Severe Vasoplegic Shock After Heart Transplant Successfully Treated With Multimodal Therapeutic Approach.

Vasoplegia describes a constellation of low vascular resistance and normal cardiac output. Vasoplegia is common after cardiac surgery in general and in heart transplant recipients more specifically and occurs in over one-half of all heart transplant recipients with a varying degree of severity. The pathophysiology of vasoplegia is multifactorial and associated with a cascade of inflammatory mediators. Routine treatment of vasoplegia is based on medical vasopressor therapy, but in severe cases this may be insufficient to maintain adequate blood pressure and does not address the underlying pathophysiology. We report a case of severe vasoplegic shock in a heart transplant recipient who was successfully managed with a multimodal therapy combination of methylene blue, immunoglobulins enriched with immunoglobulin M, cytokine adsorption, and broad-spectrum antibiotics. This represents a promising therapeutic approach for heart transplant patients with vasoplegia.

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.

Updates in the Management of Perioperative Vasoplegic Syndrome.

Vasoplegic syndrome occurs relatively frequently in cardiac surgery, liver transplant, major noncardiac surgery, in post-return of spontaneous circulation situations, and in pateints with sepsis. It is paramount for the anesthesiologist to understand both the pathophysiology of vasoplegia and the different treatment strategies available for rescuing a patient from life-threatening hypotension.

Hydroxocobalamin or Methylene Blue for Vasoplegic Syndrome in Adult Cardiothoracic Surgery.

OBJECTIVE: To compare hydroxocobalamin and methylene blue for the treatment of vasopressor-refractory vasoplegic syndrome (VS) after adult cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A retrospective, propensity-matched, cohort study was performed. The primary endpoints were the percentage change in vasopressor use at 30, 60, and 120 minutes, characterized as both norepinephrine equivalents and vasoactive inotropic score. Eligible patients who received methylene blue were matched 3:1 with patients who received hydroxocobalamin based on sequential organ failure assessment score, preoperative mechanical circulatory support, CPB duration, and use of pre-CPB vasopressors, angiotensin-converting enzyme inhibitors, or beta-blockers. SETTING: A quaternary care academic medical center. PARTICIPANTS: Adult patients who underwent cardiac surgery with CPB from July 2013 to June 2019. INTERVENTIONS: Patients were included who received either hydroxocobalamin (5,000 mg) or methylene blue (median 1.2 mg/kg) for VS in the operating room during the index surgery or in the intensive care unit up to 24 hours after CPB separation. MEASUREMENTS AND MAIN RESULTS: Of the 142 included patients, 120 received methylene blue and 22 received hydroxocobalamin. After matching, 66 patients in the methylene blue group were included in the analysis. Baseline demographics, surgical characteristics, and vasoactive medications were similar between groups. There were no significant between-group differences in percentage change in norepinephrine equivalents or vasoactive inotropic score at each timepoint. CONCLUSIONS: In adult patients undergoing cardiothoracic surgery using CPB with VS, the ability to reduce vasopressor use was similar with hydroxocobalamin compared with methylene blue.

Vasoplegic Syndrome in Patients Undergoing Cardiac Surgery: A Literature Review.

Vasoplegic syndrome is a rising problem affecting morbidity and mortality in patients undergoing cardiac surgery. Vasoplegia is a vasodilatory, shocklike syndrome characterized by decreased systemic vascular resistance, normal to high cardiac index, and hypotension refractory to fluid resuscitation and vasopressors. This review describes the presentation, physiology, risk factors, treatments, and implications of vasoplegia after cardiac surgery. No standardized methods for diagnosing and treating vasoplegia are available. Vasoplegia is caused by surgical trauma, systemic inflammation, and vascular dysregulation. Patients with comorbidities and those undergoing complex surgical procedures are at increased risk for vasoplegia. The use of ß-blockers is protective. Vasoplegia is potentially reversible. Vasopressin is likely the most effective first-line vasopressor, and the use of methylene blue and/or hydroxocobalamin may restore vascular tone. Alternative therapies such as methylene blue and hydroxocobalamin show promise, but additional research and education are needed.

