Vasoplegic Syndrome and Noncatecholamine Therapies

Etiology

Cardiac surgery and exposure to an extracorporeal circuit are prevalent contributors to vasoplegia. The risk of VPS increases proportionally with the duration of cardiopulmonary bypass (CPB). Vasoplegia is more likely to happen during cardiac surgery in older people who have longer aortic cross-clamp times or are prescribed angiotensin-converting enzyme inhibitors (ACEi) or diuretics before surgery.[1] Liver transplantation is strongly associated with the development of VPS and is a serious perioperative risk factor.[2] Kidney, heart, and lung transplants are also at significantly increased risk for VPS.[3][4] Other risk factors for developing VPS include blood transfusions, ventricular assist devices, β-blockers, calcium channel blockers, amiodarone, heart failure, and diabetes mellitus.[5][6] (See Table 1. Clinical risk factors for VPS for cardiac and non-cardiac surgery).

Table 1. Clinical risk factors for vasoplegic syndrome for cardiac and non-cardiac surgery.[7]

BMI: basic metabolic index, ESRD: end-stage renal disease, LVAD: left ventricular assist device, CPB: cardiopulmonary bypass, EF: ejection fraction, ACEi: angiotensin-converting enzyme inhibitors, ARBs: angiotensin receptor blockers, DM: diabetes mellitus, MI: myocardial infarction, CABG: coronary artery bypass graft.

Epidemiology

The incidence of VPS ranges from 5% to 25% in the cardiac literature.[8] Cases of VPS have also been reported in other surgeries, such as liver transplantation. The lack of consensus on a universal definition for VPS complicates the accurate quantification of VPS cases.[9] Additionally, multiple terms, such as distributive shock, vasoplegic shock, and post-cardiac surgery vasoplegia, describe similar conditions, obscuring the incidence. VPS is universally fatal if untreated, and mortality rates are as high as 25% with treatment, especially in cases of catecholamine-resistant VPS.[10]

Pathophysiology

Exposure to an extracorporeal circuit during cardiac surgeries is believed to cause cellular damage and stress, leading to a “sterile” inflammatory response commonly referred to as a damage-associated molecular pattern (DAMP). In the same way that pathogen-associated molecular patterns (PAMPs) from infectious microorganisms trigger a strong immune response, DAMPs can cause vasodilation and increased capillary permeability.[11] This vasodilation and capillary permeability can lead to hypotension; the initial systemic response to hypotension is the release of catecholamines. A hyper-catecholaminergic state may result from profound and prolonged hypotension, which can lead to the resistance of catecholamine receptors and the depletion of catecholamine stores. This can cause vascular smooth muscles to constrict in the presence of catecholamines and, therefore, a state of vasodilatory shock.[12]

Such inflammatory mediators also induce nitric oxide synthase, increasing nitric oxide (NO).[13] NO plays a pivotal role in regulating vascular function, and excessive NO production can cause significant vasodilation.[14] Furthermore, hyperpolarization of smooth muscle cells due to NO-induced vasodilation can deplete calcium stores. Controlling vascular tone in normal physiology is largely dependent on calcium concentration. Given calcium’s crucial role in smooth muscle contraction, calcium depletion disrupts the intracellular vs. extracellular gradient necessary for maintaining vascular tone. This cascade of events can result in the profound hypotension seen in VPS.[15]

Other substances linked to vasoplegia include adenosine, which activates myocardial mechanoreceptors and affects baroreflex activation. Prostanoids increase during an inflammatory process and cause vasodilation. Endothelin 1 acts as a vasoconstrictor by activating receptors in smooth muscle cells. The renin-angiotensin-aldosterone system that regulates blood pressure and fluid balance can become dysregulated in vasoplegia. Hydrogen sulfide, produced during homocysteine metabolism, can activate ATP-sensitive potassium channels, leading to hyperpolarization and reduced vascular tone.[16] 

History and Physical

When evaluating a patient's risk for VPS, it is important to consider medical history for possible risk factors. These may include prolonged cardiopulmonary bypass or aortic cross-clamp time, advanced age, pre-operative use of angiotensin-converting enzyme inhibitors (ACEi), and renal failure. (See Table 1. Clinical risk factors for vasoplegic syndrome for cardiac and non-cardiac surgery.)

