This is part of a series on the consequences following cardiac surgery and cardiopulmonary bypass.
A 67-year-old male presents to your ICU following an aortic valve replacement and three vessel coronary artery bypass. His intraoperative course was remarkable for a prolonged cardiopulmonary bypass (CPB) run and multiple blood product transfusions. On arrival to the unit, he is intubated and sedated. He is requiring escalating doses of norepinephrine, epinephrine and vasopressin to maintain a mean arterial pressure (MAP) of 65 mmHg. A pulmonary artery catheter calculates a cardiac index (CI) of 3.1 L/min/m2 and a systemic vascular resistance of 650 dynes*sec/cm5. Ten minutes after arrival, his blood pressure is now 90/38, MAP 55mmHg.
What is going on, and what are appropriate next steps?
This patient is suffering from vasoplegia.
Vasoplegia, broadly speaking, is characterized by a low systemic vascular resistance with concomitant low systemic blood pressure but a normal or raised cardiac output. Definitions in the literature vary, but most studies use a MAP of 50-70 requiring vasopressor treatment and a CI of at least 2.2 L/min/m2(1). The elements of decreased peripheral resistance and preserved or increased cardiac output differentiate vasoplegia from other, more common, causes of postcardiotomy shock, such as hemorrhage or left ventricular dysfunction.
The pathophysiology of vasoplegia is not completely understood, but vasoplegia essentially results from a combination of a vasodilatory post-CPB inflammatory cascade, nitric oxide-induced smooth muscle vasodilation and a developed vasopressin deficiency (1). Incidence varies, with reports of 5-25% of cardiac surgery patients suffering from some form of vasoplegia in their postoperative course. Of note, vasoplegia is not isolated to the post-cardiac surgery patient. A similar pathophysiology occurs post-liver transplantation, in sepsis and anaphylactic shock, among other causes.
Vasoplegia is associated with worse survival, prolonged ICU length of stay, and increased hospital cost (2).
Risk factors for developing vasoplegia can be separated into preoperative and intraoperative factors (3):
Of note, LVAD implantation and heart transplantation are also associated with a higher incidence of postoperative vasoplegia (4,5)
Treatment of vasoplegia is philosophically similar to most high-quality ICU care: provide organ support for the time necessary for the pathology to be reversed or run its course. Vasoplegia will resolve as the duration of time from both the CPB run and the cardiac surgery insult increases. The main intervention to provide blood pressure support is vasopressor medications.
What is the vasopressor of choice in vasoplegia?
A systematic review in 2007 found no consensus for one vasoactive medication over another, but opined that “the most remarkable finding…is the lack of randomized trials focusing on clinical outcomes of a relatively common clinical scenario” (6). Nicely, the VANCS randomized control trial answered this call in 2017(7).
Norepinephrine was compared to vasopressin in patients with vasoplegic shock following cardiac surgery. The primary outcome was a composite endpoint of death or severe postoperative complications within 30 days. Severe complications included such things as stroke, acute renal failure, and need for mechanical ventilation for 48 hours postoperatively. The primary outcome favored vasopressin, with 32% of patients in the vasopressin group having suffering either death or a complication, as opposed to 49% of the norepinephrine group (p <0.0014). There was no difference in mortality within the composite outcome, with the majority of benefit being seen in reduction of acute renal failure in the vasopressin group (10% vs 35%, P<0.001) and need for RRT (2.7% vs 13.9%, p<0.0016). Further, there was a reduced incidence in post-operative atrial fibrillation in the vasopressin arm.
Despite the signal of benefit of using a vasopressin first strategy, most patients will additionally require catecholamine support. Norepinephrine and epinephrine are fine choices.
What if the cocktail of vasopressin and catecholamine vasopressors are insufficient to achieve your MAP goal?
Steroids: The Adrenal trial made plain that the effect of steroids in vasopressor resistant septic shock was to hasten shock reversal (8). Since vasoplegia features a similar pathophysiology, I would advocate for using stress dose steroids when a second vasopressor is being added. Of note, use of intraoperative steroids to attenuate vasoplegia following cardiac surgery yielded no mortality benefit in two large randomized control trials (9, 10), though evaluation of hemodynamic endpoints was not included in the analysis. As such, I borrow from the robust sepsis literature in applying steroids to this population.
Methylene Blue: An inhibitor of nitric oxide synthase, methylene blue is an accepted salvage therapy for refractory vasoplegia. Small RCTs showed improvements in SVR, MAP and a lower norepinephrine requirement after administration of methylene blue (11). Contraindications to its use include contribution to serotonin syndrome, hemolysis from G6PD deficiency, induction of methemoglobinemia and elevations in pulmonary vascular resistance via inhibition of NO synthase. The dosing regimen is 2-3 mg/kg over 10 minutes, followed by an infusion of 0.5 mg/kg/hr for 6 hours. Pro tip: remember to advise the family about blue urine discoloration before they walk in the room.
