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.

When the pressure drops: A case of vasoplegia during a structural heart intervention.

A 67-year-old male underwent general anesthesia for left atrial appendage occlusion. During the procedure, the patient developed catecholamine refractory hypotension requiring the administration of several vasopressin boluses to maintain adequate perfusion pressure. At the conclusion of the procedure, mild venous bleeding necessitated the administration of protamine. This led to a further decrease in the patient's blood pressure. Tamponade and continued volume loss were quickly ruled out leading to a diagnosis of vasoplegia syndrome (VS). The patient was appropriately treated with a vasopressin infusion with normalization of blood pressure and no significant morbidity or adverse outcome. With the use of general anesthesia during structural heart interventions on the rapid rise, we discuss the two common causes for vasoplegia along with evidence-based treatments and possible prevention strategies.

Use of Hydroxocobalamin (Vitamin B12a) in Patients With Vasopressor Refractory Hypotension After Cardiopulmonary Bypass: A Case Series.

Hydroxocobalamin (vitamin B12a) is an emerging treatment for vasoplegic syndrome (VS) associated with cardiopulmonary bypass (CPB). Given its cost and scarcity, an institutional guideline for its use as a rescue treatment in cases of suspected VS was developed. Hemodynamic variables and vasopressor requirements were reviewed for a series of 24 post-CPB patients who received B12a. Favorable changes in hemodynamic parameters and vasopressor requirements were seen after B12a administration although guideline criteria for VS were inconsistently met. These findings support the continued study of B12a in patients with CPB-associated VS.

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.

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.

Vasoplegia treatments: the past, the present, and the future.

Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.

Dynamic arterial elastance measured by uncalibrated pulse contour analysis predicts arterial-pressure response to a decrease in norepinephrine.

BACKGROUND: Dynamic arterial elastance (Eadyn) has been proposed as an indicator of vascular tone that predicts the decrease in arterial pressure in response to changes in norepinephrine (NE). The purpose of this study was to determine whether Eadyn measured by uncalibrated pulse contour analysis (UPCA) can predict a decrease in arterial pressure when the NE dosage is decreased. METHODS: We conducted a prospective study in a university hospital intensive care unit. Patients with vasoplegic syndrome for whom the intensive care physician planned to decrease the NE dosage were included. Haemodynamic and UPCA (VolumeView and FloTrac; Edwards Lifesciences, Irvine, CA, USA) values were obtained before and after decreasing the NE dosage. Responders were defined by a >10% decrease in mean arterial pressure (MAP). RESULTS: Of 35 patients included, 11 (31%) were pressure responders with a median decrease of 13%. Eadyn was correlated to systolic arterial pressure (SAP) (r=0.255; P=0.033), diastolic arterial pressure (r=0.271; P=0.024), MAP (r=0.310; P=0.009), heart rate (r=0.543; P=0.0001), and transthoracic echography cardiac output (r=0.264; P=0.024). Baseline Eadyn was correlated with MAP changes (r=0.394; P=0.019) and SAP changes (r=0.431; P=0.009). Eadyn predicted the decrease in arterial pressure with an area under the receiver-operating-characteristic curve of 0.84 (95% confidence interval: 0.70-0.97). The best cut-off was 0.90. CONCLUSIONS: The present study confirms the ability of Eadyn measured by UPCA to predict an arterial pressure response to a decrease in NE. Eadyn may constitute an easy-to-use functional approach to arterial tone assessment regardless of the monitor used to measure its determinant. CLINICAL TRIAL REGISTRATION: DRCIT95.

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.

Methylene Blue: Magic Bullet for Vasoplegia?

Methylene blue (MB) has received much attention in the perioperative and critical care literature because of its ability to antagonize the profound vasodilation seen in distributive (also referred to as vasodilatory or vasoplegic) shock states. This review will discuss the pharmacologic properties of MB and review the critical care, liver transplantation, and cardiac anesthesia literature with respect to the efficacy and safety of MB for the treatment of shock. Although improved blood pressure has consistently been demonstrated with the use of MB in small trials and case reports, better oxygen delivery or decreased mortality with MB use has not been demonstrated. Large randomized controlled trials are still necessary to identify the role of MB in hemodynamic resuscitation of the critically ill.

Vasoplegia in septic shock (review).

