Vasoplegic syndrome is one of the most clinically relevant complications in the postoperative period following cardiac surgery. Although it has been recognized for more than 3 decades (initially described in 1994 by Walter Gomes), there is still no universally accepted definition. Nevertheless, most authors agree on 3 core elements:
- Vasoplegic syndrome occurs predominantly after procedures involving CPB.
- From a hemodynamic standpoint, patients present with arterial hypotension and reduced systemic vascular resistance (SVR), preserved cardiac function, and no other identifiable cause of shock.
- The consequence is impaired tissue perfusion due to microcirculatory dysfunction, ultimately leading to metabolic acidosis.
The reported incidence varies across series but is estimated to affect approximately 5–25% of patients undergoing cardiac surgery with CPB.
Despite its clinical relevance, vasoplegic syndrome remains a heterogeneous entity, involving multiple pathophysiological mechanisms and lacking a clearly standardized therapeutic strategy. The recent review published in JACC aims to organize current knowledge and propose a practical approach grounded in pathophysiology.
From a hemodynamic standpoint, vasoplegic syndrome is characterized by persistent arterial hypotension, typically with a mean arterial pressure (MAP) below 65 mm Hg, in the setting of reduced systemic vascular resistance and a normal or even elevated cardiac index. In more severe or refractory cases, this profile is further defined by a minimal or absent response to fluid administration and catecholamines, often requiring a reassessment of the therapeutic strategy.
It is essential to differentiate vasoplegic syndrome from other common causes of postoperative shock after cardiac surgery, such as ventricular dysfunction, cardiac tamponade, or hypovolemia (eg, active bleeding). In vasoplegia, the primary abnormality lies in vascular tone rather than cardiac performance; therefore, the hemodynamic profile corresponds to distributive shock.
One of the central mechanisms involved is excessive nitric oxide (NO) production. Activation of inducible nitric oxide synthase (iNOS) in the endothelium results in sustained NO release, leading to profound and persistent vasodilation.
Cardiac surgery performed with CPB triggers a marked systemic inflammatory response. This response results from blood contact with the artificial surfaces of the bypass circuit, the mechanical shear stress generated by passage through the pump, and the repeated removal and reinfusion of blood within the thoracic cavity. The ensuing release of proinflammatory cytokines disrupts the balance between vasoconstrictive and vasodilatory pathways. This imbalance leads to reduced responsiveness of vasoconstrictor receptors, increased nitric oxide (NO) production, and a compensatory rise in vasoconstrictive neuromodulators such as vasopressin and norepinephrine. Over time, however, this compensatory mechanism contributes to progressive depletion of these mediators.
These factors contribute to reduced effectiveness of conventional vasopressors such as norepinephrine, explaining the frequent need for escalating doses or alternative therapies.
According to this review, risk factors can be grouped into 3 categories:
- Intrinsic factors: obesity, advanced heart failure with depressed ejection fraction, thyroid dysfunction, advanced age, reoperations, among others.
• Extrinsic factors: preoperative anemia; use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), beta-blockers, amiodarone, or milrinone.
• Iatrogenic factors: prolonged CPB duration or multiple transfusions of blood products.
Diagnosis is primarily clinical and hemodynamic. There is no specific confirmatory test. In patients with persistent hypotension after cardiac surgery, other causes of shock must first be systematically excluded. Once ruled out, the presence of adequate cardiac output combined with low SVR supports the diagnosis. Advanced hemodynamic monitoring may be helpful in confirming the vasodilatory profile and guiding therapy.
Management should be early, individualized, and physiologically driven. A structured, stepwise escalation according to clinical response is advisable.
Preventive measures
Addressing modifiable risk factors is fundamental. However, controversy persists regarding preoperative medications. Although withdrawal of ACE inhibitors and ARBs has been associated with fewer perioperative hypotensive episodes, improved survival has also been reported in patients who continued these therapies. Similar concerns apply to beta-blockers and amiodarone due to the risk of rebound tachycardia. In patients receiving milrinone, switching to vasoactive agents with shorter half-lives may be considered. Correction of anemia before surgery may reduce transfusion requirements during CPB.
Hemoadsorption devices integrated into the CPB circuit have been proposed to remove circulating cytokines. Although used in other forms of distributive shock such as septic shock, clear reductions in morbidity and mortality have not been consistently demonstrated. A clinical trial is currently evaluating their role in preventing vasoplegic shock in patients undergoing CPB.