The physical signs of circulatory failure encompass the clinical manifestations of hypotension, which are not universally present. Patients may have warm extremities after low blood pressure due to vasodilation. The heart rate is typically within normal or elevated ranges as the body tries to compensate for low systemic vascular resistance. Lastly, signs of inadequate tissue perfusion can manifest as mottling or delayed capillary refill. Decreased urine output, measuring less than 0.5 ml/kg/min, and altered mental function may exist, including obtundation and confusion.

Evaluation

VPS is a form of vasodilatory shock characterized by abnormally low systemic vascular resistance and hypotension with normal or increased cardiac output (see Table 2. Characteristics of vasoplegic syndrome).[11]  Several organizations have proposed specific parameters for mean arterial pressure and cardiac output to define VPS, but these definitions have yet to be universally accepted.[17] Historical records trace the recognition of vasoplegia back to the early 1950s.[18] However, recent decades have brought attention to the role in causing refractory hypotension during organ transplantation, cardiac surgery, anaphylaxis, and septic shock.[19] 

Table 2. Characteristics of vasoplegic syndrome

CI: cardiac index, MAP: mean arterial pressure, SVR: systemic vascular resistance, HR: heart rate, RAP: right atrial pressure, LAP: left atrial pressure, PCWP: pulmonary capillary wedge pressure, MPAP: mean pulmonary artery pressure

Treatment / Management

Vasoplegic syndrome is a medical condition characterized by persistent hypotension and vasodilation. Traditional catecholamine therapies may be insufficient or pose adverse effects in this syndrome. Alternative treatment options must be explored and considered to address the therapeutic challenges of vasoplegia. Non-catecholamine treatments, such as vasopressin, methylene blue, hydroxocobalamin, angiotensin II, and ascorbic acid (vitamin C), offer distinct mechanisms of action (see Table 3. Summary of non-catecholamine therapies for the treatment of vasoplegic syndrome, dosing, mechanism of action, adverse effects, and advantages).

Vasoplegic syndrome is managed through non-catecholamine approaches that show promising potential. These approaches work by restoring vascular tone and inhibiting critical enzymes in vasodilation. This compilation explores the mechanisms underlying each therapy and addresses essential considerations such as dosing, adverse effects, and the associated advantages. As the medical community continues to seek optimal strategies for treating vasoplegia, this resource provides insights for understanding and implementing non-catecholamine therapies in clinical practice.

Vasopressin

When high doses of catecholamines are ineffective for maintaining blood pressure or result in adverse effects, vasopressin may be utilized as an additional treatment option. Vasopressin (at doses up to 0.03 µmol/min) is used as a second-line or extra treatment for catecholamine-resistant vasodilatory shock.[19] By acting on the vasopressin receptor 1, it reinstates vascular tone. Vasopressin directly deactivates the K-ATP channel, inhibiting the increase in cGMP caused by NO, reducing NO synthesis, and minimizing the effects of membrane hyperpolarization, myosin dephosphorylation, and NO accumulation.[20] These actions make vasopressin a viable alternative when high doses of catecholamines are ineffective or unsafe.

Methylene Blue

Methylene blue is a potential treatment option for VPS. However, the evidence supporting the effectiveness is from retrospective cohort studies and case reports. Further research is needed to determine the impact of methylene blue on clinical outcomes such as morbidity and mortality. Nevertheless, a study by Levin et al suggests that methylene blue can reduce mortality and morbidity following cardiac surgery in cases of vasoplegia. The evidence indicates that methylene blue therapy can effectively improve hemodynamic parameters and reduce the need for vasopressors, preventing adverse effects such as mesenteric ischemia or tissue necrosis.[1] (B2)

The mechanism of action of methylene blue involves inhibiting 2 enzymes, namely NO synthase and guanylyl cyclase. This inhibition leads to a reduction in the vasodilatory effects of cytokines that are released in response to shock. Additionally, the binding affinity for the M3 receptor exerts inhibitory effects on cholinesterase activity. Methylene blue should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and caution should be exercised when administering serotonin-metabolizing drugs. Methylene blue is considered a safe treatment option for different shock states. In the case of distributive shock, an infusion of 1 to 2 mg/kg may be administered over 10 to 20 minutes to an hour. In cases where a continuous infusion is required, a preload followed by a continuous infusion of 1 mg/kg per hour over 48 to 72 hours has significant benefits without adversely affecting splanchnic circulation.[21] (B3)

