Vasoplegia After Cardiovascular Procedures—Pathophysiology and Targeted Therapy

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Review Article

Vasoplegia After Cardiovascular Procedures— Pathophysiology and Targeted Therapy Shahzad Shaefi, MD, MPHn,1, Aaron Mittel, MD†, John Klick, MD‡, Adam Evans, MD, MBA§, Natalia S. Ivascu, MD¶, Jacob Gutsche, MD‖, John G.T. Augoustides, MD‖ n

Divisions of Cardiac Anesthesia and Critical Care, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA † New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY ‡ Case Western Reserve University School of Medicine, Cleveland, OH § Departments of Cardiothoracic Surgery and Anesthesiology, Perioperative, and Pain Medicine, Icahn School of Medicine, Mount Sinai Hospital, New York, NY ¶ Weill Cornell Medicine, New York, NY ‖ Cardiovascular and Thoracic Section, Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Vasoplegic syndrome, characterized by low systemic vascular resistance and hypotension in the presence of normal or supranormal cardiac function, is a frequent complication of cardiovascular surgery. It is associated with a diffuse systemic inflammatory response and is mediated largely through cellular hyperpolarization, high levels of inducible nitric oxide, and a relative vasopressin deficiency. Cardiopulmonary bypass is a particularly strong precipitant of the vasoplegic syndrome, largely due to its association with nitric oxide production and severe vasopressin deficiency. Postoperative vasoplegic shock generally is managed with vasopressors, of which catecholamines are the traditional agents of choice. Norepinephrine is considered to be the first-line agent and may have a mortality benefit over other drugs. Recent investigations support the use of noncatecholamine vasopressors, vasopressin in particular, to restore vascular tone. Alternative agents, including methylene blue, hydroxocobalamin, corticosteroids, and angiotensin II, also are capable of restoring vascular tone and improving vasoplegia, but their effect on patient outcomes is unclear. & 2017 Elsevier Inc. All rights reserved. Key Words: pathophysiology of vasoplegic shock; cardiopulmonary bypass; nitric oxide; vasopressin; methylene blue; angiotensin II; hydroxocobalamin

VASODILATORY SHOCK is a common complication of major cardiovascular surgery, affecting 5% to 45% of procedures.1–4 In the majority of these cases, shock is limited in severity and duration. However, a subset of patients exhibit profound vasoplegia, which carries with it significant morbidity and mortality.1 Its pathophysiology often is assumed to be 1

Address reprint requests to Shahzad Shaefi, MD, MPH, Beth Israel Deaconess Medical Center, Rosenberg 660, 1 Deaconess Road., Boston, MA 02215. E-mail address: sshaefi@bidmc.harvard.edu (S. Shaefi).

similar to sepsis-induced vasodilatory shock, although the inciting factor and some mediators may differ. Management of vasoplegic shock is largely via pharmacologic therapy in the form of vasopressor medications. Several recent trials have investigated the role of these drugs and the use of nonvasopressor adjuncts. These adjuncts occasionally lead to relatively rapid hemodynamic improvement where more traditional agents have failed. Particular attention recently has been directed toward methylene blue and hydroxocobalamin, among others. The findings from recent trials and the emergence of potentially new therapies are the impetus for

http://dx.doi.org/10.1053/j.jvca.2017.10.032 1053-0770/& 2017 Elsevier Inc. All rights reserved.

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this review and will be discussed in conjunction with an overview of the basic mechanism and approach to the management of vasoplegia after cardiovascular surgery. Methodology Even though postoperative vasoplegia is a common clinical problem, it has not been the focus of large-scale investigations. Indeed, an August 2017 search of the PubMed database using the terms “cardiovascular surgery AND vasoplegia” limited to publications in English and research conducted on humans returned only 58 citations, many of which were case reports or editorial opinions. Given the sparse results from this broadbased inquiry, the authors instead chose to query their author group for inclusion of impactful publications that focus on the recognition and management of vasoplegia. Ultimately, this pragmatic search strategy netted several recent clinical trials with a focus on the diagnosis, pathophysiology, and treatment of vasoplegic shock. This review therefore brings attention to evidence-based approaches used by this expert group of writers. Vasoplegia Definition and Risk Factors Definition Vasoplegic syndrome, also sometimes termed vasodilatory or distributive shock, is characterized by end-organ hypoperfusion due to profoundly low systemic vascular resistance (SVR) despite normal or supranormal cardiac output.1 Although postcardiotomy vasoplegia is a well-documented entity, the lack of a strict definition has hampered more robust investigation and accounts for its wide purported range of incidence. Generally, the syndrome is recognized by a persistent need for high-dose vasopressor drugs to maintain appropriate blood pressure. The low SVR state described in vasoplegic syndrome is found in a number of disease entities, including sepsis, glucocorticoid deficiency, hepatic failure, or long-lasting severe shock of any cause.5 Sepsis is the most common cause of vasoplegia and therefore has been the focus of many clinical trials.5 However, even though the hemodynamic consequences are similar, the differences between sepsis and cardiac surgery–related vasoplegia remain relatively unexplored. Therefore, it is prudent to acknowledge that treatments for sepsis, and the evidence supporting those choices, may not be entirely generalizable to a postoperative population. Incidence, Risk Factors, and Outcomes Vasoplegic syndrome is common after major cardiovascular surgery and is associated with poor outcomes, largely due to end-organ failure. Patients exhibiting postoperative vasoplegia experience high rates of renal failure, prolonged hospital stays, and death.6 Although the rate of postcardiac surgery

