Intravenous Levosimendan and Vasopressin in New- Onset Acute Pulmonary Hypertension After Weaning from Cardiopulmonary Bypass

Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 328333

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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 dysfunction 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 pulmonary 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 pulmonary circulation, along with the combination of vasopressin and norepinephrine for systemic vasopressor therapy, may be an effective alternative 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 35 1 left ventricular assist devices. The in-hospital mortality Address reprint requests to Hans Knotzer, MD, Department of Anesthesiol- 35 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) 328333 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 loadinduced 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 postoperative 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 anesthesia was induced in all patients with a combi- the ICU. In a third patient, epinephrine boluses were adminis- nation of midazolam, propofol, and sufentanil, as clinically tered for 30 minutes until arteriovenous extracorporeal mem- appropriate. All patients were monitored with arterial, central brane oxygenation was instituted after 12 hours. One patient venous, and pulmonary artery catheters, and transesophageal received epinephrine at a dose of 0.10 mg/kg/min for 12 hours 330 Table 1 Demography and Characteristics of Patients

Patient Procedure Age Sex Height Weight EF EuroSCORE Hospital Stay ICU Stay 30-d Mortality RRT Surgical Revisions New-Onset Aﬁb Comments No. (cm) (kg) II (d) (d)

13£ CABG 76 M 167 80 40 3.3 14 7 N N Y Y +AVR 2 AVR 76 F 155 104 60 2.7 24 18 N Y N Y 34£ CABG 80 M 170 56 25 3.0 15 4 N N N N 4 AVR 77 F 168 93 60 3.1 1 1 Y N Y N Died on the same day; redo surgery after 20 min; additional epinephrine infusion 328 (2019) 33 Anesthesia Vascular and Cardiothoracic of Journal / al. et Poidinger B. 53£ CABG 70 M 157 70 50 17.4 14 7 N N N N 65£ CABG 72 F 172 60 45 27 21 10 N Y N Y Additional epinephrine infusion for 30 min; +MVR av-ECMO 12 h after ICU admission 74£ CABG 75 M 181 83 50 6.2 95 31 N Y N Y Additional epinephrine infusion for 12 h; +AVR IABP 1 h after ICU admission 85£ CABG 58 F 154 51 55 10.4 60 21 N Y N Y Dialysis patient; history of kidney transplantation 93£ CABG 70 F 165 89 55 1.5 12 4 N N N N 10 4 £ CABG 57 M 178 81 65 0.6 10 3 N N Y N Revision after graft dysfunction 11 AscAo + AVR 67 M 176 65 65 4.5 21 14 N Y N Y +2£ CABG 12 4 £ CABG 77 M 176 78 40 9.0 51 10 N Y N Y Mechanical CPR in the ICU; + carotid additional IABP in the ICU 13 MVR + 2 £ CABG 75 M 172 66 25 8.1 14 6 N N N Y 14 MVR + 3 £ CABG 46 M 180 100 55 27.9 13 5 N N N N Papillary muscle rupture 15 4 £ CABG 61 M 180 85 30 20.2 16 8 N N Y Y Mechanical CPR due to ventricular ﬁbrillation; IABP after CPR 16 MVR + 2 £ CABG 80 M 180 106 40 8.5 21 11 N N N Y Additional IABP after 6 h 17 Re 2 £ CABG 71 M 178 100 55 21 41 5 Y N N Y Additional epinephrine boluses 18 4 £ CABG 73 M 165 105 50 4.8 1 1 Y N Y N Redo surgery on day of initial surgery; IABP insertion; died on the same day 19 4 £ CABG 62 M 173 79 30 14.5 18 14 N N N N Additional IABP 4 h after ICU admission