Hydroxocobalamin (vitamin B12a): Another inhibitor of nitric oxide synthase, though has an additional effect of hastening the elimination of the endogenous vasodilator hydrogen sulfide. Case series show an improvement in MAP and a reduction in vasopressor requirements (12). The notable side effect, and desirable in this case, is extreme hypertension. There are no concerns for serotonin syndrome or hemolysis in the presence of G6PD deficiency. Hydroxocobalamin does interfere with a variety of lab markers, falsely elevating hemoglobin, creatinine and bilirubin levels. Further, it can alter aPTT and prothrombin time values for up to 24 hours post use. It is also more expensive than methylene blue (~$1200 vs $100 USD). The dosing regimen is 5 g infused over 15 minutes, with the ability to give an additional dose.
Angiotensin II: Angiotensin II is an endogenous vasopressor that has a norepinephrine sparing effect when given to patients suffering from severe vasodilatory shock (13). A case report demonstrated reduced need for norepinephrine and higher MAP in patients with post cardiotomy vasoplegia (14). A concerning side effect seen in the ATHOS-3 study was higher signal for thromboembolic events. Additionally, a 2.5 mg vial of angiotensin II costs $1500. The dosing regimen is 10-40 ng/kg/min. I have no personal experience with this agent, but given its unique vasoconstrictive pathway, may be of some use if on your institution’s formulary.
- Vasoplegia is a consequence of cardiopulmonary bypass and is defined by a low SVR and hypotension despite an adequate cardiac output.
- Vasoplegia will resolve with time, but blood pressure support is necessary with vasopressors.
- Vasopressin and catecholamine vasopressors are good initial choices; steroids, methylene blue, hydroxocobalamin and angiotensin II are salvage therapies.
- Shaefi, Shahzad, et al. “Vasoplegia after cardiovascular procedures—pathophysiology and targeted therapy.” Journal of cardiothoracic and vascular anesthesia 32.2 (2018): 1013-1022.
- Tsiouris A., Wilson L., Haddadin A.S., et al: Risk assessment and outcomes of vasoplegia after cardiac surgery. Gen Thorac Cardiovasc Surg 2017; 65: pp. 557-56
- Dayan V., Cal R., and Giangrossi F.: Risk factors for vasoplegia after cardiac surgery: A meta-analysis. Interact Cardiovasc Thorac Surg 2019; 28: pp. 838-844
- de Waal E.E.C., van Zaane B., van der Schoot M.M., et al: Vasoplegia after implantation of a continuous flow left ventricular assist device: Incidence, outcomes and predictors. BMC Anesthesiol 2018; 18: pp. 185
- Chan J.L., Kobashigawa J.A., Aintablian T.L., et al: Characterizing predictors and severity of vasoplegia syndrome after heart transplantation. Ann Thorac Surg 2018; 105: pp. 770-777
- Egi M., Bellomo R., Langenberg C., et al: Selecting a vasopressor drug for vasoplegic shock after adult cardiac surgery: A systematic literature review. Ann Thorac Surg 2007; 83: pp. 715-723
- VANCS Hajjar L.A., Vincent J.L., Barbosa Gomes Galas F.R., et al: Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: The VANCS randomized controlled trial. Anesthesiology 2017; 126: pp. 85-93
- Venkatesh, Balasubramanian, et al. “Adjunctive glucocorticoid therapy in patients with septic shock.” New England Journal of Medicine 378.9 (2018): 797-808.
- Whitlock, Richard P., et al. “Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial.” The Lancet 386.10000 (2015): 1243-1253
- Dieleman, Jan M., et al. “Intraoperative high-dose dexamethasone for cardiac surgery: a randomized controlled trial.” Jama 308.17 (2012): 1761-1767.
- Ortoleva, Jamel P., and Frederick C. Cobey. “A systematic approach to the treatment of vasoplegia based on recent advances in pharmacotherapy.” Journal of Cardiothoracic and Vascular Anesthesia 33.5 (2019): 1310-1314.
- Shapeton A, Mahmood F, and Ortoleva JP: Hydroxocobalamin for the treatment of vasoplegia, a review of current literature and considerations for use. J Cardiothorac Vasc Anesth 2018; undefined:
- Khanna, Ashish, et al. “Angiotensin II for the treatment of vasodilatory shock.” New England Journal of Medicine 377.5 (2017): 419-430.