vasoplegia hovers somewhere in the range of 5% to 25% in groups without preoperative features of risk, in those with known predisposing factors, this rate is anywhere from 30% to 50%.6,7 Many preoperative factors have been associated with a higher incidence of postoperative vasoplegia, namely preoperative use of angiotensin-converting enzyme inhibitors, preoperative use of beta-blockers, and higher comorbid disease burden before surgery.7 Patients with low preoperative systolic ejection fraction consistently have shown a high affinity for the development of vasoplegia.2 Intraoperative aspects such as the need for vasopressors before or during cardiopulmonary bypass (CPB), warmer core temperatures while on bypass, and longer duration of CPB also confer a greater risk of developing vasoplegia.2

Pathophysiology of Vasoplegia Cellular Physiology From a cellular perspective, vasodilatory shock is complex but is fundamentally a deficit in vascular smooth muscle contraction. In general, vascular smooth muscle contracts when intracellular calcium levels rise, through surface-receptor binding and opening of voltage-gated calcium channels (where angiotensin and catecholamines bind). This rise in cytoplasmic calcium concentration generates a stepwise reaction in which calcium phosphorylates myosin, which in turn catalyzes the cross-linking of myosin-actin filaments and generates the contraction of the muscle and vasoconstriction.5 This process is balanced by regulatory vasodilatory molecules, such as nitric oxide (NO) or atrial natriuretic peptide. These molecules trigger vasodilation via several mechanisms, all leading to a rise in intracellular cyclic guanosine monophosphate (cGMP) concentrations. Inverse to the contractile process, this results in activation of myosin phosphatase, dephosphorylation of myosin, and vasodilation (Fig 1).5 Thus, the downstream effect of vasoconstriction is dependent on the influx of calcium into the cytoplasm via voltagegated channels. If these channels are deactivated, such as may occur with intracellular acidosis or depletion of adenosine triphosphate (ATP) through membrane hyperpolarization, vasoconstriction will not be possible even if the cell is exposed to high levels of catecholamines. High levels of other compounds, including NO, atrial natriuretic peptide, adenosine, and others, also can lead to activation and prolonged opening of these channels. Presumably, this is an important physiologic mechanism to counteract periods of temporary local tissue ischemia. However, this can become counterproductive if prolonged periods of vasodilation lead to a persistently low pressure system and compromise of flow to other vessel beds.7 NO, implicated as an activator of ATP-sensitive potassium channel (KATP) channel opening, is a particularly important intercellular mediator of vasodilatory shock. NO is synthesized by the nitric oxide synthase (NOS) family of enzymes, which

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Fig 1. The cellular mechanisms of vasodilatory shock. Vascular smooth muscle contracts when intracellular calcium levels rise and lead to cross-linking of actin and newly phosphorylated myosin. This process is triggered after vasoconstrictive mediators, such as angiotensin II or catecholamines, bind to surface receptors. Inversely, vasodilation occurs when molecules such as nitric oxide or atrial natriuretic peptide yield an increase in intracellular cyclic guanosine monophosphate and subsequent dephosphorylation of myosin.

are differentiated by their typical organ location and baseline activity. Constitutive, calcium-dependent isoforms of NOS are responsible for constant, low-level NO production, which is important for interneuronal signaling, regional blood flow autoregulation, and immunologic modulation. Inducible, calcium-independent NOS isoforms (iNOS) synthesize NO on demand and take several hours to respond to physiologic stress. This inducible NOS often is implicated as the mediator of distributive shock and may precipitate mitochondrial dysfunction, apoptosis, and multiorgan failure. However, it plays important physiologic roles and perhaps should be thought of as a “necessary poison,” having both direct and indirect injurious and protective effects.8 For example, induction of NOS is important to increase myocardial NO levels, which encourages left ventricular relaxation and appropriate filling during diastole.9,10 Ultimately, NO increases intracellular cGMP (thereby decreasing myosin phosphorylation), inactivates calmodulin, and encourages opening of calciumsensitive potassium efflux channels (KCA channels) to blunt the effects of vasoconstriction. Thus, the presence of NO leads to a state in which vascular smooth muscle contraction is antagonized.6 In addition to membrane hyperpolarization and high concentrations of NO, vasopressin is an important modulator of vasodilation. Prolonged shock is associated with a relative vasopressin deficiency, which may be inadequate for the severity of physiologic stress.11 Initially, vasopressin serum concentrations are quite high in acute hypotension but gradually taper to lower-than-normal levels. This drop off is believed to be caused by a depletion of neurohypophyseal stores after prolonged arterial baroreflex stimulation.11,12 This is mechanistically important because vasopressin directly inactivates KATP channels,13 blunts the NO-induced increase in cGMP (by binding to AVPR1 receptors), and reduces NO synthesis.14

