Vasoplegia During Cardiopulmonary Bypass: Current Literature and Rescue Therapy Options

ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 110

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Review Article

Vasoplegia During Cardiopulmonary Bypass: Current Literature and Rescue Therapy Options Jamel Ortoleva, MD*, Alexander Shapeton, MDy, ,1 Mathew Vanneman, MDz, Adam A. Dalia, MD, MBA, FASEz * Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Boston, MA Department of Anesthesia, Critical Care and Pain Medicine, Veterans Affairs Boston Healthcare System, Harvard Medical School, Boston, MA z Department of Anesthesiology, Pain Medicine, and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA y

Vasoplegia syndrome in the cardiac surgical intensive care unit and postoperative period has been an area of interest to clinicians because of its prevalence and effects on morbidity and mortality. However, there is a paucity of evidence regarding the treatment of vasoplegia syndrome during cardiopulmonary bypass (on-CPB VS). This review aims to detail the incidence, outcomes, and possible treatment options for patients who develop vasoplegia during bypass. The pharmacologic rescue agents discussed are used in cases in which vasoplegia during CPB is refractory to standard catecholamine agents, such as norepinephrine, epinephrine, and phenylephrine. Methods to improve vasoplegia during CPB can be both pharmacologic and nonpharmacologic. In particular, optimization of CPB parameters plays an important nonpharmacologic role in vasoplegia during CPB. Pharmacologic agents that have been demonstrated as being effective in vasoplegia include vasopressin, terlipressin, methylene blue, hydroxocobalamin, angiotensin II (Giapreza), vitamin C, flurbiprofen (Ropion), and hydrocortisone. Although these agents have not been specifically evaluated for vasoplegia during CPB, they have shown signs of effectiveness for vasoplegia postoperatively to varying degrees. Understanding the evidence for, dosing, and side effects of these agents is crucial for cardiac anesthesiologists when treating vasoplegia during CPB bypass. Ó 2019 Elsevier Inc. All rights reserved. Key Words: vasoplegia; vasoplegia syndrome; hypotension during bypass; intraoperative vasoplegia; vasoplegia during bypass

VASOPLEGIA SYNDROME (VS) has been reported in up to 20% of patients undergoing cardiac surgery,1 with even higher rates in specific patient populations.2,3 Vasoplegia is defined by a low mean arterial pressure (MAP), a normal or elevated cardiac index (CI), and a low systemic vascular resistance (SVR) that is refractory to conventional doses of commonly used vasopressors, such as norepinephrine.4,5 Vague terms such as “low MAP” often appear in the literature regarding this definition because institutional, regional, and clinical practices vary with differing MAP goals ranging from 55 to 65 mmHg.4,5 Even though transient hypotension upon initiation 1

Address reprint requests to Adam Dalia, MD, MBA, FASE, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. E-mail address: [email protected] (A.A. Dalia). https://doi.org/10.1053/j.jvca.2019.12.013 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.

of cardiopulmonary bypass (CPB) commonly occurs because of hemodilution and cardioplegia administration, this typically resolves without intervention or with minimal doses of vasopressors. In contrast to transient hypotension, vasoplegia during CPB (on-CPB VS) refers to vasoplegia that occurs during cardiac surgery exclusively on bypass that is refractory to high-dose vasopressors. Although there is no broadly accepted definition, for the purposes of the present review, on-CPB VS is defined as a bypass flow sufficient for a CI
2.2 and a MAP <60 mmHg despite high doses of vasopressors (0.2-0.5 mg/ kg/min norepinephrine equivalents).5 Other studies that have examined vasoplegia both during CPB and in other settings have used similar definitions.6-9 The lack of a universal definition has resulted in significant heterogeneity in the reported incidence and clinical outcomes of vasoplegia during cardiac surgery across different studies.

