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.

Altered kinetics of circulating progenitor cells in cardiopulmonary bypass (CPB) associated vasoplegic patients: A pilot study.

Vasoplegia observed post cardiopulmonary bypass (CPB) is associated with substantial morbidity, multiple organ failure and mortality. Circulating counts of hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPC) are potential markers of neo-vascularization and vascular repair. However, the significance of changes in the circulating levels of these progenitors in perioperative CPB, and their association with post-CPB vasoplegia, are currently unexplored. We enumerated HSC and EPC counts, via flow cytometry, at different time-points during CPB in 19 individuals who underwent elective cardiac surgery. These 19 individuals were categorized into two groups based on severity of post-operative vasoplegia, a clinically insignificant vasoplegic Group 1 (G1) and a clinically significant vasoplegic Group 2 (G2). Differential changes in progenitor cell counts during different stages of surgery were compared across these two groups. Machine-learning classifiers (logistic regression and gradient boosting) were employed to determine if differential changes in progenitor counts could aid the classification of individuals into these groups. Enumerating progenitor cells revealed an early and significant increase in the circulating counts of CD34+ and CD34+CD133+ hematopoietic stem cells (HSC) in G1 individuals, while these counts were attenuated in G2 individuals. Additionally, EPCs (CD34+VEGFR2+) were lower in G2 individuals compared to G1. Gradient boosting outperformed logistic regression in assessing the vasoplegia grouping based on the fold change in circulating CD 34+ levels. Our findings indicate that a lack of early response of CD34+ cells and CD34+CD133+ HSCs might serve as an early marker for development of clinically significant vasoplegia after CPB.

Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options.

Vasoplegic syndrome is a common occurrence following cardiothoracic surgery and is characterized as a high-output shock state with poor systemic vascular resistance. The pathophysiology is complex and includes dysregulation of vasodilatory and vasoconstrictive properties of smooth vascular muscle cells. Specific bypass machine and patient factors play key roles in occurrence. Research into treatment of this syndrome is limited and extrapolated primarily from that pertaining to septic shock, but is evolving with the expanded use of catecholamine-sparing agents. Recent reports demonstrate potential benefit in novel treatment options, but large clinical trials are needed to confirm.

Vasoresponsiveness in patients with heart failure (VASOR): protocol for a prospective observational study.

BACKGROUND: Vasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved. METHODS: This is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with (N = 12) and without heart failure (N = 12). DISCUSSION: Understanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome. TRIAL REGISTRATION: The Netherlands Trial Register (NTR), NTR5647. Registered 26 January 2016.

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.

Vasoplegia After Surgical Left Ventricular Restoration: 2-Year Follow-Up.

BACKGROUND: Vasoplegia is a severe complication that can develop after surgical procedures for heart failure. The current study evaluated the effect of vasoplegia on survival, cardiac function, and renal function 2 years after surgical left ventricular restoration (SVR). METHODS: Heart failure patients with a left ventricular ejection fraction (LVEF) of 0.35 or less who underwent SVR in 2006 to 2014 were included. Vasoplegia was defined as the continuous need of vasopressors (norepinephrine ≥0.2 µg · kg-1 · min-1 or terlipressin [any dose], or both) combined with a cardiac index of 2.2 L · min-1 · m-2 or higher for at least 12 consecutive hours, starting within the first 3 days postoperatively. The effect of vasoplegia on mortality, New York Heart Association Functional Classification, LVEF, and creatinine clearance was assessed up to 2 years of follow-up. RESULTS: SVR was performed in 113 patients (80% men), aged 62 ± 10 years, and with an LVEF of 0.25 ± 0.06. Postoperative vasoplegia developed in 23%. Survival was lower in patients with vasoplegia compared with patients without vasoplegia at 6 months (62% vs 90%, p = 0.001) and at 2 years (50% versus 84%, p < 0.001). At the 2-year follow-up, New York Heart Association class and LVEF had improved and were similar in both groups (respectively, p = 0.319 and p = 0.444). Creatinine clearance was lower in patients with vasoplegia compared with patients without vasoplegia 2 years postoperatively (p < 0.001), even after correcting for baseline creatinine clearance (p = 0.009). CONCLUSIONS: Vasoplegia after SVR is associated with decreased survival. Despite an improved and similar cardiac function, renal function was compromised in vasoplegic patients at the 2-year follow-up.

Definitions and pathophysiology of vasoplegic shock.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition.

Determinants and Outcomes of Vasoplegia Following Left Ventricular Assist Device Implantation.