Vasopressin thus mitigates the effects of membrane hyperpolarization, myosin dephosphorylation, and NO accumulation and is an important modulator of vasomotor tone.5 Precipitants of Vasoplegia During Cardiovascular Surgery Triggering factors for vasoplegia after cardiovascular surgery are poorly understood. Considerable investigation into the underlying mechanism has been performed, largely focusing on the physiologic response to extracorporeal circulation. CPB causes a broad-based immunologic response secondary to ischemia-reperfusion injury of the heart and lung, endotoxin release from mucosal surfaces, and complement cascade activation after exposure of blood to the CPB circuitry.15 These processes result in increased production of oxygen free radicals, endothelins, NO, platelet activating factors, thromboxane A2, prostaglandins, a wide variety of cytokines, and other vasoactive molecules. Of particular interest, CPB leads to increased production of inducible NO, the concentration of which directly correlates with the length of CPB.16 High serum concentrations of these molecules also have been found to correlate with the development of the systemic inflammatory response syndrome, supporting the hypothesis that postoperative vasoplegia is, at least in part, an inflammatory response.17 The downstream effects of these inflammatory and vasoactive agents are variable (eg, potential vasoconstriction or vasodilation differs by concentration and physiologic action of each molecule), but lead to derangement of baseline vascular reactivity and tone.16 Possibly, patients with chronically high levels of inflammatory mediators, such as those with preexisting heart failure, may be particularly prone to a predominantly vasodilatory effect.18 This may explain why patients with reduced ejection fraction are more likely to develop vasoplegia after CPB.2

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Nevertheless, a generalized inflammatory response with increased NO production is not the sole cause of post-CPB vasoplegia. Indeed, poor neurohumoral control of vascular tone in the form of a vasopressin deficiency plays a significant role. Serum vasopressin levels are known to increase during CPB, and in patients who do not develop vasoplegia, they remain elevated or normal postoperatively. However, serum vasopressin concentrations in patients who develop postoperative vasodilation have been found to be inappropriately low, suggesting a chronic depletion of neurohypophyseal vasopressin stores. This relative vasopressin deficiency is similar but more severe than that seen in septic shock, suggesting that CPB is a particularly stressful trigger and can lead to severe vasoplegia in susceptible patients (Fig 2).5,6,19,20 Thus, the development of postoperative vasoplegic shock is likely secondary to the coupling of a profound inflammatory response and a potential for relative vasopressin deficiency. These are themselves caused by the immunologic reaction that occurs in response to CPB and other nonspecific perioperative triggers in the background of chronic cardiovascular neurohumoral stress. When these risk factors are combined with patient-specific risk factors, such as an extensive noncardiac disease burden or need for complex surgical repair, there is a high likelihood of developing postoperative vasoplegic shock. Management of Vasoplegia Early management of the postoperative vasoplegic syndrome focuses on recognition of the problem. Namely, the clinician should confirm the presence of hypotension, low

SVR, and normal/supranormal cardiac output. Alternative etiologies of vasodilatory shock should be considered; early administration of antibiotics is important if infection is suspected.21,22 It may be necessary in some patients, such as those who have had long aortic cross-clamp times or have undergone complex procedures, to transduce central (eg, femoral) pressure because it may be significantly higher than radial artery pressure. This is a common issue after CPB and may mitigate the need for aggressive anti-vasoplegic therapy.23 Ultimately, an adequate understanding of the existence and severity of vasoplegia is important in order to guide therapy. Prevention In an ideal setting, the clinician caring for the patient at risk of postoperative vasoplegia would be able to intervene before the onset of shock. However, many of the risk factors previoulsy listed are not modifiable in the immediate preoperative period or are inherent components of the surgical procedure to be performed. Furthermore, the pathophysiology of the vasoplegic syndrome is nuanced and associated with basic physiologic mechanisms of homeostasis. Manipulation of these mechanisms generally has not been associated with clinical benefit, such as unsuccessful trials of NO antagonism.10 One group of investigators did find a reduction in the incidence of postoperative shock after empiric, early administration of vasopressin to patients at high risk of postoperative vasoplegia.24 However, it is difficult to determine whether this approach was reflective of a particular preventative benefit

Fig 2. Mechanisms of cardiopulmonary bypass-related vasoplegia. Cardiopulmonary bypass triggers a profound inflammatory reaction that results in increased production of nitric oxide, depletion of ATP, and increased acidemia of vascular smooth muscle, resulting in a decrease in phosphorylation of myosin and subsequent vasodilation. Simultaneously, neurohypophyseal stores of endogenous vasopressin are depleted rapidly, compounding the vasodilatory effect and creating vasoplegic shock. ATP, adenosine triphosphate; cGMP, cyclic guanosine monophosphate; H þ , hydrogen ion; KATP, ATP-sensitive potassium channel.