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The pathophysiology and etiology of vasoplegia may occur intraoperatively during CPB, after weaning from CPB, or postoperatively in the intensive care unit (ICU).5 The etiology of vasoplegia is complex and not fully understood but likely involves nitric oxide (NO) dysregulation, vasopressin depletion, endothelial dysfunction, abnormal hydrogen sulfide metabolism, ascorbic acid sequestration, and prostaglandin release.5 Patients who specifically develop hypotension or vasoplegia during CPB are at increased risk of worse cardiac or neurologic outcomes compared with patients who develop vasoplegia after completion of CPB, despite both cohorts experiencing similar pathophysiologic mechanisms.10,11 Numerous patient-specific risk factors, such as sex, body mass index, and presence of a left ventricular assist device, also correlate with vasoplegia during CPB (Table 1).7,12 CPB itself may amplify vasoplegia for the following 2 reasons. First, hemodilution from crystalloid pump primes may reduce blood viscosity, reducing overall vascular resistance. Second, blood interaction with CPB components may result in the release of inflammatory mediators, worsening vascular tone and resulting in hypotension. Because at least part of the etiology of on-CPB VS is a result of direct patient contact with the bypass machine, some cases of vasoplegia during CPB may resolve after weaning from bypass; others, however, may persist into the post-bypass and ICU periods. Understanding the causes and treatment options for vasoplegia during bypass is important because patients who develop VS have significantly increased ICU length of stay (LOS), hospital LOS, risk of kidney injury, and mortality.1 Although numerous studies have investigated patients with postoperative vasoplegia, the prevalence and clinical outcomes of patients who develop on-CPB VS is less understood.1,4,5,14 The present review differs from previous reviews regarding vasoplegia, which often is described postoperatively in the ICU, because herein the incidence, outcomes, and possible treatment options for patients who develop vasoplegia during CPB are discussed. The pharmacologic treatment options for on-CPB vasoplegia are similar to those used to treat vasoplegia in the ICU. The pharmacologic rescue agents discussed are agents used in cases in which vasoplegia during bypass is refractory to standard doses of catecholamine agents such as norepinephrine, epinephrine, and phenylephrine. Prevalence and Outcomes of On-CPB VS Few studies have examined the prevalence of vasoplegia during CPB. Truby et al. assessed 138 patients undergoing Table 1 Risk Factors for Vasoplegia During Cardiopulmonary Bypass7,13 Left ventricular ejection fraction >40% Male sex Elderly Higher body mass index Presence of left ventricular assist device Longer duration of cardiopulmonary bypass Hypotension immediately upon initiation of cardiopulmonary bypass Perioperative angiotensin-converting enzyme inhibitor use Infected endocarditis

orthotopic heart transplantation and found that 16% developed vasoplegia during CPB.7 Compared with other heart transplantation patients, patients with on-CPB VS had significantly longer ICU LOS, increased rates of renal replacement therapy, and higher mortality at 30 and 60 days.7 Another study of 80 patients found that 10% of patients undergoing aortic valve procedures developed on-CPB VS compared with 20% of patients with prior cardiac surgery.8 Levin et al. assessed 2,800 patients undergoing cardiac surgery and found that 58% experienced at least transient vasoplegia during bypass.13 The higher frequency of vasoplegia in that study may have been attributed to a broader definition of vasoplegia, which was defined as any patient experiencing a >20% decrease in MAP within 5 minutes of CPB initiation for more than 2 minutes. Despite this broad definition, patients in the cohort who developed vasoplegia during bypass had increased rates of postoperative vasoplegia, prolonged hospital stay, and death. In another retrospective cohort study, Tsiouris et al. found that 20% of cardiac surgical patients experienced vasoplegia; of these, 77% experienced vasoplegia intraoperatively.1 A majority of these studies are heterogenous and restricted to smaller subgroups of cardiac surgical patients, impairing overall estimation of the prevalence and clinical implications of vasoplegia during CPB. Risk factors, prevalence, and outcomes for vasoplegia during CPB are derived from the literature and are presented in Tables 1 and 2.6-8,10,11,14,15 Effects of Hypotension During CPB Large studies specifically investigating vasoplegia during bypass are lacking, partially because a universally accepted definition of vasoplegia is lacking. Alternatively, some larger studies have evaluated the clinical outcomes of hypotension during CPB (defined as a MAP <65 mmHg). Because prolonged hypotension is a necessary element of vasoplegia, outcomes from these larger studies of on-CPB hypotension may be extrapolated to patients who develop the refractory hypotension central to vasoplegia during CPB. Systemic hypotension may not necessarily result in end-organ hypoperfusion. Local vascular autoregulation may result in microvascular vasoconstriction in the setting of systemic hypotension, maintaining adequate tissue perfusion. Despite possible autoregulatory mechanisms, patients who experience on-CPB hypotension may experience worse outcomes.7 In a large retrospective cohort of cardiac surgical patients, Sun et al. found that patients with a MAP <65 mmHg during CPB were significantly more likely to have end-organ injury, such as stroke, compared with patients with a MAP >65 mmHg.11 The risk of stroke was both MAP- and time-dependent during bypass; additional reductions of MAP <65 mmHg and increased time with MAP <65 mmHg were associated with incremental increases in stroke risk. Importantly, this risk was only amplified with hypotension during CPB; hypotension during either the pre- or postbypass period was not associated with stroke risk. In another study, Gold et al. randomly assigned patients undergoing coronary artery bypass grafting to a goal bypass MAP of 50 to 60 mmHg (low-MAP group) or 80 to 100

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Table 2 Studies Involving On-CPB Hypotension or Vasoplegia With Prevalence and Outcomes Study

Study Type and Population

Patients Reported Study Prevalence (Number)