Methylene blue for vasoplegic syndrome in cardiopulmonary bypass surgery: A systematic review and meta-analysis.

BACKGROUND: To evaluate the benefit of methylene blue as an adjunct treatment by assessing hemodynamic, morbidity rate, intensive care unit length of stay, and mortality rate outcomes in adult patients with vasoplegic syndrome. METHODS: A systematic search through electronic databases including Pubmed, Embase, Scopus, and Medline for studies assessing the use of methylene blue in patients with vasoplegic syndrome compared to control treatments. The Newcastle-Ottawa Scale tool was used for observational studies, and Jadad Scale was used for controlled trials to assess the risk of bias. RESULTS: This systematic review included six studies for qualitative synthesis and five studies for quantitative synthesis. Pooled analysis revealed that mean arterial pressure, systemic vascular resistance, heart rate, and hospital stay were not statistically significant in methylene blue administration compared to control. However, administration of methylene blue in vasoplegic syndrome patients significantly reduces renal failure (OR = 0.25; 95% CI = 0.08-0.75), development of multiple organ failure (OR = 0.09; 95% CI = 0.02-0.51), and mortality rate (OR = 0.12; 95% CI = 0.03-0.46). CONCLUSION: Adjunct administration of methylene blue for vasoplegic syndrome patients significantly reduces renal failure, multiple organ failure, and mortality.

Angiotensin II for Critically Ill Patients With Shock After Heart Transplant.

Patients undergoing heart transplant are at high risk for vasodilatory shock in the postoperative period, due to a combination of vascular dysfunction from end-stage heart failure and inflammatory response to cardiopulmonary bypass and, increasingly, long-term exposure to nonpulsatile blood flow in those who have received a left ventricular assist device as a bridge to transplant. Patients who have this vasoplegic syndrome, which may be refractory to traditional agents used in the treatment of shock, are vulnerable to organ dysfunction and death. Angiotensin II (ANG-2) is of increasing interest as an adjunct to traditional therapy, both for improvement in blood pressure and for sparing the use of high-dose catecholamine vasopressors. This case series describes the use of ANG-2 in 4 clinical scenarios for the treatment of shock due to heart transplant surgery, supporting its use in this role and justifying further prospective studies to clarify the appropriate place for ANG-2 in the hierarchy of adjunctive therapies.

Treatment With Angiotensin II Is Associated With Rapid Blood Pressure Response and Vasopressor Sparing in Patients With Vasoplegia After Cardiac Surgery: A Post-Hoc Analysis of Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) Study.

OBJECTIVE: The present study investigated outcomes in patients with vasoplegia after cardiac surgery treated with angiotensin II plus standard-of-care vasopressors. Vasoplegia is a common complication in cardiac surgery with cardiopulmonary bypass and is associated with significant morbidity and mortality. Approximately 250,000 cardiac surgeries with cardiopulmonary bypass are performed in the United States annually, with vasoplegia occurring in 20%to-27% of patients. DESIGN: Post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. SETTING: Multicenter, multinational study. PARTICIPANTS: Sixteen patients with vasoplegia after cardiac surgery with cardiopulmonary bypass were enrolled. INTERVENTIONS: Angiotensin II plus standard-of-care vasopressors (n = 9) compared with placebo plus standard-of-care vasopressors (n = 7). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was mean arterial pressure response (mean arterial pressure ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3 without an increase in the dose of standard-of-care vasopressors). Vasopressor sparing and safety also were assessed. Mean arterial pressure response was achieved in 8 (88.9%) patients in the angiotensin II group compared with 0 (0%) patients in the placebo group (p = 0.0021). At hour 12, the median standard-of-care vasopressor dose had decreased from baseline by 76.5% in the angiotensin II group compared with an increase of 7.8% in the placebo group (p = 0.0013). No venous or arterial thrombotic events were reported. CONCLUSION: Patients with vasoplegia after cardiac surgery with cardiopulmonary bypass rapidly responded to angiotensin II, permitting significant vasopressor sparing.