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from vasopressin as opposed to treatment of unrecognized shock with any vasopressor.25 Others have advocated that angiotensin-converting enzyme inhibitors should be withheld preoperatively from patients at high risk of perioperative vasoplegia.26 However, the appropriate timeline to withhold administration of these agents and the potential outcomes associated with this approach have not been investigated. Thus, the clinician with concern for potential vasoplegia should be aware of the treatment options described in the following. Fluid and Blood Product Resuscitation Identifying fluid responsiveness is an important component of early treatment of postoperative vasoplegia. Due to perioperative hemorrhage, hypovolemia may be concomitant with vasoplegic shock; judicious transfusion of blood products should be used to correct severe anemia. Generally, restrictive transfusion strategies are preferred over more liberal strategies.26 However, overly aggressive fluid resuscitation (beyond 20-30 mL/kg) leads to excessive vascular shear stress, unnecessary increases in cardiac filling pressures, and harmful accumulations of extravascular lung water.27 Ultimately, inordinate fluid administration is associated with increased mortality in pure vasodilatory shock and should be avoided.28 Vasoactive Drugs The cornerstone of vasoplegic shock management is the use of vasoactive agents to restore vascular tone. These agents act on various receptors to increase SVR and raise mean arterial pressure (MAP), and thus are broadly termed “vasopressors.” Catecholamines are the mainstay of treatment but may be required in high doses and may yield insufficient hemodynamic stability. Other, noncatecholamine vasopressors historically have not been used for vasodilatory shock but may be particularly beneficial and have been more intensely scrutinized in recent years; they are described here (Table 1). An important caveat to the decision to choose any one particular vasoactive agent over another is the observation that many of these recommendations are based on results from randomized trials of vasopressors for septic shock. Thus, although likely generalizable to patients with postCPB vasoplegia, they may not be directly comparable. This is particularly important when considering the potential for concomitant cardiogenic shock. Ventricular dysfunction is common after cardiovascular surgery and in sepsis.29 Thus, even though increasing SVR remains the goal of treating vasoplegic states, the use of vasopressors must be balanced with the need to ensure appropriate left ventricular afterload to allow for effective end-organ perfusion. Even though outside the scope of this review, assessment of cardiac performance (such as that which is easily performed with echocardiography) therefore is a critical component of managing vasoplegia.30

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Catecholamines Catecholamines exert their physiologic effects by modulation of adrenergic receptors. Traditionally they have been the agents of choice to treat vasodilatory shock. Norepinephrine, phenylephrine, epinephrine, and dopamine all have been used successfully to increase MAP without limiting end-organ perfusion. Norepinephrine has been studied extensively in sepsis-induced vasodilatory shock. It may provide a mortality benefit compared with other catecholamines and is the recommended first-line agent specifically in septic shock.22,31,32 However, trials comparing norepinephrine with combinations of other catecholamines, such as epinephrine or dobutamine, have failed to show a definitive benefit.33 On the other hand, dopamine carries an increased risk of arrhythmia and mortality compared with norepinephrine in randomized controlled trials and probably should not be used as a first-line agent.34 A frequent concern about using high-dose vasopressors is the potential for severe peripheral vasoconstriction and endorgan injury. However, there is insufficient evidence to support this theory. Nevertheless, the need for high-dose catecholamines should prompt the clinician to consider switching to, or adding, a noncatecholaminergic agent.35 Vasopressin The use of noncatecholaminergic agents for the treatment of vasodilatory shock bypasses some of the difficulties when dealing with severe vasoplegia, including membrane hyperpolarization and associated catecholamine resistance.5 Noncatecholamines also may simply exert a synergistic effect and allow for reduced doses of any one particular agent, creating a more balanced approach to vasopressor therapy.35 This perhaps is especially notable with vasopressin, the use of which is biochemically supported by the presence of a vasopressin deficiency after CPB.6,19 Vasopressin binds to AVPR1a, AVPR1b, and AVPR2; oxytocin; and purinergic receptors. The AVPR1a receptor is especially important because it promotes vasoconstriction by inhibiting KATP channel opening and reduces NO production, providing an entirely catecholamine-independent mechanism of mediating vasodilation. Several recent randomized controlled trials focused explicitly on outcomes after use of vasopressin for septic shock. In the VASST trial, patients with septic shock who already were receiving norepinephrine were randomly assigned to either norepinephrine or vasopressin. The investigators did not identify a difference in their primary outcome of mortality between the groups at 28 days but did observe a significant reduction in catecholamine dose necessary to achieve target MAP in the vasopressin group and did not identify harm associated with vasopressin.36 Of note, post hoc analysis of VASST found improved renal outcomes in patients in the vasopressin group who had mild kidney injury at enrollment.37 The 2016 VANISH trial explored this finding further. Powered primarily to detect a difference in renal failure between vasopressin and norepinephrine for