BACKGROUND: Vasoplegia is associated with adverse outcomes following cardiac surgery; however, its impact following left ventricular assist device implantation is largely unexplored. METHODS AND RESULTS: In 252 consecutive patients receiving a left ventricular assist device, vasoplegia was defined as the occurrence of normal cardiac function and index but with the need for intravenous vasopressors within 48 hours following surgery for >24 hours to maintain a mean arterial pressure >70 mm Hg. We further categorized vasoplegia as none; mild, requiring 1 vasopressor (vasopressin, norepinephrine, or high-dose epinephrine [>5 µg/min]); or moderate to severe, requiring ≥2 vasopressors. Predictors of vasoplegia severity were determined using a cumulative logit (ordinal logistic regression) model, and 1-year mortality was evaluated using competing-risks survival analysis. In total, 67 (26.6%) patients developed mild vasoplegia and 57 (22.6%) developed moderate to severe vasoplegia. The multivariable model for vasoplegia severity utilized preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time, which yielded an area under the curve of 0.76. Although no significant differences were noted in stroke or pump thrombosis rates (P=0.87 and P=0.66, respectively), respiratory failure and major bleeding increased with vasoplegia severity (P<0.01). Those with moderate to severe vasoplegia had a significantly higher risk of mortality than those without vasoplegia (adjusted hazard ratio: 2.12; 95% confidence interval, 1.08-4.18; P=0.03). CONCLUSIONS: Vasoplegia is predictive of unfavorable outcomes, including mortality. Risk factors for future research include preoperative INTERMACS profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time.

Postoperative Vasoplegic Syndrome Is Associated With Impaired Endothelial Vasomotor Response in Cardiac Surgery: A Prospective, Observational Study.

OBJECTIVES: Vasoplegic syndrome (VS) affects up to 30% of cardiac surgery patients. Onset of VS may be associated with overproduction of nitric oxide (NO). The response of the brachial artery to NO can be assessed using flow-mediated vasodilation (FMD). The aim of this study was to assess brachial artery diameter and FMD response immediately after cardiac surgery. DESIGN: Prospective, observational study. SETTING: Single-center study in a tertiary teaching hospital. PATIENTS: Patients older than 18 years undergoing elective cardiac surgery with cardiopulmonary bypass who provided informed consent. INTERVENTIONS: Brachial artery diameter and FMD response were measured before cardiac surgery and just after surgery on admission to the intensive care unit. Patients were screened for VS for the following 48 hours. RESULTS: Eleven (39%) of the 28 patients included in the study developed VS. Brachial artery diameter and FMD differed between VS and non-VS patients. On intensive care unit admission, mean (± standard deviation) brachial artery diameter was greater in VS patients than in non-VS patients (3.9 ± 0.7 mm v 3.0 ± 0.8 mm, respectively; p = 0.002). Similarly, the FMD response after surgery was greater in VS patients than in non-VS patients (42% ± 8% v 31% ± 1%, respectively; p = 0.014). Brachial artery diameter and FMD response after surgery were both predictive of VS, with an area under the curve (95% confidence interval) of 0.850 (0.705-0.995) (p = 0.002) and 0.755 (0.56-0.95) (p = 0.047), respectively. CONCLUSION: Cardiac surgery with cardiopulmonary bypass appears to alter the NO-mediated endothelial vasomotor response.

Risk assessment and outcomes of vasoplegia after cardiac surgery.

OBJECTIVE: The aim of this study was to analyze risk factors and outcomes of vasoplegia after cardiac surgery based on our experience with almost 2000 cardiac operations performed at our institution. METHODS: We retrospectively analyzed patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) between 2011 and 2013. Data were available for a total of 1992 patients. We defined vasoplegia as hypotension with persistently low systemic vascular resistance (<800 dyn/s/cm) and preserved Cardiac Index (>2.5). RESULTS: The rate of vasoplegia in our cohort was 20.3% (n = 405). The incidences of mild, moderate, and severe vasoplegia were 13.2, 5.7, and 1.5%, respectively. Factors that increased risk of vasoplegia included valve operations, heart transplants, dialysis-dependent renal failure, age >65, diuretic therapy, and recent myocardial infarction. B blocker therapy was protective against vasoplegia. CONCLUSION: Vasoplegic syndrome is still a frequently occurring adverse event following cardiac surgery. In high risk patients for vasoplegia, it may be sensible to proceed with preoperative volume loading (instead of diuresis), initiation of low dose vasopressin therapy if needed, and attempting to up titrate beta-blocker therapy.

Key Points for Curbing Cardiopulmonary Bypass Inflammation

PURPOSE: Cardiopulmonary bypass (CPB) procedures are thought to activate systemic inflammatory reaction syndrome (SIRS). Strategies to curb systemic inflammation have been previously described. However, none of them is adequate, since "curbing" the extent of the inflammatory response requires a multimodal approach. The aim of the present mini-review is to discuss the main key points about the main principles in cardiopulmonary bypass curbing inflammation. METHODS: No systematic literature search (MEDLINE) and extracted data from the accumulated experience of the authors. The preconceived idea of an association between severe inflammation and coagulation disorders is reviewed. Also, some fundamental concepts, CPB inflammatory biomarkers, the vasoplegic syndrome and the need forindividual CPB protocols for children, diabetes and old patients, are discussed. CONCLUSION: The ways in which surgical technique (atraumatic vein harvest, biocompatibility and shear resistance of the circuit, monitoring, minimizing organ ischemia, minimal cross-clamping trauma, and blood management) are thought to curb SIRS induced by CPB and affect positively the patient outcome.Improved patient outcomes are strongly associated with these modalities of care, more than single or combinatorial drug strategies (aprotinin, tranexamic acid, pentoxifylline) or CPB modalities (minicircuits, heparin-coated circuits, retrograde autologous prime).

