Measurements and results: No correlation between the timing of administration and reduction in vasopressor requirements was observed. Administration of methylene blue within 8 hours of the onset of shock refractory to 5 mcg/min of noradrenaline was found to weakly correlate with reduced total SOFA score on Day 1 (Rs=0.39, p=0.04), and patients who received methylene blue within eight hours had a lower mortality (60.0% vs 78.2%). Conclusions: These findings suggest that a prolonged period of vasoplegic shock before consideration of methylene blue should not discourage its use. A prospective randomized control study will be a valuable direction for future research. [ABSTRACT FROM AUTHOR]

Introduction: Severe metformin overdose can result in life-threatening conditions such as metabolic acidosis with hyperlactatemia and vasoplegic shock. Current treatment guidelines recommend hemodialysis and supportive care. However, this case report presents the use of methylene blue as an additional treatment for severe metformin overdose-induced vasoplegic shock, which is not commonly described in the literature or guidelines. Case report: A 55-year-old woman presented to the emergency department after ingesting 82.5 g of metformin, resulting in severe metabolic acidosis with hyperlactatemia and refractory vasoplegic shock. Despite continuous hemodialysis and high levels of noradrenalin and vasopressin, the shock persisted. Methylene blue was administered, leading to an immediate and persistent reduction in the noradrenalin dose and rapid shock resolution. Discussion: This case illustrates the potential use of methylene blue in the treatment of severe metformin overdose. The mechanism for metformin-induced vasoplegia is likely mediated by nitric oxide (NO). Methylene blue has been used to treat NO-mediated vasoplegia in other conditions, such as sepsis and poisoning with beta-blockers and calcium channel blockers, but it is rarely described in metformin toxicity. Methylene blue has a rapid onset of action, with only a few mild side effects. This case report emphasizes the need for clinicians to consider methylene blue as a potential treatment option in cases of refractory vasoplegic shock due to severe metformin overdose.

This article titled "Methylene Blue–Induced Serotonin Toxicity: Case Files of the Medical Toxicology Fellowship at the New York City Poison Control Center" discusses a case of serotonin toxicity caused by methylene blue. The article explores the use of naloxone in ACE-I toxicity and the mechanism of methylene blue as a vasopressor. It also discusses the mechanism of methylene blue-induced serotonin toxicity. The case study provides insights into the management of these conditions. The article also discusses the history of methylene blue-induced serotonin toxicity, dosage and timing of methylene blue administration, and its contribution to the risk of serotonin toxicity. It further examines the prevalence of vasoplegic shock versus cardiogenic shock in patients with amlodipine toxicity and the use of high-dose insulin therapy to treat CCB toxicity. The article also discusses the potential synergistic effect of dihydropyridine CCB toxicity combined with ACE-I toxicity in causing vasoplegic shock. Finally, the article addresses the question of whether methylene blue should be withheld in patients on therapeutic SRI therapy who develop acute methemoglobinemia. [Extracted from the article]

A dysregulated host response is a common feature in critically ill patients due to both infectious and non-infectious origins that can lead to life-threatening organ dysfunction, which is still the primary cause of death in intensive care units worldwide. In its course, pathologic, unregulated levels of inflammatory mediators are often released into the circulation, a phenomenon also referred to as a "cytokine storm". To date, there are no approved therapies to modulate the excessive immune response and limit hyperinflammation with the goal of preventing related organ failure and death. In this context, extracorporeal blood purification therapies aiming at the alteration of the host inflammatory response through broad-spectrum, non-selective removal of inflammatory mediators have come into focus. A novel hemoadsorption device (CytoSorb®, CytoSorbents Inc., Princeton, NJ, USA) has shown promising results in patients with hyperinflammation from various origins. Although a significant body of literature exists, there is ongoing research to address many important remaining questions, including the optimal selection of patient groups who might benefit the most, optimal timing for therapy initiation, optimal schedule for adsorber exchanges and therapy duration, as well as an investigation into the potential removal of concomitant antibiotics and other medications. In this review, we discuss the existing evidence and provide a consensus-based best practice guidance for CytoSorb® hemoadsorption therapy in patients with vasoplegic shock. [ABSTRACT FROM AUTHOR]