Vasopressors
Regarding vasopressor therapy, norepinephrine remains the first-line agent. The SOAP-2 trial compared norepinephrine with dopamine and showed no difference in mortality, although norepinephrine was associated with a lower incidence of arrhythmic events, reinforcing its position as the preferred vasopressor. Its effect is mediated through alpha-adrenergic vasoconstriction, allowing effective increases in arterial pressure in most cases. However, in many patients with vasoplegic syndrome, the response is only partial, necessitating progressive dose escalation and exposing patients to the risks associated with high catecholamine levels.
In this setting, vasopressin is commonly used as adjunctive therapy, particularly when norepinephrine requirements become substantial. Because it acts independently of adrenergic receptors, it represents a physiologically sound option in vasoplegic shock. Moreover, it has been suggested that vasopressin may exert an additional benefit by reducing nitric oxide production. Epinephrine is generally reserved as a second-line agent due to the risk of tachyarrhythmias and increased myocardial oxygen consumption. Finally, angiotensin II may be considered in selected cases of refractory vasoplegic shock, although its precise role in this context has yet to be clearly established.
Nitric oxide modulators
Methylene blue inhibits the NO–cGMP pathway and may be effective in refractory cases. Its use requires caution due to potential adverse effects, including systemic and pulmonary vasoconstriction with impaired oxygenation, mesenteric ischemia, methemoglobinemia at high doses, and serotonin syndrome (particularly when combined with opioids or certain antidepressants).
Hydroxocobalamin is a more recent alternative with NO-scavenging properties. Although available data are limited, it represents a promising therapeutic option.
Metabolic resuscitation
Metabolic resuscitation encompasses the use of corticosteroids, ascorbic acid, and thiamine. Although corticosteroids are currently recommended in septic shock, available evidence in vasoplegic shock after cardiac surgery has not demonstrated a significant improvement in survival or a consistent reduction in adverse events. Likewise, for ascorbic acid and thiamine, there is currently no robust evidence clearly supporting their benefit in distributive shock.
From a prognostic standpoint, vasoplegic syndrome is associated with worse outcomes, particularly when it is prolonged or refractory to treatment. Sustained exposure to high doses of catecholamines may further contribute to the development of organ dysfunction. Clinically, its occurrence is linked to longer durations of mechanical ventilation, extended stays in the intensive care unit (ICU) and hospital, and a significant increase in mortality. Several studies have reported a 2- to 3-fold increase in mortality compared with postoperative patients who do not develop vasoplegia, with reported mortality rates
COMMENTARY:
From my perspective, vasoplegic syndrome remains one of those complications that, despite being well understood in theory, continues to pose practical challenges in daily clinical practice. The JACC review is valuable in that it organizes existing evidence and provides an integrative framework in a field where many decisions are still made on limited data.
One of the most relevant aspects is the emphasis on pathophysiology as a guide to therapy. In practice, it is common to encounter patients with progressively increasing norepinephrine requirements without a meaningful hemodynamic response. Recognizing that the underlying problem is not merely insufficient adrenergic stimulation but NO-mediated vasodilation and vascular dysfunction supports earlier use of nonadrenergic therapies.
At the same time, the article highlights an uncomfortable reality: many recommendations are based on observational studies, small case series, or extrapolation from other forms of shock. Robust randomized clinical trials defining optimal timing, patient selection, and combination strategies are still lacking.
In this context, individualized management and early recognition of the vasoplegic profile appear critical. Identifying high-risk patients preoperatively and promptly diagnosing the hemodynamic pattern may prevent delayed and disorganized vasopressor escalation.
In summary, vasoplegic syndrome after cardiac surgery is a frequent and complex complication with significant prognostic implications. Although multiple therapeutic options exist, clinical practice remains largely experience-driven rather than evidence-based. A stepwise approach grounded in pathophysiology, with early integration of nonadrenergic strategies, seems reasonable. Nonetheless, well-designed trials are urgently needed to establish more definitive and reliable treatment pathways.
REFERENCE:
Castagna F, Mehra MR, Nabzdyk CGS, Givertz MM. Vasoplegia Syndrome After Cardiac Surgery: Insights Into Mechanisms and Treatment. J Am Coll Cardiol Heart Fail. 2025;13(7):102482. doi:10.1016/j.jchf.2025.02.028.