Study Definition of Hypotension or Vasoplegia

Reported Study Outcomes

Christakis et al.6

Prospective cohort; CABG patients

555

28% of patients required >800 mg phenylephrine during CPB

No difference in stroke No difference in mortality

Gold et al.10

Randomized controlled trial; CABG patients

248

Levin et al.13

Retrospective cohort; 2,823 broad cardiac surgical patients Retrospective cohort; 30 isolated aortic valve surgery or redo cardiac surgery after right-sided congenital heart disease repair Retrospective cohort; 138 heart transplantation patients

124 patients with MAP 50-60 mmHg (“low” group), 124 patients with MAP 80-100 mmHg (“high” group) 58% at least transient VS

Vasoplegia defined as >800 mg of phenylephrine to maintain a MAP >50 mmHg with a CI >2.2 L/min/m2 during CPB Hypotension defined as “low” MAP (50-60 mmHg) compared with “high” MAP group (80100 mmHg) Hypotension defined as >2 min with a MAP >20% baseline within the first 5 min of CPB Vasoplegia defined as vasopressor amount/CPB time ratio >1 standard deviation from mean

Wittwer et al.8

Truby et al.7

10% in aortic valve surgery 20% in prior right-sided congenital heart disease

16% of heart transplantation patients

Rettig et al.14

Retrospective cohort; CABG patients

1,891

Vedel et al.15

Randomized controlled trial; CABG, aortic or mitral valve surgical patients

192

98% of patients with MAP <50 mmHg, median duration 28 min 98 patients goal MAP 40-50 mmHg (“low” group), 94 patients goal MAP 70-80 mmHg (“high” group)

Sun et al.11

Retrospective cohort; CABG or valve surgery

7,457

Not measured specifically

Increased rate of composite of cardiovascular and neurologic complications in “low” MAP group Increased risk of post-CPB VS Increased LOS Increased mortality Not investigated

Vasoplegia defined as mean SVR Increased ICU LOS <800 dynes s/cm5 despite CI Increased CVVH >3 L/min/m2 and cumulative Increased mortality dose of >1,500 mg phenylephrine during CPB Hypotension defined as duration No difference in acute kidney and area under curve for MAP injury No other outcomes investigated <50 mmHg Hypotension defined as “low” No difference in clinical stroke or MRI white matter infarct MAP (40-50 mmHg) compared with “high” MAP group (70-80 volume mmHg) No difference in any secondary outcomes (eg, hemodialysis, myocardial infarction, death) Hypotension defined as duration Dose-dependent increased risk of and area under curve for MAP stroke with lower MAP (<65 <65 mmHg mmHg) and longer CPB times with MAP <65 mmHg

Abbreviations: CABG, coronary artery bypass grafting; CI, cardiac index; CPB, cardiopulmonary bypass; CVVH, continuous veno-venous hemofiltration; ICU, intensive care unit; LOS, length of stay; MAP, mean arterial pressure, MRI, magnetic resonance imaging; VS, vasoplegia syndrome; SVR, systemic vascular resistance.

mmHg (high-MAP group).10 Compared with patients assigned to the high-MAP group, patients in the low-MAP group were almost 3-fold more likely to experience either cardiac or neurologic complications (4.8% v 12.9%). An important weakness of this that trial was the wide target of CI during CPB (1.6-2.4 L/min/m2), implying that some results in the “low-MAP” group may have been related to inadequate pump flow rates using modern perfusion standards and therefore would not be considered vasoplegia. The recent Perfusion Pressure Cerebral Infarcts trial assigned 197 patients to a fixed CI of 2.4 L/min/ m2 during CPB and randomly assigned patients to a MAP goal of 45 mmHg (low target) or 70 mmHg (high target) with vasopressor administration.15 That trial found no difference in the risk of clinical stroke or magnetic resonance imagingdetectable white matter changes, but it did not investigate any other clinical outcomes. Given these data, it remains unclear whether the administration of vasoactive agents to correct onCPB hypotension affects clinical outcomes. Large randomized trials with broader outcome measures are needed to fully

address this question. Nonetheless, there is no current evidence of harm using a vasopressor-based strategy to target a MAP of 65 mmHg during CPB periods with adequate flow rates. Treatment Options for On-CPB VS It is crucial when diagnosing vasoplegia during CPB to rule out other causes of perceived hypotension, such as errors in arterial line monitoring, anaphylaxis, aortic dissection, mechanical failure of the bypass machine, improper cannula size, erroneous medication administration, or unintentional torsion/clamping of cannula. If these causes are ruled out, it is imperative to evaluate the possible pharmacologic or nonpharmacologic methods to reverse on-CPB VS. Optimizing Bypass Parameters Both vascular and nonvascular components contribute to a patient’s MAP during bypass. The vascular components

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generally are nonmodifiable and include vessel length, diameter and number of vessels, and precapillary shunting.16 The nonvascular components include bypass flow rate, blood temperature, hematocrit, and blood viscosity. Optimizing these nonvascular components can curtail the duration and incidence of vasoplegia during bypass. One of the common theorized causes of on-CPB VS is the rapid change in viscosity of blood upon initiation of bypass because of crystalloid volume priming of the pump.16 The hemodilution that occurs during bypass reduces the viscosity of the circulating blood thereby decreasing the patient’s resistance, which is reflected by a decrease in the SVR. This is based on Poiseuille’s law/equation, where (h) is blood viscosity and (R) is a patient’s SVR, as follows:

CPB VS is attributed to the volatile anesthetic, a switch to total intravenous anesthesia with fewer hemodynamic side effects can be considered (remifentanil, dexmedetomidine, fentanyl, midazolam, or ketamine). In addition, it should be noted that patients undergoing hypothermic CPB require less anesthesia; studies have shown that a lower dose of propofol is needed to maintain a constant bispectral index.17 Potency of both inhaled and intravenous anesthetics are increased in hypothermic conditions and can lead to hypotension if levels are maintained at the levels they were before bypass during normothermia.

R ¼ ½8hL=pr 4

Arginine vasopressin (vasopressin), also known as antidiuretic hormone, is a nonapeptide hormone produced endogenously by the hypothalamus and stored in the posterior pituitary, which serves a critical role in blood pressure regulation, osmotic balance, and renal function. Terlipressin is a synthetic prodrug analog of vasopressin, which is cleaved by endothelial peptidases to its active form, lysine-vasopressin.18 Although terlipressin has been used successfully to treat postbypass vasoplegia, data directly comparing it to vasopressin in this setting are lacking. In addition, terlipressin is not approved by the U.S. Food and Drug Administration (FDA) for use in the United States and Canada; however, it is commonly used in Europe, Australia, and New Zealand. Binding to arginine vasopressin receptor 1a appears to play the primary role in treating vasoplegia because this mechanism promotes vasoconstriction via a decrease in production of NO; terlipressin has more selectivity for the arginine vasopressin receptor 1a than does vasopressin.5 Landry et al.19 first identified that patients experiencing vasodilatory shock have a quantitative deficiency in circulating vasopressin; Argenziano et al.20 later observed the same phenomenon in patients experiencing cardiogenic shock. A deficiency in circulating vasopressin was subsequently also recognized as a factor in the development of post-bypass vasoplegia, leading some investigators to evaluate prophylactic administration of vasopressin in cardiac surgery.21 An initial randomized controlled trial (RCT) exploring this topic by Morales et al. demonstrated improved hemodynamics and a decrease in inotropic requirements post-CPB in cardiac surgical patients who were prophylactically treated with vasopressin (0.03 U/min, initiated before CPB).22 Papadopolous et al. later published an RCT confirming the findings of Morales et al., in which they also reported significantly lower rates of post-CPB vasodilatory shock and significantly lower inotropic and catecholamine requirements in patients who received prophylactic vasopressin.23 Neither trial specifically addressed hemodynamics during CPB. More recently, investigators in the VANCS (Vasopressin vs Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery) trial, which randomly assigned more than 300 patients with postbypass vasoplegia to receive either norepinephrine or vasopressin, demonstrated a significantly lower primary outcome (composite mortality and severe complications) in the vasopressin group.24

Because of this change in blood viscosity, ways to improve on-pump hypotension is to either increase afterload with vasoactive drugs (commonly phenylephrine), increase the viscosity by retroactively priming the bypass circuit (autologous blood), or transfuse packed red blood cells in anemic conditions. The latter solution should be guided by the on-pump dilutional hematocrit level or degree of unrelenting hypotension; close monitoring of repeated decreases in the hematocrit level during CPB can signal an unknown source of bleeding either at the cannula site or in the thorax. A continued decrease in the hemoglobin level should prompt an evaluation of the quality of venous drainage and venous reservoir levels. Priming the bypass circuit with exogenous blood to increase circuit volume viscosity carries the usual risks as those for blood transfusion but should be taken into consideration for patients at high risk of bypass-induced vasoplegia (see Table 1). Other bypass parameters that can be adjusted include pump flow; the target CI can be increased if vasoplegia during bypass is encountered. Increases in pump flow can lead to hemolysis and manifest on-pump as hematuria or after separation of bypass. Alternatively, pre-bypass if a patient has risk factors for on-CPB VS, larger venous and arterial cannulae can be placed to enable higher flow rates (see Table 1).16 Duration of CPB is a variable that has been linked to vasoplegia and may not be adjusted easily for open heart procedures but can be suggested in possible off-pump scenarios, such as coronary artery bypass grafting, if sustained hypotension is observed. Adjusting Anesthetic Conditions During CPB Certain anesthetic agents, such as propofol and volatile anesthetics, during bypass can negatively affect MAP and should be modified if vasoplegia during bypass is encountered.17 It is known that pharmacokinetic and pharmacodynamics are altered during bypass.17 With the administration of inhaled anesthetics, parameters such as oxygenator design, disturbances in blood/gas partition coefficients, and tissue solubility are altered during bypass.17 Concurrently, intravenous anesthetics experience changes in volume of distribution, altered plasma protein binding, drug sequestration, lung isolation, and altered drug clearance.17 If a potential cause of on-