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Suggested Dose Catecholamines Norepinephrine

Phenylephrine Epinephrine

Dopamine Noncatecholamines Vasopressin

Terlipressin

Methylene blue

Advantages

Disadvantages

Evidence

High doses may be required to achieve hemodynamic goals in severe vasoplegia

0.01-0.1 mg/kg/min Increases MAP predominantly via continuous infusion increased SVR but may also provide inotropic support 0.5-5 mg/kg/min Increases MAP by increasing SVR continuous infusion 0.01-0.5 mg/kg/min Increases MAP and provides inotropic continuous infusion support

Few studies focus on its use as a first-line agent for vasodilatory shock

0-20 mg/kg/min Dose-dependent increases in SVR and continuous infusion inotropy

Increased risk of arrhythmia compared with other catecholamines

Recommended first-line agent based on RCTs of septic shock. May have mortality benefit over other catecholamines used in isolation. Retrospectively associated with decreased survival compared with norepinephrine Comparable in efficacy to combination of norepinephrine and dobutamine when both vasopressor and inotropic support required Meta-analysis of RCTs suggests increased risk of mortality compared with norepinephrine

1.2-6.0 U/h continuous Reduces catecholamine dose required to infusion achieve MAP goal May reduce severity of renal failure 1.3 mg/kg/h continuous Comparable with vasopressin but has a infusion longer half-life

As a first-line agent, no significant mortality benefit compared with norepinephrine

Use is supported by several RCTs and the observation of severe vasopressin deficiency post-CPB

1.5-2 mg/kg bolus

Hydroxocobalamin 5 g infusion over 5 min Angiotensin II Continuous infusion starting at 20 ng/kg/ min Corticosteroids Varies by study and drug of choice Hydrocortisone 50 mg q 6 h is frequently chosen Vitamin C 6 g intravenous bolus per day

In single boluses, may rapidly improve MAP in severe vasoplegia Raises MAP and avoids some risks associated with methylene blue May dramatically improve MAP and reduce catecholamine requirements

Few studies support its use as a single agent

More selective than vasopressin for AVPR1 receptors, Small studies suggest it is equally as effective as theoretically causing profound SVR increase and norepinephrine for raising MAP decrease in CO May precipitate serotonergic syndrome and hemolytic No high-quality RCTs investigating its use anemia and interferes with pulse oximetry Retrospectively associated with mortality benefit when given early in vasoplegic shock More expensive than methylene blue Only described in case reports Not well-investigated Limited data One recent RCT suggested hemodynamic improvement May interfere with endogenous vasopressin synthesis compared with placebo

Likely hasten the resolution of shock

Not associated with mortality benefit in either septic shock or in non-vasoplegic cardiac surgery populations

No studies have specifically investigated their use in post-CPB vasoplegia

May hasten the reversal of shock when combined with hydrocortisone and thiamine

Limited safety and efficacy data

One recent retrospective study suggested hemodynamic and mortality benefit in septic shock patients

NOTE. Vasoactive agents useful for the treatment of vasoplegic syndrome after cardiovascular surgery. As described in the text, catecholamines (norepinephrine in particular) are the mainstay of therapy. Noncatecholamines, particularly vasopressin, may provide benefit by reducing the catecholamine dose required to achieve hemodynamic goals. Evidence supporting the use of any particular noncatecholamine, aside from vasopressin, is relatively weak. Abbreviations: CO, cardiac output; RCT, randomized controlled trial.

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Table 1 Vasoactive Drugs for the Management of Vasoplegia

