Vasopressin—Magic Bullet in Vasoplegia Syndrome After Cardiac Surgery?

Abstract

Vasoplegia syndrome is a well-recognized complication after cardiopulmonary bypass (CPB) that occurs in 5% to 40% of patients depending on definitions and pre-existing risk factors.1Omar S. Zedan A. Nugent K. Cardiac vasoplegia syndrome: Pathophysiology, risk factors and treatment.Am J Med Sci. 2015; 349: 80-88Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 2Shaefi S. Mittel A. Klick J. et al.Vasoplegia after cardiovascular procedures—Pathophysiology and targeted therapy.J Cardiothorac Vasc Anesth. 2018; 32: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar It is characterized by profound systemic vasodilation causing hypotension despite normal to high cardiac output. In most patients, vasoplegia resolves within relatively short times after therapeutic interventions, but some patients exhibit profound and prolonged hypotension.3Gomes W.J. Carvalho A.C. Palma J.H. et al.Vasoplegic syndrome after open heart surgery.J Cardiovasc Surg (Torino). 1998; 39: 619-623PubMed Google Scholar, 4Weis F. Kilger E. Beiras-Fernandez A. et al.Association between vasopressor dependence and early outcome in patients after cardiac surgery.Anaesthesia. 2006; 61: 938-942Crossref PubMed Scopus (59) Google Scholar The latter is associated with relevant morbidity and mortality.5Levin M.A. Lin H.M. Castillo J.G. et al.Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome.Circulation. 2009; 120: 1664-1671Crossref PubMed Scopus (155) Google Scholar, 6Sun X. Boyce S.W. Herr D.L. et al.Is vasoplegic syndrome more prevalent with open-heart procedures compared with isolated on-pump CABG surgery?.Cardiovasc Revasc Med. 2011; 12: 203-209Crossref PubMed Scopus (20) Google Scholar The underlying pathophysiology of vasoplegia syndrome is complex but manifests basically as a loss of vascular smooth muscle contraction.2Shaefi S. Mittel A. Klick J. et al.Vasoplegia after cardiovascular procedures—Pathophysiology and targeted therapy.J Cardiothorac Vasc Anesth. 2018; 32: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Both reduced plasma levels of endogenous vasopressin, due to absolutely or relatively diminished secretion and excess nitric oxide release are causative for vasoplegia syndrome.2Shaefi S. Mittel A. Klick J. et al.Vasoplegia after cardiovascular procedures—Pathophysiology and targeted therapy.J Cardiothorac Vasc Anesth. 2018; 32: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Jochberger S. Velik-Salchner C. Mayr V.D. et al.The vasopressin and copeptin response in patients with vasodilatory shock after cardiac surgery: A prospective, controlled study.Intensive Care Med. 2009; 35: 489-497Crossref PubMed Scopus (38) Google Scholar, 8Landry D.W. Oliver J.A. The pathogenesis of vasodilatory shock.N Engl J Med. 2001; 345: 588-595Crossref PubMed Scopus (867) Google Scholar Despite some pathogenic features and hemodynamic consequences similar to severe septic shock, it seems that septic shock and cardiac surgery-related vasoplegia have little common etiology.2Shaefi S. Mittel A. Klick J. et al.Vasoplegia after cardiovascular procedures—Pathophysiology and targeted therapy.J Cardiothorac Vasc Anesth. 2018; 32: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Although massive systemic inflammatory response to CPB in susceptible patients has been claimed as a contributing factor, vasoplegia syndrome also has been reported after cardiac surgery without CPB.9Okamoto Y. Nohmi T. Higa Y. et al.Vasopressin does not raise cardiac enzymes following cardiac surgery: A randomized double-blind clinical trial.J Cardiothorac Vasc Anesth. 2015; 29: 46-51Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Further, recent preoperative intake of drugs interacting with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, has been postulated as a trigger. Additional risk factors include a higher preoperative comorbidity burden, low preoperative left ventricular (LV) function, the need for vasopressors before and during CPB, longer duration of CPB, and, finally, specific procedures including heart transplant or LV assist device implantation.1Omar S. Zedan A. Nugent K. Cardiac vasoplegia syndrome: Pathophysiology, risk factors and treatment.Am J Med Sci. 2015; 349: 80-88Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar The initial treatment usually includes volume resuscitation and administration of vasoactive drugs including norepinephrine and epinephrine to restore vascular tone. However, vasoplegia syndrome might be challenging when this conventional therapy fails or produces an insufficient hemodynamic improvement. In such cases, vasopressin and non-vasopressor adjuncts, particularly methylene blue and hydroxocobalamin,2Shaefi S. Mittel A. Klick J. et al.Vasoplegia after cardiovascular procedures—Pathophysiology and targeted therapy.J Cardiothorac Vasc Anesth. 