Vasopressin and Terlipressin

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At present, there are no RCTs or large retrospective studies evaluating vasopressin or terlipressin to specifically treat vasoplegia during CPB. Given the existing literature, it is reasonable to consider a prophylactic infusion of vasopressin before initiation of CPB in patients with multiple risk factors for vasoplegia. Vasopressin should be considered as a first line agent (along with phenylephrine and norepinephrine) for treating vasoplegia on bypass and is FDA-approved for treatment of vasoplegia. Side effects of vasopressin include, but are not limited to, myocardial ischemia, reductions in cardiac output and systemic oxygen delivery, decreased platelet count and renal blood flow, hyponatremia, splanchnic vasoconstriction, and ischemic skin necrosis if administered through an infiltrated peripheral intravenous line.24 The only absolute contraindication to vasopressin is hypersensitivity to the medication itself. Terlipressin is contraindicated when there is hypersensitivity to the medication; severe asthma; history of cerebral vascular disease; and during pregnancy, for which terlipressin has been shown to cause uterine contraction, increased intrauterine pressure, and decreased uterine blood flow.25 Methylene Blue Methylene blue acts as an inhibitor of NO synthase and soluble guanylate cyclase, 2 enzymes involved in endothelial muscle relaxation that are important in the cascade of refractory vasodilatory shock.26 In cardiac surgical patients with vasodilatory shock refractory to catecholamines, approximately 40% of patients have a positive blood pressure response to methylene blue as defined by a decrease in vasopressor doses by at least 20%.27 In the literature, methylene blue has been used off-label for cases of vasoplegia for nearly 2 decades.28 Intravenous methylene blue comes as a 5 mL ampule with a total of 50 mg in each vial, making a concentration of 10 mg/mL. For patients experiencing on-CPB VS, there are very limited data on the use of methylene blue. In a randomized trial of 30 patients receiving preoperative angiotensin-converting enzyme (ACE) inhibitors divided in 1:1 fashion that could not be blinded because of methylene blue coloring the urine, Maslow et al. found that a dose of 3 mg/kg of methylene blue administered after the initial dose of cardioplegia significantly increased MAP during bypass.29 In that study, lactate levels in the methylene blue group also were found to be lower, and vasopressor requirements were reduced both during and after separation from bypass. The increased dose of 3 mg/kg of methylene blue was used because of the larger volume of distribution that is present in patients on bypass. A case report on the use of methylene blue at 2 mg/kg added to the CPB prime in a patient with infectious endocarditis described the resolution of severe vasodilation during and after bypass; of note, before the induction of general anesthesia, the patient had a blood pressure of 170/53 and was receiving no vasoactive agents.30 Another case report described a patient undergoing double lung transplantation who experienced vasoplegia on bypass, and 2 mg/kg of methylene blue was administered, which resulted in a significant reduction in vasopressor

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requirements.31 A current ongoing randomized trial by Low et al., the Hemodynamic effects of Methylene Blue versus Hydroxocobalamin in Patients at Risk of Vasoplegia During Cardiac Surgery (protocol NCT03446599), is being performed to measure the hemodynamic effects of 2 mg/kg methylene blue, 5 g hydroxocobalamin, or placebo (normal saline) during and after CPB in patients at risk for vasoplegia. That trial is scheduled to be completed by June 2020. Before methylene blue use, flows should be maximized, which typically, per the manufacturer, cannot be more than approximately 6 L/min (ideally large cannulae are used in patients at risk for vasoplegia); the administration of catecholamine and noncatecholamine vasoconstrictors should be attempted; and other, more easily reversible causes of vasodilatory shock should be explored (eg, adrenal insufficiency, severe anemia, and anaphylaxis).32 It is important to know the risks of high flows, including hemolysis (although this ceases with the termination of CPB), increased inflammation, and platelet activation and destruction. In addition, the off-label use of methylene blue during CPB must be discussed with the surgeon and the perfusion team so as not to respond to artefactual alterations in oxygen sensors and to be prepared for possible rare side effects, such as methemoglobinemia.32,33 Although limited, there is some evidence that starting methylene blue early in the diagnosis of vasoplegia may be beneficial.34 Methylene blue exhibits important side effects, which include serotonin syndrome, hemolysis in patients experiencing glucose-6-phosphate dehydrogenase deficiency (approximately 5% of the population), interference with pulse oximetry, elevations in pulmonary vascular resistance through inhibition of NO synthase, methemoglobinemia, and even anaphylaxis.26,32,33,35 Given that the largest amount of research on the subject has involved a dose of 3 mg/kg of methylene blue for vasoplegia, the authors of the present review recommend a 2 to 3 mg/kg dose for vasoplegia during bypass. The use of a methylene blue infusion after this bolus dose also is reasonable to maintain the hemodynamic response, with typical dosing being 0.5 mg/kg/h for 6 hours.26 Hydroxocobalamin Hydroxocobalamin is a highly bioavailable form of vitamin B12 that currently carries FDA approval for the treatment of only cyanide toxicity. An emerging off-label use for hydroxocobalamin is rescue therapy in cases of vasoplegia post-bypass or during liver transplantation when other therapies have been unsuccessful or are contraindicated. Hydroxocobalamin and other cobalamins are potent direct inhibitors of NO and NO synthase. In addition, hydroxocobalamin directly binds sulfide and increases elimination of hydrogen sulfide, an endothelium-derived hyperpolarizing factor that has been shown to act as an endogenous vasodilator36,37 This important mechanism of action addresses a potential key cause of vasoplegia during bypass—NO-mediated vasodilation. Hydroxocobalamin in the post-CPB setting was first described by Roderique et al. in 2014, and since then, several other case reports and case series have been published.38 In the