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septic shock, the authors randomly assigned patients to vasopressin and hydrocortisone, vasopressin and placebo, norepinephrine and hydrocortisone, or norepinephrine and placebo. There was no significant difference in renal failure between the vasopressin and norepinephrine groups, but dialysis was used less frequently in the groups that received vasopressin, which suggests it may reduce the severity of renal failure compared with norepinephrine.38 Ultimately, VASST and VANISH were large, well-performed trials that failed to identify a definite benefit of vasopressin over catecholamines for septic-type vasodilatory shock, although the observation that vasopressin may limit the severity of renal failure is intriguing. Of importance, the vasopressin deficiency seen after CPB is even more severe than that seen during septic shock. Patients with post-CPB vasoplegia therefore may theoretically obtain greater benefit from vasopressin administration than the septic shock population.19 Several small, early trials demonstrated vasopressin to be safe and potentially effective after CPB but generally were underpowered to address clinical outcomes and did not include head-to-head comparison with norepinephrine.19,39 To address these issues, Hajjar et al conducted the recent VANCS trial, in which patients with post-CPB vasoplegic shock were randomly assigned to vasopressin or norepinephrine as a primary agent. Patients who were randomly assigned to vasopressin demonstrated a significant reduction in a composite end point of 30-day mortality or severe postoperative complications, driven almost exclusively by a decrease in the occurrence of acute renal failure.40 Taken as a group, VASST, VANISH, and VANCS represent a large population of patients with either septic or CPB-induced vasoplegic shock who generally benefit from vasopressin as a single or additive vasopressor. However, this largely is limited to a reduction in the need for catecholamines or a decrease in the severity or incidence of renal failure, rather than an improvement in mortality. Nevertheless, a reduction in renal failure (and the potential need for dialysis) is an important finding that should promote the perioperative use of vasopressin. The results of the VANCS trial are especially encouraging in patients with vasoplegia after cardiac surgery and lend support to the practice of early, and possibly preferential, use of vasopressin over catecholamines. Methylene blue Several endogenous compounds, including NO, carbon monoxide, and oxygen-free radicals, produce local vascular vasodilation, which may be an important counterbalance of systemic vasoconstriction in early shock states but can become pathologic if widespread vasodilation results in global hypoperfusion. Most of these substances, of which NO has been the most extensively investigated, mediate vasodilation via cGMP second messenger pathways and thus are broadly antagonized by agents that disrupt this signaling cascade.41 Methylene blue is one of these agents and, more than any other drug, often is considered to be a rescue agent capable of treating post-CPB vasoplegia. It directly competes with NO for activation of

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guanylyl cyclase, the enzyme responsible for synthesizing cGMP from guanosine triphosphate (GTP). Furthermore, it inhibits inducible NO synthase, potentially reducing the upswing in NO concentration that occurs with CPB and other physiologic stress. Methylene blue therefore prevents NO-mediated dephosphorylation of myosin and associated vasodilation.5 However, the potential downstream effects of its broad-sweeping action on basic physiologic mechanisms of vascular reactivity are unknown. Adverse reactions with methylene blue are uncommon but can be serious. They largely are explained by the global antagonism of NO-mediated vasodilation and include coronary vasoconstriction, decreases in splanchnic blood flow, and increases in pulmonary vascular resistance. Furthermore, methylene blue is reduced in red blood cells to leukomethylene blue, which requires nicotinamide adenine dinucleotide phosphate (NADPH). This can precipitate hemolytic anemia, especially in patients with G6PD deficiency. Methylene blue and leukomethylene blue are excreted in the urine, reliably coloring urine green. Methylene blue also interferes with pulse oximetry readings, even though this is transient, and has been associated with a nonspecific elevation in liver function tests.42 In addition, methylene blue is a potent inhibitor of monoamine oxidase and may precipitate serotonin syndrome, particularly in patients taking selective serotonin reuptake inhibitors. Even though these side effects are uncommon, they are relatively wide ranging and associated with severe disruption of normal cardiovascular physiology.43 Early case reports identified successful use of methylene blue to rapidly reverse severe vasoplegia after CPB with only single 1.5 to 2 mg/kg boluses.44,45 These reports prompted small-scale prospective interventional studies that confirmed methylene blue’s ability to rapidly and dramatically improve MAPs of post-CPB vasoplegic patients and suggested a possible mortality benefit of the drug.46–49 Retrospectively, methylene blue may be most efficacious if administered early in the course of vasoplegic shock (eg, while still in the operating room as opposed to postoperatively), when it may reduce the risk of mortality or end-organ failure.50 However, not all studies have been supportive of the use of methylene blue. In one retrospective analysis, methylene blue was associated with an increased likelihood of developing renal failure and mortality. However, the vasoplegic patients in that study who had received methylene blue were sicker than their counterparts who were not given the drug, and the authors were not able to solidify their findings with propensity matching.51 Without question, readily available noncatecholamine vasopressors (eg, vasopressin and methylene blue) have a role in treating post-CPB vasoplegia. However, until more rigorous trials are performed, they are limited to additive and/or rescue roles. A recent systematic review and meta-analysis, which did not include the VANISH or VANCS trials but did include more than 1,600 patients in 20 trials, concluded that vasopressin, terlipressin (discussed later), and/or methylene blue improved survival compared with catecholamines. However, this analysis incorporated patients with diverse etiologies of vasoplegic shock and included some potentially biased studies.

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In addition, neither vasopressin, terlipressin, nor methylene blue was superior to catecholamines when analyzed independently.52 Thus, evidence supports the use, but not superiority, of noncatecholamine vasopressors to improve outcomes in vasodilatory shock.

it is plausible that corticosteroids may hasten reversal of post-CPB shock, as they do in sepsis, but fail to reduce mortality rates.

Corticosteroids

Several potential therapies have not permeated into conventional practice yet but are supported by case series or early investigations. They may become viable treatment options in the near future and are discussed here.