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.

Cardiac vasoplegia syndrome: pathophysiology, risk factors and treatment.

Vasoplegia syndrome is a well known complication after cardiac surgery and has a significant morbidity and mortality. It is characterized by profound vasodilation and loss of systemic vascular resistance leading to hypotension. The pathogenesis of vasoplegia involves the activation of contact, coagulation and complement systems and the activation of leukocytes, platelets and endothelial cells resulting in an imbalance in the regulation of the vascular tone leading to postcardiac surgery vasoplegia. Multiple risk factors have been identified that help predict vasoplegia. Treatment requires mainly vasopressors, but hypotension can be refractory to vasopressors. Some studies suggest that methylene blue can reverse refractory hypotension in these patients and may prevent the development of the syndrome, but more studies are needed with this drug. In this review, we will discuss the pathophysiology of the vasoplegia syndrome and associated risk factors for this complication and briefly outline current therapeutic strategies.

[Factors involved in the development of vasoplegia after cardiac surgery with extracorporeal circulation. A prospective observational study]. / Factores implicados en el desarrollo de vasoplejía tras cirugía cardiaca con circulación extracorpórea. Estudio prospectivo observacional.

OBJECTIVE: The incidence and risk factors for vasoplegia in the early postoperative period and at 24h are investigated in patients subjected to cardiopulmonary bypass surgery. Vasoplegia following cardiac surgery with cardiopulmonary bypass is associated with a high morbimortality. The risk factors described emerged from retrospective, non-controlled studies. METHODS: Observational prospective study of 188 consecutive patients subjected to cardiac surgery with cardiopulmonary bypass in a single hospital between November 2011 and May 2012. Emergency surgery or complex procedures were excluded. Vasoplegia was assessed during the immediate postoperative period, and at 24h after surgery, and was defined as a mean arterial pressure below 50mmHg, and the need for a noradrenaline perfusion of more than 0.08µg/kg/min, monitored by cardiac output and systemic vascular resistances. The anaesthetic and cardiopulmonary bypass protocols, as well as haemodynamic management, were the same in all patients. RESULTS: Almost half (48%) of patients had vasoplegia in the immediate postoperative period, and 34% at 24h. Risk factors for immediate vasoplegia development were preoperative use of angiotensin converting enzyme inhibitor drugs, a mean arterial pressure<50mmHg immediately after beginning cardiopulmonary bypass, duration of aortic clamping as well as the cardiopulmonary bypass, and minimum temperature in cardiopulmonary bypass. Vasoplegia at 24h after surgery was correlated to preoperative angiotensin converting enzyme inhibitor drug treatment and cardiopulmonary bypass duration. CONCLUSION: The incidence of vasoplegia after cardiac surgery with cardiopulmonary bypass is high during the first 24 postoperative hours. Preoperative treatment with angiotensin converting enzyme inhibitor and the mean arterial pressure at the beginning of cardiopulmonary bypass are the more easily controllable risk factors. In patients arriving to surgery with those drugs, treatment or prevention of vasoplejia should be planned.

The incidence of vasoplegia in adult patients with right-sided congenital heart defects undergoing cardiac surgery and the correlation with serum vasopressin concentrations.

BACKGROUND: In adults with right-sided congenital heart disease, vasoplegia during and after cardiopulmonary bypass appears to be a frequent complication. The incidence of vasoplegia in the general adult and pediatric cardiac surgical population has been investigated, but the incidence in adult patients with right-sided congenital heart disease is unknown. Perioperative vasopressin levels during cardiac surgery have been studied in other cardiac surgical patients, but are not known in adults with right-sided congenital heart disease. The purpose of this study was to investigate the incidence of vasoplegia in adult patients undergoing right-sided cardiac surgical procedures requiring cardiopulmonary bypass and to determine the vasopressin response to cardiac surgery in this population. METHODS: Twenty patients were enrolled and demographic, hemodynamic, cardiopulmonary bypass, and use of vasoactive medication data were collected. In addition, perioperative serum vasopressin levels were measured. Sixty adult patients undergoing left-sided cardiac surgery served as controls. RESULTS: The incidence of vasoplegia in the control patients was 10% and the incidence in the adult patients with right-sided congenital heart disease was 20%. Vasopressin levels were low at baseline (0.5 ± 0.5 pg/mL), increased slightly after induction of anesthesia (0.6 ± 0.6 pg/mL), increased after initiation of cardiopulmonary bypass (99.7 ± 168.2 pg/mL), and decreased after surgery (31.3 ± 43.6 pg/mL). CONCLUSIONS: This study showed that the incidence of vasoplegia (20%) in patients with right-sided congenital heart disease undergoing cardiac surgery was double that of a population of patients undergoing aortic valve surgery (10%). Serum vasopressin concentration was not associated with vasoplegia in this population of congenital cardiac surgical patients.