• Methylene blue and hydroxocobalamin were associated with reduction in vasopressor requirements in refractory vasoplegic shock (VS). • Methylene blue and hydroxocobalamin were associated with improved MAP in refractory VS. • Hydroxocobalamin was associated with a greater reduction in vasopressor requirements compared to methylene blue in refractory VS. To compare changes in vasopressor requirements and hemodynamic responses after hydroxocobalamin or methylene blue administration for vasoplegic shock (VS). Retrospective cohort analysis. Single-center, academic medical center. Cardiothoracic surgery adult patients. Hydroxocobalamin or methylene blue. The primary outcome was a change in vasopressor requirements over the first 24 hours (1, 3, 6, 12, and 24 hours) after hydroxocobalamin or methylene blue initiation. Secondary outcomes included changes in mean arterial pressure (MAP), systemic vascular resistance, and lactate. A total of 120 adult patients who received hydroxocobalamin (n = 77) or methylene blue (n = 43) were included. Vasopressor requirements at baseline were 0.34 µg/kg/min (95% CI 0.28-0.4) norepinephrine equivalent (NEE) in the hydroxocobalamin group, and 0.59 µg/kg/min (95% CI 0.52-0.66) NEE in the methylene blue group; p < 0.001. Vasopressor requirements decreased significantly at each time point within each group (hour 1 mean [95% CI] NEE, hydroxocobalamin 0.27 µg/kg/min [0.21-0.33]; methylene blue 0.44 µg/kg/min [0.38-0.51]; p < 0.001). The mean MAP at baseline was 65 mmHg (95% CI 63-67) in the hydroxocobalamin group, and 57 mmHg (95% CI 54-59) in the methylene blue group; p < 0.001. The mean MAP increased significantly from baseline at each time point within each group (hour 1 mean [95% CI] hydroxocobalamin 73 mmHg [71-75]; methylene blue 67 mmHg [65-70]; p < 0.001). After adjusting for baseline characteristics, a significantly greater reduction in vasopressor requirements and an increase in MAP were noted in the hydroxocobalamin group compared with the methylene blue group. Hydroxocobalamin was associated with a greater reduction in vasopressor requirements than methylene blue in treating VS associated with cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]

IntroductionVenoarterial extracorporeal membrane oxygenation (ECMO) is a rescue therapy that can stabilize patients with hemodynamic compromise. Indications continue to evolve, including drug overdose. However, the indication merely for vasoplegic shock following drug overdose is controversial.Case summaryWe report a case of a 57-year-old male with high-risk idiopathic pulmonary arterial hypertension treated with upfront triple combination therapy (sildenafil, bosentan, and intravenous treprostinil infusion via subcutaneous abdominal implantable pump). In one of the refills of the drug reservoir, accidental administration of 1 months's supply of treprostinil (200 mg) into the subcutaneous tissue occurred, causing refractory vasoplegic shock. He required urgent VA-ECMO for 96 h, surviving to discharge 28 days later.DiscussionTreprostinil poisoning is rare due to its less frequent use but is life-threatening. ECMO may be considered in vasoplegic shock due to overdose of vasodilatory medication. It allows organ perfusion to be maintained, with the knowledge that recovery is as rapid as drug elimination.