The use of corticosteroids to treat vasodilatory shock has been controversial for several decades and is based on the assumption that the hypothalamic-pituitary-adrenal axis may be suppressed in periods of critical illness. Putatively, corticosteroids ameliorate the underlying inflammatory process that causes loss of vascular tone and may increase the efficacy of vasopressors by increasing the expression of vascular adrenergic receptors. However, clinical investigations of corticosteroids for vasoplegia have not shown a mortality benefit but have found an increased risk of infection. This was most recently demonstrated in the CORTICUS trial, published in 2008, which evaluated the use of a 5-day course of 50 mg of hydrocortisone every 6 hours in patients with septic shock. The authors found no significant mortality benefit with hydrocortisone compared with placebo, both in patients who were unresponsive to corticotropin stimulation and in those who were responsive (presumably adrenally suppressed and not suppressed, respectively). However, patients who received hydrocortisone had more rapid reversal of shock.53 This finding also was seen in an earlier trial, published in 2002, which also found a mortality benefit with corticosteroids in corticotropin nonresponders who were hypotensive despite fluid resuscitation and administration of vasopressors. In addition, formative work precluding the VANISH trial demonstrated evidence for interaction of corticosteroids and vasopressin, with a halving of vasopressin dose in those receiving steroids, interestingly without a change in overall vasopressin levels. Cumulatively, these studies support the notion that corticosteroids may hasten the resolution of vasodilatory shock, even though they do not provide an overall mortality benefit, possibly unless the patient is hypotensive despite vasopressors.54 The use of corticosteroids for treatment of nonseptic vasoplegic shock has not been evaluated explicitly. However, their role in the cardiac surgery population must be considered in light of the potential for increased perioperative complications (including delayed wound healing, poor glucose control, and gastrointestinal bleeding) and recent findings from the 2015 SIRS trial.55 In that trial, methylprednisolone did not confer a benefit with respect to mortality or end-organ function when given before and during CPB to high-risk patients undergoing cardiac surgery.55 Similarly, the earlier DECS trial did not find significant benefit from intraoperative use of dexamethasone given to patients undergoing cardiac surgery with use of CPB.56 However, both the DECS and SIRS trials were designed to detect a reduction of adverse outcomes (eg, death, stroke, myocardial infarction) rather than the effect on vasoplegia. In summary, neither of these studies focused explicitly on postoperative vasoplegic shock. Thus,

Future Directions

Vitamin C Vitamin C (ascorbic acid) has known anti-inflammatory effects and may improve autoregulation of microcirculatory blood flow. These qualities, putatively similar to those of corticosteroids, may reduce the dose of vasopressors required to achieve hemodynamic goals.57 A recent preliminary, retrospective study of patients with severe septic shock identified a dramatic reduction in mortality in patients who were treated with a daily intravenous combination of 6 g vitamin C, 50 mg hydrocortisone every 6 hours, and 200 mg thiamine every 12 hours. Of importance to the present review, the authors of this trial found a significant and rapid reduction in vasopressor requirements in patients who received the study regimen.57 The effects of the individual agents (eg, vitamin C without use of hydrocortisone) on hemodynamics is unknown. Ultimately, the generalizability of these results to a postcardiotomy population is unclear. Future research may encourage the use of vitamin C as another noncatecholamine vasopressor. Hydroxocobalamin There are isolated case reports of hydroxocobalamin’s successful use in the setting of vasoplegic syndrome.58,59 Although traditionally used in the treatment of cyanide poisoning, the mechanisms of hydroxocobalamin-induced hypertension are yet to be fully elucidated but may lie in its ability to bind the vasodilatory compound hydrogen sulfide. Unlike methylene blue, it does not carry a risk of serotonin syndrome, although it is more expensive and may cause chromaturia.60 In terms of dosing, successive aliquots of 250 mg of intravenous hydroxocobalamin have been administered alongside infusions of 500 mg/h in liver transplantation. The same group has reported the use of 5 g administered intravenously over 15 minutes in the cardiac surgical setting.61 Although premature to advocate for its widespread use, hydroxocobalamin may be another possible rescue therapy in the setting of profound refractory vasoplegia. Terlipressin Terlipressin is an established vasopressin analog used primarily outside of North America with similar pharmacodynamic properties to vasopressin. However, it has a much longer half-life than vasopressin (4-6 h as opposed to 6 min) and thus can be intermittently bolused without the need for