2018; 32: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 10Burnes M.L. Boettcher B.T. Woehlck H.J. et al.Hydroxocobalamin as a rescue treatment for refractory vasoplegic syndrome after prolonged cardiopulmonary bypass.J Cardiothorac Vasc Anesth. 2017; 31: 1012-1014Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 11Roderique J.D. VanDyck K. Holman B. et al.The use of high-dose hydroxocobalamin for vasoplegic syndrome.Ann Thorac Surg. 2014; 97: 1785-1786Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 12Shanmugam G. Vasoplegic syndrome—The role of methylene blue.Eur J Cardiothorac Surg. 2005; 28: 705-710Crossref PubMed Scopus (126) Google Scholar, 13Zundel M.T. Feih J.T. Rinka J.R.G. et al.Hydroxocobalamin with or without methylene blue may improve fluid balance in critically ill patients with vasoplegic syndrome after cardiac surgery: A report of two cases.J Cardiothorac Vasc Anesth. 2018; 32: 452-457Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 14Riha H. Augoustides J.G. Pro: Methylene blue as a rescue therapy for vasoplegia after cardiac surgery.J Cardiothorac Vasc Anesth. 2011; 25: 736-738Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 15Weiner M.M. Lin H.M. Danforth D. et al.Methylene blue is associated with poor outcomes in vasoplegic shock.J Cardiothorac Vasc Anesth. 2013; 27: 1233-1238Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar recently have gained some attention. Vasopressin directly interacts with vasopressin receptors on vascular smooth muscle, thereby attenuating vasodilation by a catecholamine-independent mechanism. Methylene blue counteracts excess nitric oxide and other nitrovasodilator effects on the endothelium and vascular smooth muscle.8Landry D.W. Oliver J.A. The pathogenesis of vasodilatory shock.N Engl J Med. 2001; 345: 588-595Crossref PubMed Scopus (867) Google Scholar However, the use of methylene blue is limited by its side effects, including methemoglobinemia and hyperbilirubinemia, and it potentially increases morbidity.2Shaefi S. Mittel A. Klick J. et al.Vasoplegia after cardiovascular procedures—Pathophysiology and targeted therapy.J Cardiothorac Vasc Anesth. 2018; 32: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 14Riha H. Augoustides J.G. Pro: Methylene blue as a rescue therapy for vasoplegia after cardiac surgery.J Cardiothorac Vasc Anesth. 2011; 25: 736-738Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 15Weiner M.M. Lin H.M. Danforth D. et al.Methylene blue is associated with poor outcomes in vasoplegic shock.J Cardiothorac Vasc Anesth. 2013; 27: 1233-1238Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Finally, hydroxocobalamin has been suggested as a rescue medication in severe refractory vasoplegia, but evidence for its effectiveness is limited to case reports,10Burnes M.L. Boettcher B.T. Woehlck H.J. et al.Hydroxocobalamin as a rescue treatment for refractory vasoplegic syndrome after prolonged cardiopulmonary bypass.J Cardiothorac Vasc Anesth. 2017; 31: 1012-1014Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 11Roderique J.D. VanDyck K. Holman B. et al.The use of high-dose hydroxocobalamin for vasoplegic syndrome.Ann Thorac Surg. 2014; 97: 1785-1786Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 13Zundel M.T. Feih J.T. Rinka J.R.G. et al.Hydroxocobalamin with or without methylene blue may improve fluid balance in critically ill patients with vasoplegic syndrome after cardiac surgery: A report of two cases.J Cardiothorac Vasc Anesth. 2018; 32: 452-457Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar and its mechanism of action is not understood fully. In this issue of the Journal of Cardiothoracic and Vascular Anesthesia, a meta-analysis performed by Dünser and colleagues16Dunser M.W. Bouvet O. Knotzer H. et al.Vasopressin in cardiac surgery: A meta-analysis of randomized controlled trials.J Cardiothorac Vasc Anesth. 