Vasoplegia is considered as a key factor responsible for the death of patients with septic shock, due to persistent and irreversible hypotension. The latter associated with vascular hyporeactivity to vasoconstrictors is a significant independent prognostic factor of mortality in severe sepsis. Loss of control of the vascular tone occurs through the complex, multifactorial mechanism and implicates deeply disrupted balance between vasoconstrictors and vasodilators. The aim of this review is to discuss in detail the recent suggested alternative mechanisms of vasoplegia in severe sepsis: Overproduction of nitric oxide (NO) by activation of inducible form of nitric oxide synthase (iNOS); up-regulation of prostacyclin (PG12); vasopressin deficiency; significantly elevated levels of circulating endothelin; increased concentrations of vasodilator peptides such as adrenomedulin (AM) and calcitonin gene-related peptide (CGRP); oxidative stress inducing endothelial dysfunction and vascular hyporeactivity to vasoconstrictors; inactivation of catecholamines by oxidation; over-activation of ATP-sensitive potassium channels (KATP channels) during septic shock and their involvement in vascular dysfunction. The review also discusses some therapeutic approaches based on pathogenetic mechanisms of severe sepsis and their efficacy in treatment of patients with septic shock. The loss of vascular tone control occurs through the complex, multifactorial mechanism and implicates deeply disrupted balance between vasoconstrictors and vasodilators in the pathogenesis of septic shock. Overproduction of nitric oxide (NO) by the inducible form of nitric oxide synthase (iNOS); up-regulation of prostacyclin (PG12); vasopressin deficiency; elevated levels of circulating endothelin; increased concentrations of vasodilator peptides such as adrenomedulin (AM) and calcitonin gene-related peptide (CGRP); oxidative stress inducing endothelial dysfunction and vascular hyporeactivity to vasoconstrictors; inactivation of catecholamines by oxidation; over-activation of ATP-sensitive potassium channels (KATP channels) and their involvement in vascular dysfunction - all these factors combined together lead to steady refractory shock with the lethal outcome in patients.

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.

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

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

[Vasoplegic syndrome and its treatment with vasopressin during cardiac surgery with cardiopulmonary bypass]. / Cirugía cardiaca con circulación extracorpórea: síndrome vasoplégico y vasopresina.

Cardiac surgery with cardiopulmonary bypass is associated with systemic inflammatory response. In some cases this clinical condition is characterized by severe hypotension due to low systemic vascular resistance during and after cardiopulmonary bypass. A few of these cases do not respond to volume or catecholamines. This condition is known as vasoplegic syndrome. Its etiology is not fully understood today and carries associated morbidity and mortality In this syndrome, vasopressin levels are reduced, as in septic and hypovolemic shock. Supplementary vasopressin improves blood pressure and might be considered as an alternative treatment. Several reports have shown benefits when used alone or in combination with catecholamines. However, further studies are necessary to find the most appropriate use of the drug for vasoplegic syndrome.

Vasoplegic shock during liver transplantation: is the preoperative cGMP plasma level a potential predictor of hemodynamic instability?

BACKGROUND: Refractory hypotension is a frequent event during reperfusion of a liver graft. Measures that help maintain hemodynamic stability include correction of electrolytes and acid-base abnormalities as well as administration of fluid and/or catecholamines. Vasoplegic syndrome represents the most severe form of hemodynamic instability. Management of this condition is very difficult due primarily to the inadequate response to even very high doses of catecholamines. CASE REPORT: A 60-year-old patient presented for liver transplantation due to end stage liver disease. After an initially uneventful hepatic phase, the patient developed excessive tachycardia and refractory hypotension during cross-clamping of the vena cava. The situation rapidly deteriorated despite administration of fluid and extremely high doses of norepinephrine and vasopressin. A transesophageal echocardiogram (TEE) performed at that time failed to demonstrate any cardiac dysfunction or signs of pulmonary emboli. Subsequent blood cultures and imaging studies did not confirm any signs of sepsis. Further investigation revealed an increased preoperative level of cyclic guanosine monophosphate (cGMP). cGMP is the second messenger for nitric oxide, and is responsible for relaxation of vascular smooth muscle with subsequent vasodilatation. This finding suggests a release of nitric oxide in the systemic circulation which could have been a potential cause for vasoplegic shock. CONCLUSIONS: Release of nitric oxide in the systemic circulation can be a potential cause of vasoplegic syndrome. Future investigation will demonstrate whether a patient's preoperative cGMP plasma level can be a potential predictor of intraoperative hemodynamic instability.

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.

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.