Despite efforts to improve treatment outcomes, mortality in septic shock remains high. In some patients, despite the use of several adrenergic drugs, features of refractory vasoplegic shock with progressive multiorgan failure are observed. We present a case report of the successful reversal of vasoplegic shock following the use of methylene blue, a selective inhibitor of the inducible form of nitric oxide synthase, which prevents vasodilation in response to inflammatory cytokines. We also briefly review the literature. [ABSTRACT FROM AUTHOR]

To describe angiotensin II (ANGII) use in patients on mechanical circulatory support (MCS). To evaluate the efficacy and safety of ANGII in patients with shock on MCS. Retrospective cohort study. A single-center, quaternary care academic medical center. The study comprised critically ill patients on MCS. None. Fourteen patients were included in this retrospective analysis. The median age was 54 years (44.8, 68.3) and 78.6% were men. Six patients were receiving venoarterial extracorporeal membrane oxygenation support, 4 patients were receiving venovenous extracorporeal membrane oxygenation support, and 4 patients were on left ventricular assist devices. Five patients (36%) achieved hemodynamic response to ANGII at 3 hours, defined as a mean arterial pressure (MAP) of ≥65 mmHg or a 10-mmHg increase in MAP with a decrease or no change in total vasopressor dose. Overall, the median MAP increased from 61 mmHg (51, 73) at baseline to 66 mmHg (58, 71) at 3 hours, and the median norepinephrine dose decreased from 0.45 µg/kg/min (0.28, 0.6) at baseline to 0.2 µg/kg/min (0.18, 0.32) at 3 hours. The in-hospital mortality rate was 78.6%. Two patients experienced severe adverse drug events and 1 patient had a sentinel thrombotic event. This study suggested that ANGII may provide a salvage treatment option in patients on MCS with refractory vasodilatory shock. There are several safety considerations with the use of ANGII in these patients. Prospective randomized controlled trials are needed to evaluate the safety and efficacy of ANGII in patients on MCS. [ABSTRACT FROM AUTHOR]

Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure. VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP. Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given. [ABSTRACT FROM AUTHOR]

Abstract Background Pheochromocytoma is a rare medical condition caused by catecholamine-secreting tumor cells. Operative resection can be associated with significant hemodynamic fluctuations due to the nature of the tumor, as well as associated post-resection vasoplegia. To allow for cardiovascular recovery before surgery, patients require pre-operative alpha-adrenergic blockade, which would be limited in the setting of co-existent severe aortic stenosis. In this report, we describe a patient with severe aortic stenosis and symptomatic pheochromocytoma. Case presentation A 51-year-old man with severe aortic stenosis (valve area 0.8 cm2) was found to have a highly active 4 × 4 cm left adrenal pheochromocytoma. Alpha-adrenergic blockade for his pheochromocytoma was limited by syncope in the setting of his aortic stenosis. Open aortic valve replacement (AVR) was performed, followed by adrenalectomy the next day. The perioperative course for each surgical procedure was hemodynamically volatile, exacerbated by severe alcohol withdrawal. During the adrenalectomy, cardiogenic and vasoplegic shock developed immediately after securing the vascular supply to his tumor. This shock was refractory to vasopressin and methylene blue, but responded well to angiotensin II and epinephrine. After both surgeries were completed, his course was further complicated by severe ICU psychosis, ileus, fungal bacteremia, pneumonia/hypoxic respiratory failure and atrial fibrillation. He ultimately recovered and was discharged from the hospital after 38 days. Conclusion To our knowledge, this is the first report of surgical AVR and pheochromocytoma resection in a patient with critical aortic stenosis. The appropriate order and timing of surgeries when both these conditions co-exist remains controversial.

Indeed, systemic concentrations of pro-inflammatory cytokines in patients with severe COVID-19 are not as high as has been reported in patients with other causes of acute respiratory distress syndrome. On April 10, 2020, the U.S. Food and Drug Administration granted Emergency Use Authorization for CytoSorb use in critically ill COVID-19 patients with confirmed or imminent respiratory failure. Keywords: COVID-19; cytokine adsorber; organ failure; vasoplegic shock EN COVID-19 cytokine adsorber organ failure vasoplegic shock 1026 1029 4 05/27/22 20220601 NES 220601 "However beautiful the strategy, you should occasionally look at the results." is a famous saying by Sir Winston Churchill. In a prospective, randomized, open-label study, Supady et al ([11]) investigated 34 COVID-19 patients with ECMO therapy and showed that the median IL-6 drop over 72 hours occurred regardless of the use of CytoSorb ([11]). [Extracted from the article]