2018; 32: 2225-2232Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar reports on the effects of vasopressin in 8 randomized controlled studies including 625 patients undergoing cardiac surgery. They found a significant reduction in perioperative complications including new-onset tachyarrhythmia, acute renal failure, thromboembolic ischemic events, right heart failure, hepatic insufficiency, and water intoxication (odds ratio [OR] 0.33; 95% confidence interval [CI] 0.20-0.54; p < 0.001). However, the authors found no effect on mortality (OR 0.83; 95% CI 0.45-1.53; p = 0.55). Some limitations must be considered when interpreting this meta-analysis. First, the most common indication for the use of vasopressin is the vasodilatory shock refractory to catecholamines after CPB. However, only 2 of the 8 included studies used vasopressin with a therapeutic intention in patients with advanced vasoplegia syndrome after cardiac surgery. The other studies used vasopressin for different clinical scenarios and indications. In 5 trials, the medication was used prophylactically in patients with 1 or several risk factors for postoperative vasoplegia syndrome (patients with preoperative intake of angiotensin-converting enzyme inhibitors or moderately reduced LV function). One study used vasopressin prophylactically in patients undergoing elective and emergent coronary artery bypass graft surgery with no specific risk factors.9Okamoto Y. Nohmi T. Higa Y. et al.Vasopressin does not raise cardiac enzymes following cardiac surgery: A randomized double-blind clinical trial.J Cardiothorac Vasc Anesth. 2015; 29: 46-51Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Second, the dosages of vasopressin ranged from 0.01 to 0.067 U/min. And finally, the incidence of new-onset atrial fibrillation (AF) was 48% and 66% in the intervention and control groups, respectively. These numbers are surprisingly high, and the significant difference in overall postoperative complications was driven mainly by new-onset AF. The study by Dünser and colleagues16Dunser M.W. Bouvet O. Knotzer H. et al.Vasopressin in cardiac surgery: A meta-analysis of randomized controlled trials.J Cardiothorac Vasc Anesth. 2018; 32: 2225-2232Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar nicely illustrates the problems of meta-analyses. They are certainly powerful but also controversial statistical methods.17Walker E. Hernandez A.V. Kattan M.W. Meta-analysis: Its strengths and limitations.Cleve Clin J Med. 2008; 75: 431-439Crossref PubMed Scopus (363) Google Scholar, 18Bolliger D. Tanaka K.A. Which came first, the chicken or the egg?—Clinical dilemmas in managing postoperative bleeding and decision-making for re-exploration after cardiac surgery.J Cardiothorac Vasc Anesth. 2018; 32: 1625-1626Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Common problems of meta-analyses are the selection bias of included studies (which is often unintentional), the summation of large amounts of varied information into a single conclusion, and the incompleteness of study data as most studies only provide summary results such as means, ORs, or relative risks. Ideally, only trials with similar patients, clinical scenarios, and therapeutic indications should be included to form valid conclusions. To increase the statistical power, studies with differing protocols and varying characteristics might be included. However, such a strategy increases the risk of “mixing apples with oranges” and makes a meta-analysis less reliable. The decision as to which studies should be included is always an arbitrary judgment. Meta-analyses, therefore, often have an inherent favorable bias toward the drug of which benefits or disadvantages the authors are convinced. Finally, Dünser and colleagues16Dunser M.W. Bouvet O. Knotzer H. et al.Vasopressin in cardiac surgery: A meta-analysis of randomized controlled trials.J Cardiothorac Vasc Anesth. 2018; 32: 2225-2232Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar found a high overall risk of bias in all studies, additionally limiting the conclusions that might be drawn from this meta-analysis.18Bolliger D. Tanaka K.A. Which came first, the chicken or the egg?—Clinical dilemmas in managing postoperative bleeding and decision-making for re-exploration after cardiac surgery.J Cardiothorac Vasc Anesth. 2018; 32: 1625-1626Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Nevertheless, the authors have to be congratulated on having performed a meta-analysis on a common but life-threatening syndrome for which evidence is scarce. There is a lack of an official, strict, and robust definition of vasoplegia syndrome, and data about the optimal treatment and appropriateness of a therapeutic intervention are limited.19Fischer G.W. Levin M.A. Vasoplegia during cardiac surgery: Current concepts and management.Semin Thorac Cardiovasc Surg. 2010; 22: 140-144Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Criteria for treatment and management strategies are likely to vary significantly between countries and institutions, thereby limiting the performance of similar trials to obtain comparable study data for meta-analyses. Importantly, the