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continuous infusion. In addition, it has preferential selection for AVPR1-type receptors and thus may allow for more selective vasoconstriction, without NO liberation that may occur with agonization of AVPR2 receptors. Small studies comparing terlipressin and norepinephrine have shown them to be equally effective at raising MAP.62 However, the isolated increase in SVR that occurs with terlipressin, without perhaps being offset by beta-adrenergic effects of norepinephrine or AVPR2 effects of vasopressin, possibly could be harmful. Because of its long half-life, long-lasting reduction in cardiac index and oxygen delivery caused by high SVR could be detrimental and may require the addition of an inotropic agent.63 When compared head-to-head with vasopressin, terlipressin performed similarly but was associated with a reduction in platelet counts.62,64 Ultimately, larger controlled trials need to be performed before terlipressin can be considered an appropriate anti-vasoplegia agent. Angiotensin II Angiotensin II is an endogenous hormone that makes up a component of the renin-angiotensin-aldosterone axis and is a direct, potent vasoconstrictor. It has a serum half-life of approximately 30 seconds, though up to 30 minutes of effect while in parenchymal tissue. Angiotensin II has wide-ranging homeostatic effects, including stimulation of aldosterone release and antidiuretic hormone secretion. Much of its downstream effects are designed to increase sodium and water retention while ensuring appropriate vascular tone, and therefore recently it has been scrutinized as a possible noncatecholamine rescue vasopressor. Chawla et al performed a small study of angiotensin II, starting at 20 ng/kg/min, versus placebo to evaluate the concomitant need for norepinephrine and found a significant, dramatic reduction in norepinephrine requirement in the group receiving angiotensin II.65 A followup trial randomly assigned patients with septic shock to either angiotensin II or placebo with a primary end point of an increase in MAP at 3 hours after infusion. Although somewhat limited, with an inclusion criterion of a relatively normotensive MAP range of 55 to 70 mmHg, the results were encouragingly in favor of angiotensin II.66 Additional research is needed to determine the effects of angiotensin II on patient outcomes before it can be added to the anti-vasoplegia armamentarium. The role of exogenous vasopressin, if combined with angiotensin II, also needs to be elucidated because angiotensin II naturally encourages the release of vasopressin from the neurohypophysis. Conclusion Vasoplegic shock is common after cardiovascular surgery. Even though it often is a component of the inflammatory response that occurs with CPB, alternative diagnoses with similar presentations, such as sepsis, should be considered. After appropriate fluid resuscitation has been performed, vasopressors become the primary form of treatment. Catecholamines, norepinephrine in particular, are the best studied and

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are the suggested first-line treatment agents. Recent investigations have supported the use of noncatecholamine drugs, especially when used in conjunction with norepinephrine. Vasopressin and methylene blue are relatively well-studied and are attractive additive and/or rescue agents. Both of these drugs and other agents capable of increasing SVR may see expanded roles in the near future when treating severe vasoplegia. References 1 Gomes WJ, Carvalho AC, Palma JH, et al. Vasoplegic syndrome after open heart surgery. J Cardiovasc Surg 1998;39:619–23. 2 Levin MA, Lin HM, Castillo JG, et al. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome. Circulation 2009;120:1664–71. 3 Mets B, Michler RE, Delphin ED, et al. Refractory vasodilation after cardiopulmonary bypass for heart transplantation in recipients on combined amiodarone and angiotensin-converting enzyme inhibitor therapy: A role for vasopressin administration. J Cardiothorac Vasc Anesth 1998;12:326–9. 4 Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: Pathophysiology, risk factors and treatment. Am J Med Sci 2015;349:80–8. 5 Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001;345:588–95. 6 Fischer GW, Levin MA. Vasoplegia during cardiac surgery: Current concepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4. 7 Weis F, Kilger E, Beiras-Fernandez A, et al. Association between vasopressor dependence and early outcome in patients after cardiac surgery. Anaesthesia 2006;61:938–42. 8 Szabo C. Role of poly(ADP-ribose) synthetase activation in the suppression of cellular energetics in response to nitric oxide and peroxynitrite. Biochem Soc Trans 1997;25:919–24. 9 Hauser B, Bracht H, Matejovic M, et al. Nitric oxide synthase inhibition in sepsis? Lessons learned from large-animal studies. Anesth Analg 2005;101:488–98. 10 Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock. Critical Care Med 2004;32:21–30. 11 Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122–5. 12 Wilson MF, Brackett DJ, Tompkins P, et al. Elevated plasma vasopressin concentrations during endotoxin and E. coli shock. Adv Shock Res 1981;6: 15–26. 13 Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates K(þ)-channel activities of cultured smooth muscle cells from porcine coronary artery. Am J Physiol 1992;263:H491–6. 14 Umino T, Kusano E, Muto S, et al. AVP inhibits LPS- and IL-1betastimulated NO and cGMP via V1 receptor in cultured rat mesangial cells. Am J Physiol 1999;276:F433–41. 15 Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: Pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg 1997;85:766–82. 16 Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: Mechanisms involved and possible therapeutic strategies. Chest 1997;112:676–92. 17 Kerbaul F, Guidon C, Lejeune PJ, et al. Hyperprocalcitonemia is related to noninfectious postoperative severe systemic inflammatory response syndrome associated with cardiovascular dysfunction after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2002;16:47–53. 18 Sundaram V, Fang JC. Gastrointestinal and liver issues in heart failure. Circulation 2016;133:1696–703. 19 Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: Identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998;116: 973–80.

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