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largest of these case series, Shah et al. reported that 24 of 33 (72.7%) patients diagnosed with vasoplegia after cardiac surgery and treated with hydroxocobalamin had an improvement in MAP and a decrease in vasopressor requirements.39 A review by Shapeton et al. from early 2019 identified 7 individual case reports and 4 case series that described near universal improvements in MAP and decreases in vasopressor requirements after treatment with hydroxocobalamin.40 Subsequently, there has been rapid growth in this body of literature, with Cios et al.,41 Armour et al.,42 and Feih et al.43 all publishing separate case series with promising results. As of publication of the present review, no RCTs or large retrospective studies exist to assess efficacy, guide therapy, or determine the most appropriate dosage for hydroxocobalamin in the treatment of vasoplegia during bypass. Because high-quality evidence is lacking, hydroxocobalamin should only be considered as a rescue agent in vasoplegia during bypass. Common side effects such as chromaturia (red or orange), erythema, elevated blood pressure, headache, rash, photosensitivity, and injection site reactions have been reported. In addition, more serious side effects such as anaphylaxis, angioedema, acute renal failure, and severe hypertension also have been reported. In patients with megaloblastic anemia, administration of hydroxocobalamin must be approached with caution because it can precipitate hypokalemia. However, the only known absolute contraindication is hypersensitivity to hydroxocobalamin. Hydroxocobalamin also is known to interfere with certain laboratory values and equipment. Furthermore, hemoglobin, basophils, creatinine, glucose, bilirubin, and alkaline phosphatase may be falsely elevated for varying amounts of time after administration, whereas hematocrit, leukocytes, and platelets do not appear to be affected. Pertinent to the cardiac surgical population, hydroxocobalamin also has been known to trigger the false blood leak alarm in Fresenius (Fresenius Medical Care, Bad Homburg, Germany) dialysis machines.40 Based on a review of published cases, the predominant dosing regimen in use is 5 g administered intravenously over 15 minutes, with the option to give a second 5 g dose if the first does not achieve the desired hemodynamic effect.40 Time to peak effect has not been well-studied and appears to vary greatly from patient to patient, as does onset of action (minutes to hours).39

to date is the ATHOS III (Angiotensin II for the Treatment of High-Output Shock) trial that focused primarily on vasoplegia in the ICU with 80.7% of patients enrolled experiencing sepsis as the cause of vasodilatory shock.9 The trial involved 321 patients in vasodilatory shock who were assigned in a 1:1 ratio to receive angiotensin II or a placebo. The primary end point was a response to the medication at 3 hours measured by an increase in MAP from baseline by 10 mmHg or to 75 mmHg without increasing the baseline vasopressor doses. ATHOS III comprised almost entirely (80%) patients diagnosed with septic shock, whereas only 19 patients were diagnosed with postoperative vasoplegia.9 The results showed that patients in the angiotensin II group reached the primary end point with statistical significance (69.9% v 23.4%; p < 0.0001; odds ratio 7.95; 95% confidence interval 4.76-13.3).9 Although the effects of the drug were measured over the span of hours to days, it was noted that the MAP increased and the vasopressor dosing decreased within the first 2 hours of medication administration. The trial also included 7 patients who were undergoing extracorporeal membrane oxygenation (ECMO) therapy.46 All 7 patients who were treated with angiotensin II had a rapid decline in vasopressor dose with a concomitant increase in blood pressure; causes of vasoplegia during ECMO conditions, such as activation of inflammatory mediators upon contact with the circuit, more closely resemble CPB conditions.46 In a recent case report that described angiotensin II use for post-CPB vasoplegia, the dose of norepinephrine was reduced by 33.3% in the first hour and then by 88.9% in the second hour.45 In a separate case series of 4 patients experiencing post-CPB vasoplegia, angiotensin II was initiated at 20 ng/kg/ min and within 1 hour the MAP increased and the norepinephrine dose was reduced by 27.8%.44 The FDA-approved doses described in the literature for distributive shock range from 10 to 40 ng/kg/min, with the catecholamine-sparing effects noticed within an hour.44,45,47 The most serious side effect of angiotensin II is thromboembolic events, and this risk/benefit should be seriously considered, especially during bypass.47 As a result of the thrombosis risk noted in the ATHOS III trial, the use of angiotensin II during CPB should not be considered a standard until additional studies are undertaken. In addition, because of its expense ($1,500 per vial), it may not be on formulary in every institution.