findings of the present meta-analysis are at least partially in agreement with a former meta-analysis on the effects of vasopressin and terlipressin in a more general medical population with vasodilatory shock, showing that these substances reduced the norepinephrine requirements but did not produce a survival benefit.20Polito A. Parisini E. Ricci Z. et al.Vasopressin for treatment of vasodilatory shock: An ESICM systematic review and meta-analysis.Intensive Care Med. 2012; 38: 9-19Crossref PubMed Scopus (63) Google Scholar Similarly, 2 recent trials in patients with septic shock found no clear benefit of vasopressin over catecholamines but concluded that vasopressin might limit the severity of renal failure.21Gordon A.C. Mason A.J. Thirunavukkarasu N. et al.Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial.JAMA. 2016; 316: 509-518Crossref PubMed Scopus (323) Google Scholar, 22Gordon A.C. Russell J.A. Walley K.R. et al.The effects of vasopressin on acute kidney injury in septic shock.Intensive Care Med. 2010; 36: 83-91Crossref PubMed Scopus (175) Google Scholar The latter findings in septic patients recently were supported in patients with post-CPB vasodilatory shock.23Hajjar 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: 85-93Crossref PubMed Scopus (157) Google Scholar This randomized trial,23Hajjar 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: 85-93Crossref PubMed Scopus (157) Google Scholar also included in the present meta-analysis, showed that vasopressin significantly reduced the composite endpoint of 30-day mortality and postoperative complications (mainly acute renal failure).23Hajjar 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: 85-93Crossref PubMed Scopus (157) Google Scholar In agreement, Dünser and colleagues found a nonsignificant reduction of acute kidney injury by about 50% in the vasopressin group (OR 0.58; 95% CI 0.17-1.98; p = 0.38).16Dunser M.W. Bouvet O. Knotzer H. et al.Vasopressin in cardiac surgery: A meta-analysis of randomized controlled trials.J Cardiothorac Vasc Anesth. 2018; 32: 2225-2232Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar In summary, the meta-analysis by Dünser and colleagues16Dunser M.W. Bouvet O. Knotzer H. et al.Vasopressin in cardiac surgery: A meta-analysis of randomized controlled trials.J Cardiothorac Vasc Anesth. 2018; 32: 2225-2232Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar sheds some light on therapeutic options in patients with vasoplegia syndrome after cardiac surgery. The use of vasopressin reduces the amount of catecholamines by a synergistic noncatecholaminergic effect on vascular muscle tone, thereby allowing a more balanced vasopressor therapy.21Gordon A.C. Mason A.J. Thirunavukkarasu N. et al.Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial.JAMA. 2016; 316: 509-518Crossref PubMed Scopus (323) Google Scholar, 22Gordon A.C. Russell J.A. Walley K.R. et al.The effects of vasopressin on acute kidney injury in septic shock.Intensive Care Med. 2010; 36: 83-91Crossref PubMed Scopus (175) Google Scholar, 23Hajjar 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: 85-93Crossref PubMed Scopus (157) Google Scholar The reduced catecholamine doses might lower the incidence of catecholaminergic side effects, thereby elucidating the reduction of important postoperative complications such as AF and acute kidney injury found in several studies. The latter findings should encourage the use of vasopressin in vasoplegia syndrome despite a missing effect on mortality. What remains unclear is the ideal combination of such therapeutic approaches and their targets in vasoplegia syndrome. Which are the best goals for systolic, diastolic, or mean arterial pressure; for cardiac index; and for peripheral vascular resistance to minimize end-organ complications? Potentially, monitoring of microcirculation might further refine the optimal therapy in vasoplegia syndrome. Such type of monitoring together with an individualized administration of noncatecholamines and also nonvasopressor adjuncts finally might improve the outcome of patients with refractory vasoplegia syndrome after cardiac surgery. Future studies focusing on such strategies are warranted. The authors thank Allison Dwileski, BS, Department for Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland, for editorial assistance. Vasopressin in Cardiac Surgery: A Meta-analysis of Randomized Controlled TrialsJournal of Cardiothoracic and Vascular AnesthesiaVol. 32Issue 5PreviewTo summarize the results of randomized controlled trials on the use of vasopressin as a vasopressor agent in cardiac surgery. Full-Text PDF