Use of Intravenous Hydroxocobalamin for Vasoplegic Syndrome in Simultaneous Liver-Kidney Transplant: A Case Report.

Vasoplegic syndrome can occur after reperfusion in liver transplantation. Generally, vasopressor infusions along with volume resuscitation are used to combat this process. There are case reports of the use of hydroxocobalamin to improve vasoplegia in liver transplant and cardiac surgery. In this case report, we describe a patient who received hydroxocobalamin for a simultaneous liver-kidney transplant. Use of this medication facilitated a prompt decrease of very high-dose vasopressor infusions and allowed completion of the kidney transplantation portion of this case. To our knowledge, use in combined liver-kidney transplant has not been described. In light of the dearth of medications to improve vasoplegia outside of vasopressor infusions, the use of hydroxocobalamin as a therapeutic intervention may gain importance.

Neuroendocrine predictors of vasoplegia after cardiopulmonary bypass.

PURPOSE: Vasoplegia often complicates on-pump cardiac surgery. Systemic inflammatory response induced by extracorporeal circulation represents the major determinant, but adrenal insufficiency and postoperative vasopressin deficiency may have a role. Pathophysiological meaning of perioperative changes in endocrine markers of hydro-electrolyte balance has not still fully elucidated. Objectives of the present research study were to estimate the incidence of vasoplegia in a homogeneous cohort of not severe cardiopathic patients, to define the role of presurgical adrenal insufficiency, to evaluate copeptin and NT-proBNP trends in the perioperative. METHODS: We conducted a prospective cohort study in the cardiac intensive care unit of a tertiary referral center. We evaluated 350 consecutive patients scheduled for cardiac surgery; 55 subjects completed the study. Both standard and low-dose corticotropin stimulation tests were performed in the preoperative; copeptin and NT-proBNP were evaluated in the preoperative (T0), on day 1 (T1) and day 7 (T2) after surgery. RESULTS: Nine subjects (16.3%) developed vasoplegic syndrome with longer bypass and clamping time (p < 0.001). Reduced response to low-dose ACTH test was not associated to vasoplegia. Preoperative copeptin > 16.9 pmol/L accurately predicted the syndrome (AUC 0.86, 95% CI 0.73-0.94; OR 1.17, 95% CI 1.04-1.32). An evident correlation was observed at 7 days postoperative between NT-proBNP and copeptin (r 0.88, 95% CI 0.8-0.93; p < 0.001). CONCLUSION: Preoperative impaired response to low-dose ACTH stimulation test is not a risk factor for post-cardiotomic vasoplegia; conversely, higher preoperative copeptin predicts the complication. On-pump cardiac surgery could be an interesting model of rapid heart failure progression.

Hydroxocobalamin Versus Methylene Blue for Vasoplegic Syndrome in Cardiothoracic Surgery: A Retrospective Cohort.