Angiotensin II Patients undergoing CPB encounter a variety of physiological insults that can lead to hypotension. One of these insults includes hydrogen sulfide release, which can lead to the inhibition of endothelial ACE activity.44 In conjunction with pulmonary endothelial injury and pulmonary isolation during CPB, the level of ACE activity is greatly reduced.44,45 Because of these derangements, vasoplegia during bypass may be curtailed with angiotensin II (Giapreza; La Jolla Pharmaceutical, San Diego, CA) administration. Angiotensin II acts directly on the vessel wall to cause vasoconstriction and an increase in MAP.40,44 Angiotensin II has been studied in vasoplegia during septic shock and post-cardiac surgery, and the largest trial

Vitamin C and Combination Therapy of Hydrocortisone, Ascorbic Acid, and Thiamine (HAT) Recent studies that have examined treatments for vasoplegia also have focused on the off-label use of intravenous vitamin C (ascorbic acid) because there is some evidence to suggest that critically ill patients are deficient in this cofactor, resulting in hypotension.48 Vitamin C plays a crucial role in dopamine, epinephrine, vasopressin, and norepinephrine synthesis, and a deficiency in this cofactor can lead to reduced levels of endogenous catecholamines.49,50 Vitamin C also plays a role in increasing receptor sensitivity to catecholamines, increasing microcirculation, scavenging reactive oxygen, reducing nitric oxide

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synthase, and decreasing histamine release.48 It has been reported that patients experience a reduction in vitamin C after CPB and that CPB plays a role in sequestering vitamin C, resulting in an ascorbic acid deficiency.51 This depletion has been linked to vasoplegia postoperatively and could be a contributing factor to vasoplegia during bypass.48 In the first report of vitamin C administration for bypass-related vasoplegia, Wieruszewski et al. described 3 cases of patients undergoing CPB ranging from 55 minutes to 196 minutes who developed profound vasoplegia postoperatively.48 After initiation of vitamin C 1.5 g intravenously every 6 hours, the vasopressor requirements to maintain a MAP of 65 mmHg were reduced profoundly and as early as 4 hours after administration.48 In 2 of the cases, this reduction in vasopressor requirements was noted within 1 hour. More recently, studies have examined the effect of HAT therapy, which combines hydrocortisone, vitamin C (ascorbic acid), and thiamine, for the treatment of severe sepsis and vasoplegia.52 The largest study regarding HAT therapy was published in 2017 and was a retrospective before-after study of 94 patients with sepsis and vasoplegia.52 Even though the primary end point was survival to hospital discharge, a secondary end point was duration of vasopressor infusions. The 47 patients in the treatment group had a mean duration of vasopressors of 18.3 § 9.8 hours compared with the 47 patients in the control group who had a mean duration of vasopressors of 54.9 § 28.4 hours (p < 0.001).52 That study demonstrated a rapid reduction in vasopressor dosing within 2 hours of administration of HAT therapy. Additional research regarding HAT therapy for sepsis is ongoing and reportedly will be complete by October 2021 as part of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial (protocol NCT03509350); these results may be pertinent to the treatment of vasopressor refractory hypotension during bypass.53 In both the case series and studies the described dosing of vitamin C was 1.5 g intravenously every 6 hours for 96 hours or until vasopressor discontinuation. A relevant side effect of vitamin C, especially during CPB, is an observed decrease in platelet activation and oxalate nephropathy. In addition, in patients with glucose-6-phosphate dehydrogenase, vitamin C administration can lead to hemolysis.50 Prostaglandin Inhibitors As part of the protuberances experienced during CPB, an increase in prostaglandins has been described as a potential cause for vasoplegia during bypass.54,55 It is theorized that the production of prostaglandins is increased because of the inflammatory response of CPB. In addition, prostaglandin is inactivated in the lungs, but because CPB bypasses the lungs, this inactivation is reduced.54,55 For the treatment of CPBassociated vasoplegia, a study in Japan examined the off-label use of the nonsteroidal anti-inflammatory flurbiprofen (Ropion; Tokyo, Japan) for its prostaglandin synthesis inhibition via inactivation of cyclooxygenase properties.54 In that study 18 patients undergoing CPB were administered 50 mg of flurbiprofen before the start of CPB and 50 to 100 mg of flurbiprofen during CPB and were compared with a control group.

