Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 328À333 Contents lists available at ScienceDirect Journal of Cardiothoracic and Vascular Anesthesia journal homepage: www.jcvaonline.com Original Article Intravenous Levosimendan and Vasopressin in New- Onset Acute Pulmonary Hypertension After Weaning from Cardiopulmonary Bypass Bernhard Poidinger, MD*, Oskar Kotzinger, MD*, Kurt Rutzler,€ MDy, Axel Kleinsasser, MDz, Andreas Zierer, MDx, ,1 Hans Knotzer, MD*,{ *Department of Anesthesiology and Critical Care Medicine II, Klinikum Wels, Wels, Austria yInstitute of Anesthesiology, Departments of Outcomes Research and General Anesthesiology, Cleveland Clinic, Cleveland, OH zDepartment of Anesthesiology and Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria xUpper Austrian Reference Center of Cardiothoracic and Vascular Surgery, KlinikumWels, Wels, Austria { Klinikum Wels, Wels, Austria Objective: A novel treatment with intravenous levosimendan and vasopressin for new-onset acute pulmonary hypertension after weaning from cardiopulmonary bypass is described. Design: Retrospective analysis of a case series. Setting: Single-center study. Participants: Nineteen patients undergoing cardiac surgery exhibited new-onset acute pulmonary hypertension with acute right ventricular dys- function after cardiopulmonary bypass. Intervention: Pulmonary hypertension with acute right heart dysfunction was treated with levosimendan as inodilator therapy and vasopressin combined with norepinephrine for systemic vasopressor therapy. Measurements and Main Results: Mean pulmonary artery pressure decreased from 32 § 9to26§ 6 mmHg (p = 0.039) in the first 24 hours along with an increase in cardiac output (3.2 § 1 to 4.2 § 1.1 L/min; p = 0.012) and resolution of lactic acidosis. The ratio between mean pulmo- nary artery pressure and mean arterial pressure decreased from 1:2 to 1:3, and Wood units decreased from 3 § 1 to 1.5 § 2 (p = 0.042). At 30 days after intervention, 3 patients died. Conclusion: The combination of levosimendan for inotropic support of the right ventricle in conjunction with its vasodilatory effect on the pul- monary circulation, along with the combination of vasopressin and norepinephrine for systemic vasopressor therapy, may be an effective alterna- tive for the treatment of acute new-onset pulmonary hypertension and acute right heart dysfunction after cardiopulmonary bypass. Although there are many confounding variables in this case series, these findings justify additional sufficiently powered trials. Ó 2018 Elsevier Inc. All rights reserved. Key Words: vasopressin; levosimendan; norepinephrine; right ventricular dysfunction; pulmonary hypertension; cardiopulmonary bypass ACUTE POSTOPERATIVE pulmonary hypertension is a 1,2 rare but serious clinical finding after weaning from cardiopul- avoid subsequent right ventricular failure. Acute right ven- monary bypass and must be managed aggressively in order to tricular failure occurs in approximately 0.1% of patients after cardiac surgery and in 20% to 30% of patients requiring 3À5 1 left ventricular assist devices. The in-hospital mortality Address reprint requests to Hans Knotzer, MD, Department of Anesthesiol- 3À5 ogy and Critical Care Medicine II, Klinikum Wels, Grieskirchnerstrasse 42, rate has been reported to range between 70% and 75%. A-4600 Wels, Austria. Common causes of the development of acute new-onset post- E-mail address: [email protected] (H. Knotzer). operative pulmonary hypertension include the following: https://doi.org/10.1053/j.jvca.2018.07.013 1053-0770/Ó 2018 Elsevier Inc. All rights reserved. B. Poidinger et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 328À333 329 (1) preexisting pulmonary hypertension, (2) ischemia-reperfu- echocardiography. Anesthesia was maintained with a combi- sion injury, (3) pulmonary embolism, (4) left ventricular fail- nation of sevoflurane and continuous infusion of remifentanil ure, (5) adverse protamine reactions, and (6) excessive blood throughout the surgical procedure. All surgeries were per- transfusion.5,6 Current treatment focuses on addressing right formed on cardiopulmonary bypass. According to the authors’ heart failure associated with acute pulmonary hypertension, institutional standard of care, blood flow was set at 2.4 and with specific goals including avoidance of right ventricular was adjusted throughout the bypass period with a minimal per- volume overload, restoration of normal pulmonary vascular fusion pressure of 50 mmHg. During aortic cross-clamping, resistance, correction of right ventricular output, and remedia- cardioplegia was performed with a crystalloid cardioplegic tion of low aortic root pressure.7 solution (St. Thomas II). After bypass, heparinization was One goal