Objectives: To investigate the effect of extracorporeal cytokine reduction by CytoSorb (CytoSorbents, Monmouth Junction, NJ) on COVID-19-associated vasoplegic shock.Design: Prospective, randomized controlled pilot study.Setting: Eight ICUs at three sites of the tertiary-care university hospital Charité-Universitätsmedizin Berlin.Patients: COVID-19 patients with vasoplegic shock requiring norepinephrine greater than 0.2 µg/kg/min, C-reactive protein greater than 100 mg/L, and indication for hemodialysis.Interventions: Randomization of 1:1 to receive CytoSorb for 3-7 days or standard therapy. To account for inadvertent removal of antibiotics, patients in the treatment group received an additional dose at each adsorber change.Measurements and Main Results: The primary endpoint was time until resolution of vasoplegic shock, estimated by Cox-regression. Secondary endpoints included mortality, interleukin-6 concentrations, and catecholamine requirements. The study was registered in the German Registry of Clinical Trials (DRKS00021447). From November 2020 to March 2021, 50 patients were enrolled. Twenty-three patients were randomized to receive CytoSorb and 26 patients to receive standard of care. One patient randomized to cytokine adsorption was excluded due to withdrawal of informed consent. Resolution of vasoplegic shock was observed in 13 of 23 patients (56.5%) in the CytoSorb and 12 of 26 patients (46.2%) in the control group after a median of 5 days (interquartile range [IQR], 4-5 d) and 4 days (IQR, 3-5 d). The hazard ratio (HR) for the primary endpoint, adjusted for the predefined variables age, gender, extracorporeal membrane oxygenation-therapy, or time from shock onset to study inclusion was HR, 1.23 (95% CI, 0.54-2.79); p = 0.63. The mortality rate was 78% in the CytoSorb and 73% in the control group (unadjusted HR, 1.17 [95% CI, 0.61-2.23]; p = 0.64). The effects on inflammatory markers, catecholamine requirements, and the type and rates of adverse events were similar between the groups.Conclusions: In severely ill COVID-19 patients, CytoSorb did not improve resolution of vasoplegic shock or predefined secondary endpoints. [ABSTRACT FROM AUTHOR]

Up to one-third of all patients admitted to intensive care units carry a diagnosis of shock. The use of angiotensin II is becoming widespread in all forms of shock, including cardiogenic, after the U.S. Food and Drug Administration's (FDA's) initial approval for vasoplegic shock in 2017. Here, the authors review the literature on angiotensin II's mechanism of action, benefits, and future therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Background: Pheochromocytoma is a rare medical condition caused by catecholamine-secreting tumor cells. Operative resection can be associated with significant hemodynamic fluctuations due to the nature of the tumor, as well as associated post-resection vasoplegia. To allow for cardiovascular recovery before surgery, patients require pre-operative alpha-adrenergic blockade, which would be limited in the setting of co-existent severe aortic stenosis. In this report, we describe a patient with severe aortic stenosis and symptomatic pheochromocytoma.Case Presentation: A 51-year-old man with severe aortic stenosis (valve area 0.8 cm2) was found to have a highly active 4 × 4 cm left adrenal pheochromocytoma. Alpha-adrenergic blockade for his pheochromocytoma was limited by syncope in the setting of his aortic stenosis. Open aortic valve replacement (AVR) was performed, followed by adrenalectomy the next day. The perioperative course for each surgical procedure was hemodynamically volatile, exacerbated by severe alcohol withdrawal. During the adrenalectomy, cardiogenic and vasoplegic shock developed immediately after securing the vascular supply to his tumor. This shock was refractory to vasopressin and methylene blue, but responded well to angiotensin II and epinephrine. After both surgeries were completed, his course was further complicated by severe ICU psychosis, ileus, fungal bacteremia, pneumonia/hypoxic respiratory failure and atrial fibrillation. He ultimately recovered and was discharged from the hospital after 38 days.Conclusion: To our knowledge, this is the first report of surgical AVR and pheochromocytoma resection in a patient with critical aortic stenosis. The appropriate order and timing of surgeries when both these conditions co-exist remains controversial. [ABSTRACT FROM AUTHOR]