OBJECTIVE: To compare methylene blue with hydroxocobalamin as a rescue therapy for vasoplegic syndrome. DESIGN: Retrospective cohort. SETTING: Academic medical center. PARTICIPANTS: Patients undergoing cardiothoracic surgery treated for vasoplegic syndrome. INTERVENTIONS: Thirty-five patients were treated with methylene blue (n = 16) or hydroxocobalamin (n = 19). MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure, systemic vascular resistance, and vasopressor exposures were recorded before and after medication administration. Change in time-averaged norepinephrine equivalents in the hour after administration was the primary outcome. The average norepinephrine equivalent observed at baseline in this cohort was 0.347 µg/kg/min. Methylene blue patients had greater Acute Physiological Assessment and Chronic Health Evaluation II scores (29.8 v 22.2; p = 0.01) and trended toward greater European System for Cardiac Operative Risk Evaluation II values (26.8% v 15.1%; p = 0.07). Methylene blue and hydroxocobalamin were associated with increased mean arterial pressure and systemic vascular resistance 1 hour after administration (10.6 mmHg and 192 dyn*sec/cm5; p = 0.01 and p = 0.01, respectively; 11.8 mmHg and 254 dyn*sec/cm5; p = 0.002 and p = 0.015, respectively). Hemodynamic changes were not different between the rescue therapy groups (p = 0.79 and p = 0.53, respectively). No significant differences were observed within the 1-hour change in time-averaged norepinephrine equivalents for either agent or when methylene blue and hydroxocobalamin were compared (0.012 ± 0.218 µg/kg/min v -0.037 ± 0.027 µg/kg/min; p = 0.46, respectively). When compared with baseline time-averaged norepinephrine equivalent (0.326 ± 0.106 µg/kg/min), only hydroxocobalamin was associated with decreased vasopressor requirements at the 1-hour (0.255 ± 0.129 µg/kg/min; p = 0.03) and 4-hour time points (0.247 ± 0.180 µg/kg/min; p = 0.04) post-administration. CONCLUSION: Methylene blue and hydroxocobalamin increased mean arterial pressures and systemic vascular resistance without significantly decreasing time-averaged norepinephrine exposure in the hour after administration.

Vasoplegia After Cardiac Surgery Is Associated With Endothelial Glycocalyx Alterations.

OBJECTIVE: To assess endothelial glycocalyx (EG) alteration in vasoplegic syndrome after cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective analysis SETTING: Single university hospitals. PARTICIPANTS: Patients undergoing elective cardiac surgery under cardiopulmonary bypass. INTERVENTIONS: Observational study METHODS: Heparan sulfate and syndecan-1 levels were assessed in plasma before surgery, on intensive care unit admission, and on the first postoperative day. The primary outcome was comparisons of heparan sulfate and syndecan-1 levels in patients with and without vasoplegic syndrome. RESULTS: A total of 46 patients were analyzed. Only syndecan-1 was modified by cardiac surgery (p < 0.05). Plasma syndecan-1 levels were lower in patients with vasoplegic syndrome at the 3 time-points and were associated with the cumulative norepinephrine dose. Baseline plasma syndecan-1 predicted the development of vasoplegic syndrome with an area under the curve of 0.7 (confidence interval 95%: 0.51-0.85, p = 0.045). Heparan sulfate levels were not modified by cardiac surgery. CONCLUSION: Patients with vasoplegic syndrome after cardiac surgery present a different pattern of EG components. Lower syndecan-1 levels were associated with vasoplegic syndrome. These preliminary results suggest a specific phenotype that may reflect endothelial activation leading to alteration of the EG.

Vasoplegic syndrome in cardiac surgery: Definitions, pathophysiology, diagnostic approach and management. / Síndrome vasopléjico en cirugía cardíaca: definición, fisiopatología, enfoque diagnóstico y manejo.

Vasoplegic syndrome is a state of vasopressor resistant systemic vasodilation in the presence of a normal cardiac output. Its definition, pathophysiology, risk factors, diagnosis and therapeutic approach will be reviewed in this paper. It occurs frequently during cardiac surgery and is associated with high morbidity and mortality. A search in the LILACS, MEDLINE, and GOOGLE SCHOLAR databases was conducted to find the most relevant papers during the last 18 years. Prompt identification and diagnosis of patients at risk must be undertaken in order to implement an optimal therapeutic approach. This latter includes early treatment with vasopressors with different mechanisms of action.

Methylene Blue Monotherapy Compared With Combination Therapy With Hydroxocobalamin for the Treatment of Refractory Vasoplegic Syndrome: ARetrospective Cohort Study.