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In both groups an alpha agonist analog was used to maintain MAP >45 mmHg during CPB. The study group receiving flurbiprofen had a higher MAP and lower rates of alpha agonist infusion compared with the control group (57 § 4 mmHg v 48 § 3 mmHg; p < 0.01).54 As a marker of perfusion, urine output was examined and noted to be significantly greater in the flurbiprofen group compared with the placebo group (503 § 179 mL/h v 354 § 112 mL/h; p < 0.01). No statistically significant difference was noted between the 2 groups with respect to CPB time, aortic cross-clamp time, hematocrit, ejection fraction, or demographic variables. Despite its possible utility in the treatment of vasoplegia, the biggest limitation with this drug class is both the half-life of 5.5 hours and its negative effect on platelet function and bleeding, which is especially important in cardiac surgery.54 Steroids Inflammatory mediators released during the initiation of CPB include tumor necrosis factor; interleukins (1, 6, and 10); leukotriene; cytokines; and endotoxin.5 Corticosteroids play a significant role in reducing these inflammatory mediators, which cause systemic hypotension. In addition, suppression of the hypothalamic-pituitary-adrenal axis is observed as a result of the stress conditions of CPB.56 The role of steroids in cardiac surgery and septic shock vasoplegia has been examined extensively.57-59 However, the use of steroids in the treatment of onCPB VS has not been clearly studied. Dexamethasone and methylprednisolone were studied in the DECS (Dexamethasone for Cardiac Surgery) and SIRS (Steroids in Cardiac Surgery) trials, respectively, but neither trial found a significant benefit in mortality for patients undergoing cardiac surgery.58,59 The primary focus of these studies was serious adverse outcomes such as death and stroke but not vasoplegia.58,59 Hydrocortisone use for vasodilatory shock gained traction after the results of the CORTICUS (Corticosteroid Therapy of Septic Shock) trial.60 That study was an RCT involving 499 patients, with 251 receiving 50 mg of intravenous hydrocortisone every 6 hours for 11 days. Although the primary end point was mortality, the study did reveal that vasodilatory shock was reversed faster with hydrocortisone administration compared with placebo. The duration of vasodilatory shock was statistically shorter in the hydrocortisone group than in the placebo group (p < 0.001).5 It also should be noted that the 50 mg dosing regimen is given over several days to hours, and this may not be as beneficial in an acute setting during CPB unless the patient is experiencing adrenal insufficiency.56 The threshold to administer corticosteroids in patients with vasoplegia during bypass should be low because there is minimal risk to giving even high doses of steroids with respect to infectious outcomes and sternal complications.58,59 Conclusion and Future Investigations The evidence to support various treatment strategies for severe vasoplegia is minimal, but given the frequency and

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Fig 1. Algorithm for vasoplegia during cardiopulmonary bypass. CI, cardiac index; MAP, mean arterial pressure;

need for systemic evaluation and treatment, a proposed algorithm is presented in Fig 1. Additional studies are needed to assess whether this proposed algorithm would affect clinical outcomes. The very definition of what constitutes on-CPB VS is not well-understood as evidenced by the wide range of current definitions, which are highlighted in Table 2. Although these rescue agents have been described in the literature for vasoplegia in the ICU, their validation in vasoplegia Table 3 Current Gaps in Evidence and Major Questions for Future Clinical Trials Regarding Vasoplegia During Cardiopulmonary Bypass Establishing a universal hemodynamic threshold defining vasoplegia during CPB Examining the equipment differences among CPB circuits associated with vasoplegia Studying the relationship between various MAP targets (eg, 50, 60, 65 mmHg) and end-organ effects Validating an evidence-based algorithm for pharmacologic treatment of vasoplegia during CPB Identifying new pharmacologic treatment options for vasoplegia during CPB Evaluating the association of pharmacologic therapy for vasoplegia during CPB and postoperative outcomes Abbreviations: CPB; cardiopulmonary bypass, MAP; mean arterial pressure.

during bypass has not been well-published and leaves room for further clinical investigation (Table 3). Ongoing clinical studies evaluating treatment for vasoplegia during bypass hopefully will shed light on this understudied topic. It is important for cardiac anesthesiologists to be familiar with these rescue agents because they may become valuable therapies in the armamentarium against vasoplegia during bypass (see Table 4).

Table 4 Rescue Agents and Relevant Dosing Derived From the Current Literature Drug

Dose

Vasopressin Terlipressin*

0.02-0.1 U/min 1-2 mg/kg/h 2-3 mg/kg over 10 minutes, followed by 0.5 mg/kg/h for 6 h 5 g infused over 15 min; may repeat once 10-40 ng/kg/min 1.5 g intravenously every 6 h 50-100 mg 50-100 mg once, then 50 mg every 6 h

Methylene blue* Hydroxocobalamin* Angiotensin II (Giapreza) Vitamin C* Flurbiprofen (Ropion)* Hydrocortisone * Off-label use.

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Conflict of Interest The authors have no financial disclosures to report.

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