The treatment of refractory vasodilatory shock in patients undergoing extracorporeal membrane oxygenation (ECMO) is an area in which there is minimal literature. Based on previous literature, the authors hypothesized that at least 40% of ECMO patients with vasoplegia would respond positively to methylene blue (MB) administration and that those who responded to MB would have increased survival. Retrospective observational study. Single institution, quaternary care hospital. The study comprised 45 patients who received MB for vasoplegia during ECMO. None. Of the 45 patients who received MB, 25 patients (55.6%) experienced a ≥10% increase in mean arterial pressure (MAP) and a reduction in norepinephrine dosing in the one-to-two hour interval after MB administration. There was a trend for improvement in survival to discharge for those who responded to MB (32% v 10%; p = 0.15). In addition, patients who did not have at least a >5% increase in MAP (29 experienced a >5% increase and 16 experienced a ≤5% increase) after MB administration, experienced 100% mortality (p = 0.008). This study suggested that approximately 50% of ECMO patients with vasoplegia can be expected to respond to MB with a >10% MAP improvement. The lack of a blood pressure response >5% after MB administration may portend poor survival. Larger prospective studies are needed to verify these preliminary results. [ABSTRACT FROM AUTHOR]

Abstract Objectives Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. Trial design Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of “CytoSorb” to standard of care without “CytoSorb”. Participants Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. Intervention and comparator Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional “CytoSorb” therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of “CytoSorb” filter in order to prevent underdosing due to “CytoSorb” treatment. Main outcomes Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of “CytoSorb” and acute kidney injury. Randomization An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité – Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. Blinding (masking) The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. Numbers to be randomized (sample size) As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. Trial Status Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. Trial registration The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447 . Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Hemodynamic conditions with reduced systemic vascular resistance commonly are observed in patients undergoing cardiac surgery and may range from moderate reductions in vascular tone, as a side effect of general anesthetics, to a profound vasodilatory syndrome, often referred to as vasoplegic shock. Therapy with vasopressors is an important pillar in the treatment of these conditions. There is limited guidance on the appropriate choice of vasopressors to restore and optimize systemic vascular tone in patients undergoing cardiac surgery. A panel of experts in the field convened to develop statements and evidence-based recommendations on clinically relevant questions on the use of vasopressors in cardiac surgical patients, using a critical appraisal of the literature following the GRADE system and a modified Delphi process. The authors unanimously and strongly recommend the use of norepinephrine and/or vasopressin for restoration and maintenance of systemic perfusion pressure in cardiac surgical patients; despite that, the authors cannot recommend either of these drugs with respect to the risk of ischemic complications. The authors unanimously and strongly recommend against using dopamine for treating post-cardiac surgery vasoplegic shock and against using methylene blue for purposes other than a rescue therapy. The authors unanimously and weakly recommend that clinicians consider early addition of a second vasopressor (norepinephrine or vasopressin) if adequate vascular tone cannot be restored by a monotherapy with either norepinephrine or vasopressin and to consider using vasopressin as a first-line vasopressor or to add vasopressin to norepinephrine in cardiac surgical patients with pulmonary hypertension or right-sided heart dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies.Trial Design: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb".Participants: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication.Intervention and Comparator: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment.Main Outcomes: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury.Randomization: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center.Blinding (masking): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded.Numbers To Be Randomized (sample Size): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group.Trial Status: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending.Trial Registration: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447.Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Management of severe vasoplegic shock in overdose can be very challenging. We describe a case of severe refractory vasodilatory shock in poisoning where methylene blue (MB) was used with success. However, the patient subsequently developed severe Serotonin Syndrome (SS) as a result of an interaction between serotonergic drugs and MB.Case Report: A 15-year-old male developed severe vasoplegic shock 1.5 hours after overdosing on several different medications including quetiapine slow release, quetiapine immediate release, desvenlafaxine slow release, venlafaxine, amlodipine, ramipril, fluoxetine, promethazine and lithium. His vasoplegic shock was resistant to high doses of noradrenaline and vasopressin. MB was administered 6.5 hours post ingestion and within 1 hour there was an improvement in his hemodynamic status and reduction of catecholamine requirements. Twelve hours post ingestion, he developed severe Serotonin Syndrome that lasted 5 days as a result of interaction between MB, a reversible monoamine oxidase inhibitor (MAO-I), and the antidepressants taken in overdose. MB had a calculated half-life of 38 hours.Conclusion: MB is a useful additional strategy for severe drug induced vasodilatory shock and may be potentially life-saving. Clinicians should be aware that it can interact with other drugs and cause life-threatening Serotonin Syndrome. Lower doses or shorter durations may be wise in patients at risk of this interaction. [ABSTRACT FROM AUTHOR]