OBJECTIVE: To compare the efficacy of methylene blue with combination therapy with hydroxocobalamin in patients experiencing vasoplegic syndrome after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. PARTICIPANTS: Patients who received methylene blue with or without hydroxocobalamin for refractory vasoplegic syndrome rescue therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 0.the ability to maintain mean arterial pressure (MAP) >60 mmHg beyond 1hour after study drug administration. Other pertinent outcomes included MAP at hours 6, 12, and 24 post-administration; both raw and proportional changes of vasopressor doses from baseline at hours 1, 6, 12, and 24 post-administration; and change in pulmonary artery catheter hemodynamics. Overall, 28 doses were administered in 14 patients in the monotherapy group and 17 doses (10 methylene blue, 7 hydroxocobalamin) were administered in 6 patients in the combination therapy group. There were no differences in ability to maintain MAP at 1hour, with 71% of the monotherapy and 82% of combination therapy patients meeting MAP goals (p = 0.49). Pairwise comparisons demonstrated vasopressor reductions at 6, 12, and 24hours in both groups, but only significant reductions at 1hour were observed in the combination therapy group (-0.06 µg/kg/min; p = 0.003) but not in the monotherapy group (-0.015 µg/kg/min; p = 0.14). CONCLUSION: This is the first study to compare methylene blue monotherapy with combination therapy, which suggests there may be an advantage to combination therapy. Further characterization of ideal dosing, timing, and agent selection should be investigated on a larger scale format.

Characterizing Predictors and Severity of Vasoplegia Syndrome After Heart Transplantation.

BACKGROUND: Vasoplegia is characterized as a severe vasodilatory shock after cardiac surgery, and can be associated with substantial morbidity. Increased systemic inflammation and endothelial dysfunction, often related to prolonged cardiopulmonary bypass times, anesthesia, or mechanical circulatory support have been shown to be associated with the development of vasoplegia. We sought to identify risk factors and the impact of various degrees of vasoplegia after heart transplantation. METHODS: A retrospective review was conducted of 244 consecutive patients who underwent heart transplantation over a 3-year period. Patients were divided into three groups: no vasoplegia, mild vasoplegia (requiring one vasopressor), and moderate/severe vasoplegia (more than two vasopressors). One-year survival, freedom from rejection, and postoperative complication rates were assessed. Risk factors for vasoplegia subgroups were retrospectively identified. RESULTS: Vasoplegia syndrome was observed in 34.3% of patients after heart transplantation (mild, 74.1%; moderate/severe, 25.9%). Cardiopulmonary bypass time was significantly longer and pretransplant creatinine was significantly higher in the moderate/severe vasoplegia group. There was a strong trend toward greater use of mechanical circulatory support among moderate/severe vasoplegia patients compared with mild and no vasoplegia patients. After heart transplantation, 1-year survival, freedom from rejection, and need for hemodialysis were not significantly different between groups. CONCLUSIONS: Vasoplegia syndrome is common after heart transplantation. Risk factors for increased severity include longer cardiopulmonary bypass times and elevated preoperative creatinine. Although higher rates of mortality or graft rejection were not detected, vasoplegia was associated with prolonged intubation, greater blood product usage, and lengthened hospital stay. Further studies involving larger cohorts are warranted.

A Reminder of Methylene Blue's Effectiveness in Treating Vasoplegic Syndrome after On-Pump Cardiac Surgery.

The inflammatory response induced by cardiopulmonary bypass decreases vascular tone, which in turn can lead to vasoplegic syndrome. Indeed the hypotension consequent to on-pump cardiac surgery often necessitates vasopressor and intravenous fluid support. Methylene blue counteracts vasoplegic syndrome by inhibiting the formation of nitric oxide. We report the use of methylene blue in a 75-year-old man who developed vasoplegic syndrome after cardiac surgery. After the administration of methylene blue, his hypotension improved to the extent that he could be weaned from vasopressors. The use of methylene blue should be considered in patients who develop hypotension refractory to standard treatment after cardiac surgery.