Abbreviations: Afib, atrial fibrillation; AscAo, ascending aorta replacement; AVR, aortic valve replacement; av-ECMO, arteriovenous extracorporeal membrane oxygenation; CABG, coronary artery bypass graft; CPR, cardio pulmonary resuscitation; EF, ejection fraction (%); IABP, intra-aortic baloon pump; ICU, intensive care unit; MVR, mitral valve replacement; RRT, renal replacement therapy; 3£, 3 bypass grafts; 4£, 4 bypass grafts; re 2£, a re-operation of a coronary artery bypass graft procedure with two grafts. 333 B. Poidinger et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 328333 331 continuously to support inotropy in addition to levosimendan 45 Mean Pulmonary Artery Pressure (see Table 1). 40 p = 0.039 Data Acquisition and Statistical Analysis 35 30 Patients were ascertained retrospectively from an electronic database from an intrahospital data management system (Cen- 25 tricity High Acuity Critical Care Information System for ICU 20 Management, Centricity High Acuity Anesthesia Information 15 System; GE Healthcare, GE, Little Chalfont, UK) between Time 0 Time 2 hours Time 6 hours Time 12 hours Time 24 hours December 2015 and January 2017 according to the following search criteria: levosimendan (and) vasopressin (and) mean 85 Mean Arterial Pressure pulmonary artery pressure (PAP) >35 mmHg. Twenty-two 80 patients were identified and evaluated for this case series. 75 The diagnosis of acute pulmonary hypertension with con- 70 65 comitant dysfunction of the right ventricle was based on the 60 ratio of mean PAP-to-MAP in connection with systemic blood 55 flow. In addition, right ventricular dysfunction was confirmed p = 0.250 50 with transesophageal echocardiography, usually in a qualita- 45 tive manner. 40 Because this study was a retrospective analysis, the admin- Time 0 Time 2 hours Time 6 hours Time 12 hours Time 24 hours istration of levosimendan and vasopressin was not determined on the basis of a predefined value of right ventricular dysfunc- Fig 1. Mean pulmonary artery and arterial pressures. tion. Three patients were excluded from further analysis because of insufficient data recordings. The correlation between left and right ventricular pressure ventricular dysfunction. The Department of Cardiology per- generation was determined by the ratio between mean PAP formed echocardiographic examinations for all patients preoper- and systemic MAP (mean PAP-to-MAP). Wood units were atively with no findings of preoperative right ventricular calculated by dividing the difference of mean PAP and pulmo- dysfunction. The first values of mean PAP were recorded after nary capillary occlusion pressure by cardiac output. insertion of a pulmonary artery catheter after anesthesia induc- Demographic and clinically-derived variables were ana- tion. Mean PAP was 28 § 6 mmHg at the beginning of surgery. lyzed using paired Student t test (Gaussian distribution) and Sixteen patients were in sinus rhythm before surgery, and 6 Wilcoxon signed ranked test (non-Gaussian distribution). An patients had an ejection fraction <30%, requiring a continuous analysis of variance was performed for hemodynamic, blood infusion of levosimendan during induction of anesthesia. gas, and metabolic variables to evaluate differences within the The median hospital stay was 16 days (1-95), and the group over time. Comparisons were made using paired t tests. median ICU stay was 7 days (1-31). Patients were mechani- A p value < 0.05 was considered to be significant. Data are cally ventilated for a median of 38 hours (5-108). presented as mean values § standard deviation. After administration of levosimendan and vasopressin in addition to norepinephrine, the mean PAP decreased signifi- Results cantly (Fig 1). Vasopressin was started at time point 0, which is defined as the end of cardiopulmonary bypass and the Demographic variables and characteristics of the 19 patients beginning of right ventricular dysfunction concomitant with with acute new-onset pulmonary hypertension after cardiac pulmonary hypertension. The reduction in PAP in combina- surgery are reported in Table 1. tion with maintaining MAP led to a significant reduction in Three patients died within the first 30 days after surgery—2 the ratio of mean PAP-to-MAP (Table 2). Cardiac output patients on the same day of surgery and 1 patient 5 days later. increased over the first 24 hours and was accompanied by Three patients required redo surgery, 2 of these because of sur- reductionofWoodunits(seeTable 2).The acid-base balance gical bleeding and the other because of graft dysfunction. In 1 returned from acidosis to normal during the first 24 hours; patient, VA extracorporeal membrane oxygenation was insti- lactate levels decreased significantly from 4 § 3.5to2.1§ tuted 12 hours postoperatively in the ICU. This patient was 1.0 mMol/L (p = 0.042). excluded from further evaluation. Five patients were supported with an intra-aortic balloon pump. Mechanical cardiopulmo- Discussion nary resuscitation was performed in 2 patients in the ICU postoperatively. Four patients required epinephrine in boluses (3) In this case series, 19 patients who experienced acute new- or continuously (1). onset pulmonary hypertension with concomitant right heart The mean age of the patients was 70 years. None of the dysfunction after being weaned from cardiopulmonary bypass patients had a history of pulmonary hypertension or right in cardiac surgery were evaluated. The combination of 332 B. Poidinger et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 328333

Table 2 Drug Dosages, Arterial Blood Gas Variables, and Hemodynamic Parameters

Time 0 Time 2 h Time 6 h Time 12 h Time 24 h p Value Over Time

Vasopressin (U/h) 2.6 § 1.6 2.8 § 1.5 2.5 § 1 2.3 § 1 1.1 § 0.7 0.011 Levosimendan (mg/kg/min) 0.11 § 0.03 0.12 § 0.03 0.11 § 0.03 0.11 § 0.03 0.1 § 0.03 0.287 Norepinephrine (mg/kg/min) 0.24 § 0.09 0.24 § 0.07 0.26 § 0.12 0.21 § 0.07 0.14 § 0.06 0.001 art CO2 (mmHg) 44 § 842§ 640§ 738§ 537§ 6 0.010 art pH 7.26 § 0.07 7.29 § 0.06 7.31 § 0.07 7.34 § 0.05 7.39 § 0.06 < 0.001 art lactate (mMol/L) 4 § 3.5 3.5 § 2.5 3.7 § 2.3 3.4 § 2.1 2.1 § 1.0 0.042 Mean PAP/MAP 0.53 § 0.22 0.47 § 0.13 0.45 § 0.1 0.39 § 0.13 0.33 § 0.16 0.004 CO (L/min) 3.2 § 0.9 4.2 § 1.1 0.012 Wood units 3 § 1 1.5 § 2 0.042

NOTE. Time point 0 is deﬁned as the end of the cardiopulmonary bypass and the beginning of right ventricular dysfunction concomitant with pulmonary hypertension. At this time point, vasopressin was started. Data are expressed as mean § standard deviation.