The present review initially describes the rationale for the use of non-adrenergic vasopressors in the treatment of distributive shock and then provides an overview of the individual vasopressin-receptor agonists, namely arginine vasopressin, terlipressin, and selepressin. Following a brief summary of their current use in clinical practice, the present review focuses on the influence of vasopressin-receptor agonists on macro- and microvascular coupling, also referred to as hemodynamic coherence. On the basis of the current evidence from experimental and clinical studies, vasopressin-receptor agonists do not negatively influence macro- and microvascular coupling as compared to the standard therapy with norepinephrine, when used in established treatment regimes. A higher selectivity for the V1a-receptor seems to be beneficial; however, future clinical trials are warranted to verify this assumption. Notably, the optimal treatment regime for non-adrenergic vasopressors with respect to compound, dose, and timing still needs to be defined. [ABSTRACT FROM AUTHOR]

Background: Passive leg raising (PLR) is a so called self-volume challenge used to test for fluid responsiveness. Changes in cardiac output (CO) or stroke volume (SV) measured during PLR are used to predict the need for subsequent fluid loading. This requires a device that can measure CO changes rapidly. The Vigileo™ monitor, using third-generation software, allows continuous CO monitoring. The aim of this study was to compare changes in CO (measured with the Vigileo device) during a PLR manoeuvre to calculate the accuracy for predicting fluid responsiveness. Methods: This is a prospective study in a 20-bedded mixed general critical care unit in a large non-university regional referral hospital. Fluid responders were defined as having an increase in CO of greater than 15 % following a fluid challenge. Patients meeting the criteria for circulatory shock with a Vigileo™ monitor (Vigileo™; FloTrac; Edwards™; Lifesciences, Irvine, CA, USA) already in situ, and assessed as requiring volume expansion by the clinical team based on clinical criteria, were included. All patients underwent a PLR manoeuvre followed by a fluid challenge. Results: Data was collected and analysed on stroke volume variation (SVV) at baseline and CO and SVV changes during the PLR manoeuvre and following a subsequent fluid challenge in 33 patients. The majority had septic shock. Patient characteristics, baseline haemodynamic variables and baseline vasoactive infusion requirements were similar between fluid responders (10 patients) and non-responders (23 patients). Peak increase in CO occurred within 120 s during the PLR in all cases. Using an optimal cut point of 9 % increase in CO during the PLR produced an area under the receiver operating characteristic curve of 0.85 (95 % CI 0.63 to 1.00) with a sensitivity of 80 % (95 % CI 44 to 96 %) and a specificity of 91 % (95 % CI 70 to 98 %). Conclusions: CO changes measured by the Vigileo™ monitor using third-generation software during a PLR test predict fluid responsiveness in mixed medical and surgical patients with vasopressor-dependent circulatory shock. [ABSTRACT FROM AUTHOR]