Hydroxocobalamin

Hydroxocobalamin is a derivative of vitamin B12 that has potential as a rescue strategy for treating vasoplegia after cardiac surgery—the vitamin works by inhibiting NO synthase and guanylate cyclase. A systematic review by Brokmeier et al [22] analyzed 24 published manuscripts and conducted a meta-analysis of 3 cohort studies to evaluate the use of hydroxocobalamin in vasodilatory hypotension. The results showed that hydroxocobalamin was associated with a more significant increase in MAP than methylene blue, but neither agent significantly impacted the change in MAP from baseline or mortality. Hydroxocobalamin therapy in VPS is limited and can cause chromaturia and slight interference with common laboratory measurements.[23] A daily 5 g bolus dose should be administered for 10 to 15 minutes and repeated for up to 48 hours after cardiac surgery, according to Muhammad et al.[24] The daily dose is often a final recourse when all alternative therapeutic alternatives are ineffective in producing significant improvements. (A1)

Angiotensin II

Angiotensin II is considered a treatment option for vasoplegia when high-dose vasopressors fail. This can be implemented in catecholamine-induced mesenteric ischemia due to angiotensin II’s ability to mobilize venous blood from mesenteric arteries and stimulate lactate clearance.[25] The peptide is responsible for the vasoconstrictive effects of the renin-angiotensin-aldosterone system (RAAS) via impact on the AT-1 receptor in vascular smooth muscle. 

Angiotensin II can also treat hypotension by increasing the release of aldosterone and vasopressin from the posterior pituitary, increasing the body’s sympathetic response.[16] Notable adverse effects include arterial and venous thrombotic events, thrombocytopenia, tachycardia, decreased cardiac output, lactic acidosis, delirium, and a higher incidence of fungal infections. The recommended starting dose for continuous infusion is 20 ng/kg, and is titrated every 5 minutes, up to 80 ng/kg during the first 3 hours.[26]

Ascorbic Acid (Vitamin C)

Ascorbic acid has demonstrated benefits as a treatment. The vitamin can reduce the dose requirements of other vasopressors and lessen the potential for adverse effects. Ascorbic acid is an essential cofactor in catecholamine synthesis, and exogenous administration increases vasopressor synthesis in the adrenal medulla.[24] After CPB, vitamin C levels are notably diminished, causing a reduction in the synthesis of vasopressors.[27] Consequently, administering ascorbic acid treatment when vitamin C levels are deficient could improve the production of endogenous vasopressors. A few studies have examined combining ascorbic acid with hydrocortisone and thiamine, termed “HAT” therapy, which may be beneficial, but additional research is needed.[28](B2)

Typical administration of ascorbic acid as a treatment for VPS is one 6 g IV bolus dose per day. The recommended dose of hydrocortisone is 50 mg IV bolus every 6 hours or 100 mg every 8 hours, and the dose for thiamine is 400 mg IV daily.[29]

Table 3. Summary of non-catecholamine therapies for the treatment of vasoplegic syndrome, dosing, mechanism of action, adverse effects, and advantages

Differential Diagnosis

VPS has a distinctive hemodynamic profile compared to other hemodynamic states, such as hypovolemic shock. The latter is triggered by a reduction in intravascular volume due to fluid loss or hemorrhage, leading to a decline in cardiac output. In response to this, vascular tone increases to maintain blood pressure. In contrast, cardiogenic shock occurs when there is inadequate cardiac function following a myocardial infarction or severe heart failure. This results in decreased cardiac output and increased systemic vascular resistance due to compensatory vasoconstriction. Therefore, the 2 conditions entail distinct pathophysiological mechanisms and warrant different management strategies.

Prognosis

The prognosis of patients who develop VPS depends on the underlying etiology and the presence of risk factors. The duration of vasoplegia can extend to as much as 72 hours, and the occurrence is associated with increased mortality rates of up to 25%.[3] Orthotopic heart transplantation is linked with high early mortality rates, as high as 25%.[30]

Vasopressor dependence is identified as a significant morbid event in the postoperative phase of patients after cardiac operations. This underscores the need for risk stratification as an essential issue for prophylactic and early therapeutic concepts. Vasopressin and methylene blue are examples of non-catecholamine therapies that reduce dependence on vasopressors and improve outcomes. The treatment of vasopressor dependence is associated with improved outcomes, strengthening the need for further evaluation in large cohorts of patients.[31]

Complications

Patients suffering from this condition require extended periods of ventilation. Furthermore, after comparable blood losses, they necessitate significantly more transfusions of packed red blood cells. They also require a greater need for fresh frozen plasma, are at risk of acute renal failure, and experience delayed discharge from the intensive care unit.