Abbreviations: art, arterial; CO2, carbon dioxide; CO, cardiac output; MAP, mean arterial pressure; mean PAP, mean pulmonary artery pressure; mean PAP/MAP, ratio of mean PAP divided by MAP; Wood units, mean PAP pulmonary capillary occlusion pressure divided by CO. levosimendan for inotropic support and vasopressin in addition lacking. Preoperatively administered levosimendan in cardiac to norepinephrine infusion to maintain systemic perfusion surgical patients with known right ventricular failure decreases pressure, resulted in an increased cardiac output, decreased PAP and right ventricular dilation significantly.26 Levosimen- mean PAP, and correction of lactic acidosis in the first 24 hours dan administered postoperatively is an efficient therapy for after surgery. patients after heart transplantation and patients experiencing The pulmonary circulation usually is a high-flow and low- severe mitral stenosis with acute new-onset pulmonary hyper- pressure system. The thin-walled right ventricle poorly tolerates tension and right heart dysfunction.27,28 In both types of cases, acute increases in afterload, resulting in acute distention of the levosimendan improved cardiac contractility and output. right ventricle.19 The contractility of the right ventricle can be Vasopressin has been reported to be a promising alternative to severely compromised along with a significant increase in oxy- the sympathoadrenergic vasopressor norepinephrine.11 It causes 7 gen consumption. The result is reduced filling of the left ventri- vasoconstriction via thevasopressinergicV1 receptor in the sys- cle with decreased cardiac output, oxygen delivery, and temic circulation and has vasodilating properties in the pulmonary systemic perfusion pressure.20 Abnormal loading of the right vasculature.12 Clinically these properties of vasopressin were first ventricle affects the shape and function of the left ventricle (ie, observed in a retrospective study in cardiac surgical patients ventricular interdependence), and consequently worsens sys- experiencing post-cardiotomy shock.12 Vasopressin administration temic perfusion.21 As a result, the pressure gradient for the per- caused an increase in MAP accompanied by a significant decrease fusion of the right coronary artery drops as aortic pressure in mean pulmonary artery pressure without any change in stroke decreases and right ventricular pressure increases, leading to volume index. This reduction in the pulmonary-to-systemic vascu- right ventricular ischemia.22 To counteract this vicious cycle, lar resistance ratio was confirmed by a case series in cardiac surgical the ideal therapy should (1) improve right ventricular contractil- patients.29 In 9 cases of post-cardiotomy hypotension concomitant ity, (2) decrease pulmonary vascular resistance, and (3) increase with pulmonary hypertension, vasopressin increased systemic vas- perfusion pressure of the systemic circulation. cular resistance and MAP. Alteration in pulmonary vascular resis- In the present study, the authors used levosimendan as an tance was not significant, but the ratio of mean PAP-to-MAP was inodilator to improve contractility and reduce pulmonary vas- effectively reduced. Administration of low doses of vasopressin cular resistance. Levosimendan improves myocardial contrac- also was described in a case series of 10 neonates with refractory tility without increasing oxygen consumption.23 Furthermore, pulmonary hypertension, with improved systemic blood pressure levosimendan acts as a vasodilator because of its calcium sen- and a reduction of inhaled nitric oxide dose.14 The underlying sitization and potassium channel opening, especially in the mechanism of this decrease in pulmonary vascular resistance is the pulmonary circulation.17 Experiments performed in animals release of endothelium-derived nitric oxide as a result of agonism 12 have reported that levosimendan prevents right ventricular on pulmonary endothelial V1-receptors. failure and improves contractility in pressure overloadin- In the present study, levosimendan was administered preop- duced right ventricular dysfunction.24 In humans, a recent eratively in 6 patients because of a compromised left ventricu- meta-analysis demonstrated that levosimendan decreases sys- lar ejection fraction. Starting levosimendan preoperatively tolic pulmonary artery pressure and pulmonary vascular resis- might protect the heart more efficiently than starting it after tance, along with an increase in right ventricular ejection the emergence of right ventricular dysfunction. Nonetheless, fraction, in patients experiencing acute right heart failure.25 It excluding these 6 patients from the analysis had no effect on must be noted that most of the clinical data available were the results. In a prospective study, this factor has to be consid- derived from acute onsets of pulmonary hypertension or right ered. Furthermore, echocardiographic examinations were not ventricular dysfunction in noncardiac surgery. Data of levosi- documented in all patients at all time points. This also is a lim- mendan in acute right ventricular failure in cardiac surgery are itation that must be considered in a future prospective study. B. Poidinger et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 328333 333

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