Rabbit anti-thymocyte globulin (rATG) is an infusion of polyclonal rabbit-derived antibodies against human thymocyte markers, which can be used to prevent and treat acute rejection following organ transplantation. However, the product monograph issued by the manufacturer (Sanofi Canada) reports that serious immune-mediated reactions have been observed following the use of rATG, consisting of anaphylaxis or severe cytokine release syndrome (CRS), which is a form of vasoplegic syndrome (VS), in which distributive shock occurs refractory to norepinephrine (NE) and vasopressin (VP). Severe infusion-associated reactions are consistent with CRS and can cause serious cardiac or respiratory problems, or in certain cases, mortality. CRS is a form of systemic inflammatory response syndrome (SIRS). In SIRS, the substantial activation of endothelial inducible nitric oxide synthase (iNOS) and smooth muscle guanylate cyclase (GC) is observed, which can produce severe hypotension that is unresponsive to conventional vasopressors. Methylene blue (MB) is a direct inhibitor of iNOS and GC and has been used as an effective treatment for VS following cardiothoracic surgery. In the present study, the successful use of MB as a rescue therapy for CRS in a patient receiving rATG following a renal transplant was reported. Following an uneventful cadaveric kidney transplant involving the intravenous (IV) administration of rATG for the induction of immunological tolerance, the patient became markedly hypotensive and tachycardic. The patient required high doses of VP and NE infusions. Following the protocol described for treating refractory VS in post-cardiac surgery patients, the decision was made to initiate the patient on an IV MB infusion. This treatment protocol was shown to improve the hemodynamic status of the patient, which enabled the withdrawal of vasopressors and suggests an important role for methylene blue in the management of refractory VS. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to investigate whether patients who received methylene blue as treatment for vasoplegia during cardiac surgery with cardiopulmonary bypass had decreased morbidity and mortality. Design: Retrospective analysis. Setting: Single tertiary care university hospital. Participants: Adult patients who suffered from vasoplegia and underwent all types of cardiac surgery with cardiopulmonary bypass at this institution between 2007 and 2008. Interventions: With IRB approval, the authors reviewed the charts of the identified patients and divided them into 2 groups based on whether they had received methylene blue. Two hundred twenty-six patients were identified who met the inclusion criteria for the study. Fifty-seven of these patients had received methylene blue for vasoplegia. The authors collected data on preoperative and intraoperative variables as well as outcomes. Measurements and Main Results: The patients who received methylene blue had higher rates of in-hospital mortality, a compilation of morbidities, as well as renal failure and hyperbilirubinemia. A multiple logistic regression model demonstrated that receiving methylene blue was an independent predictor of in-hospital mortality (p value: 0.007, OR 4.26, 95% CI: 1.49-12.12), compilation of morbidities (p value: 0.001, OR 4.80, 95% CI: 1.85-12.43), and hyperbilirubinemia (p value:<0.001, OR 6.58, 95% CI: 2.91-14.89). Using propensity score matching, the association with morbidity was again seen but the association with mortality was not found. Conclusions: The current study identified the use of methylene blue as treatment for vasoplegia to be independently associated with poor outcomes. While further studies are required, a thorough risk-benefit analysis should be applied before using methylene blue and, perhaps, it should be relegated to rescue use and not as first-line therapy. [Copyright &y& Elsevier]

Refractory cardiogenic and vasoplegic shock after congenital heart surgery is a threatening condition leading to high morbidity and mortality. Control of hemodynamic and inflammatory response is fundamental in medical strategy. We report the case of a newborn with cardiogenic and vasoplegic shock secondary to cardiopulmonary bypass for atrioseptostomy and prostaglandin treatment in the context of hypoplastic left heart syndrome, successfully treated with a combination of mechanical circulatory support and cytokine hemoadsorption column (CytoSorb ® ). Vasopressor support was weaned during the time of treatment without multiple organ failure occurrence. The use of CytoSorb ® cartridge inserted in an extra-corporeal circuit even in a newborn is easy and feasible, as long as some precautions are considered. Routine monitoring of drugs levels is mandatory during the use of the cartridge and immediately after.