of therapy is to maintain systemic blood pressure reversed with protamine in a 1:1 ratio. After being weaned to preserve right coronary blood flow. Sympathomimetic vaso- from cardiopulmonary bypass and following surgical closure, pressors such as norepinephrine and phenylephrine increase patients were kept intubated and transferred to the surgical both systemic vascular resistance and pulmonary vascular intensive care unit (ICU). Continuous sedation was achieved resistance,8,9 with the latter potentially harming the already with a continuous infusion of propofol. strained right heart. In addition, these vasopressors potentially All surgical procedures were performed by experienced car- may lead to myocardial ischemia, hyperlactatemia, diastolic diac surgeons. Anesthesia was provided by senior anesthesiol- dysfunction, and tachyarrhythmias.10 An alternative non-sym- ogy attendings who had obtained special education in cardiac pathomimetic vasopressor is vasopressin for use in cardiac sur- anesthesiology. gery.11 Experimental studies have revealed vasodilating properties of vasopressin in the pulmonary circulation.12 Fur- Hemodynamic Management thermore, vasopressin has been used as a rescue therapy in adult patients and neonates with refractory pulmonary arterial Perioperatively, hemodynamic functions were evaluated in hypertension.13,14 all patients with continuous arterial blood pressure monitoring, Coronary artery perfusion pressure is the primary issue a pulmonary artery catheter, and transesophageal echocardiog- behind preservation of right ventricular systolic function. Fur- raphy. Volume management was conducted with crystalloid thermore, augmentation of right ventricular function with ino- fluids according to transesophageal echocardiographic findings tropic support is another major goal. Sympathomimetic agents until cardiopulmonary bypass began. Packed red blood cells such as dopamine and dobutamine exert their effects because were transfused to maintain a hematocrit level >23%. of stimulation of 1-adrenergic receptors. The positive inotropic Continuous norepinephrine infusion was started to achieve a effect is accompanied with a positive chronotropic effect pre- target blood pressure >65 mmHg off-pump and 50 mmHg on- cipitating tachyarrhythmias and worsening pulmonary vaso- pump. After norepinephrine infusion exceeded 0.2 to 0.25 mg/ constriction at higher doses.15,16 A promising alternative is kg/min, additional continuous arginine vasopressin was started levosimendan, a calcium-sensitizing inotrope that is used for at 2 to 4 U/h, according to local standards of care. After reach- the low-cardiac output syndrome after cardiac surgery to ing the target mean arterial pressure (MAP), vasopressin was improve myocardial contractility. Levosimendan also exhibits decreased stepwise to 2 U/h; afterwards norepinephrine and vasodilator properties in the pulmonary vasculature with a vasopressin were reduced stepwise according to the patient’s reduction in pulmonary vascular resistance via activation of blood pressure. In this case series, all patients received vaso- adenosine triphosphate (ATP) sensitive potassium channels pressin continuously in addition to norepinephrine infusion for within smooth muscles.17 In pressure loadÀinduced right ven- vasopressor therapy. tricular failure, levosimendan improves right ventricular-to- Inotropic support in all patients was managed with a contin- pulmonary artery coupling more than dobutamine .18 uous levosimendan infusion at a dose of 0.1 to 0.15 mg/kg/ The aforementioned studies were the rationale for the min without a starting bolus. Obligatory levosimendan was authors’ novel regimen of combined therapy using levosimen- administered in patients with a preexisting left ventricular dan and vasopressin in addition to norepinephrine for vaso- ejection fraction <30% (6 patients). In these patients, the con- pressor therapy in 19 patients who experienced new-onset tinuous levosimendan infusion was started after induction of pulmonary hypertension after cardiac surgery. anesthesia, continued during the perioperative and postopera- tive periods, and was guided by right heart catheter measure- Methods ments and transesophageal echocardiography. Levosimendan was administered in all patients for a minimum of 24 hours. The study included 19 patients who experienced acute-onset The mean dose was 0.11 § 0.03 mg/kg/min. pulmonary hypertension after weaning from cardiopulmonary Epinephrine was not used as a standard drug in these bypass between December 2015 and January 2017. Patient patients. In 2 patients, epinephrine was given in boluses for characteristic and demographic data are reported in Table 1. cardiopulmonary resuscitation. One of these patients died in General