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Correspondence  |   January 2018
In Reply
Author Notes
  • University of British Columbia and St. Paul’s Hospital, Vancouver, British Columbia, Canada. jim.russell@hli.ubc.ca
  • (Accepted for publication September 27, 2017.)
    (Accepted for publication September 27, 2017.)×
Article Information
Correspondence
Correspondence   |   January 2018
In Reply
Anesthesiology 1 2018, Vol.128, 230-231. doi:10.1097/ALN.0000000000001957
Anesthesiology 1 2018, Vol.128, 230-231. doi:10.1097/ALN.0000000000001957
Drs. Fan and Faraday write with concerns about the Vasopressin and Cardiac Surgery Trial1  and my editorial2 ; I agree with some, but not all, of their points. My first point of agreement is the criticism that clinical treatment was not protocolized; however, in most randomized controlled trials, nonrandomized care is most often not protocolized for simple logistical reasons. The point is that nonprotocolized care was used in both masked arms of the Vasopressin and Cardiac Surgery Trial. Greater use of dobutamine in the norepinephrine group in the Vasopressin and Cardiac Surgery Trial could have been because vasopressin had less negative inotropic effects than norepinephrine, as vasopressin has some vasodilation action due to release of nitric oxide.3,4 
Another point of agreement is Drs. Fan and Faraday’s “caution against generalizing these results across centers and to bias against specific drugs classes.” Indeed, I stated: “in settings such as the study hospital [my italics for emphasis herein], vasopressin infusion for treatment of vasodilatory shock after cardiac surgery may improve some clinically important outcomes.”2  I also stand by my recommendation that “this trial deserves replication in other multicenter healthcare settings [my italics for emphasis herein] to create confidence about generalizability.”
Drs. Fan and Faraday state that in the Vasopressin and Cardiac Surgery Trial masked infusion doses of vasopressin and norepinephrine were not equivalent, and that norepinephrine doses (10 to 60 μg/min) were about five times higher than those used in their center (a citation or a table of their actual data would be helpful here). They state that in the Vasopressin and Septic Shock Trial5  norepinephrine doses were 5 to 15 μg/min, but that is not correct. Supplemental Digital Content (http://links.lww.com/ALN/B337) shows mean doses of 15 to 17 and upper SD of 27 μg/min in the Vasopressin and Septic Shock Trial. The literature regarding norepinephrine doses in vasodilatory shock after cardiovascular surgery helps somewhat here6–9 : norepinephrine doses were up to (upper SD) 40 μg/min,6  10 μg/min,8  and 30 μg/min,9  suggesting that norepinephrine doses may have been lower in previous studies of vasopressin versus norepinephrine in cardiovascular surgery than in the Vasopressin and Cardiac Surgery Trial.
My points of disagreement include unequal dosing regimens for vasopressin and norepinephrine having the potential to unmask the clinical care and that “differences between treatment groups in duration and alternative pressor/inotrope usage would also be noticeable to clinicians.” I am not sure how one can ever prove that masked treatment arms were effectively unmasked in blinded, randomized controlled trials. Drs. Fan and Faraday assume that the vasoconstriction and increased blood pressure effects would have been greater in the norepinephrine arm; however, they do not mention that in both arms, patients are also randomly improving or deteriorating, so mean arterial pressure is changing independent of vasopressin or norepinephrine effects, therefore making efforts to unmask a risky business at best.
Another point of partial disagreement is in the assertion that “overall complication rates reported in this study are much higher than expected.” I am not entirely sure this is true because one has to review such rates in the remarkably few reported cohorts and randomized controlled trials of patients with vasodilatory shock after cardiovascular surgery. The 60 to 80% incidence of atrial fibrillation in the Vasopressin and Cardiac Surgery Trial does seem high and may indicate that patients in the Vasopressin and Cardiac Surgery Trial were sicker than those in other vasodilatory cohorts and randomized controlled trials. I also previously stated that “mortality rates were high—16 and 15% at 28 days and 17 and 16% at 90 days (norepinephrine vs. vasopressin)—in the Vasopressin and Cardiac Surgery Trial; remarkably, mortality rates were not reported in previous smaller trials of vasopressin versus norepinephrine for vasodilatory shock after cardiac surgery.”6,8–10 
To conclude, I recommend that Drs. Fan, Faraday, and others: (1) create multicenter registries of vasodilatory shock after cardiovascular surgery to understand risks and outcomes of same; (2) do proof-of-principle randomized controlled trials of novel compounds, such as the selective V1a agonist selepressin11,12  and angiotensin 213 ; and (3) do large, pivotal, randomized controlled trials of vasopressin versus norepinephrine in North America to see whether the Vasopressin and Cardiac Surgery Trial results are applicable in this setting.
Competing Interests
Dr. Russell reports patents owned by the University of British Columbia (Vancouver, British Columbia, Canada) that are related to PCSK9 inhibitor(s) and sepsis, and related to the use of vasopressin in septic shock. He is an inventor on these patents. Dr. Russell is a founder, director, and shareholder in Cyon Therapeutics, Inc. (Vancouver, British Columbia, Canada; developing a sepsis therapy). He has share options in Leading Biosciences, Inc. (Carlsbad, California), and he is a shareholder in Molecular You Corp. (Vancouver, British Columbia, Canada). Dr. Russell also reports receiving consulting fees from: Cubist Pharmaceuticals (now owned by Merck, New York, New York; formerly was Trius Pharmaceuticals; developing antibiotics); Leading Biosciences (developing a sepsis therapeutic); Ferring Pharmaceuticals (Copenhagen, Denmark; manufactures vasopressin and is developing selepressin); Grifols (Barcelona, Spain; sells albumin); La Jolla Pharmaceuticals (San Diego, California; developing angiotensin II; Dr. Russell chairs the DSMB of a trial of angiotensin II); CytoVale, Inc. (San Francisco, California; developing a sepsis diagnostic); and Asahi Kesai Pharmaceuticals of America (AKPA, Waltham, Massachusetts; developing recombinant thrombomodulin). Dr. Russell reports having received an investigator-initiated grant from Grifols that is provided to and administered by University of British Columbia.
James A. Russell, A.B., M.D., University of British Columbia and St. Paul’s Hospital, Vancouver, British Columbia, Canada. jim.russell@hli.ubc.ca
References
Hajjar, LA, Vincent, JL, Barbosa Gomes Galas, FR, Rhodes, A, Landoni, G, Osawa, EA, Melo, RR, Sundin, MR, Grande, SM, Gaiotto, FA, Pomerantzeff, PM, Dallan, LO, Franco, RA, Nakamura, RE, Lisboa, LA, de Almeida, JP, Gerent, AM, Souza, DH, Gaiane, MA, Fukushima, JT, Park, CL, Zambolim, C, Rocha Ferreira, GS, Strabelli, TM, Fernandes, FL, Camara, L, Zeferino, S, Santos, VG, Piccioni, MA, Jatene, FB, Costa Auler, JOJr, Filho, RK Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: The VANCS randomized controlled trial. Anesthesiology 2017; 126:85–93 [Article] [PubMed]
Russell, JA Vasopressin, norepinephrine, and vasodilatory shock after cardiac surgery: Another “VASST” difference? Anesthesiology 2017; 126:9–11 [Article] [PubMed]
O’Connor, PM, Cowley, AWJr Vasopressin-induced nitric oxide production in rat inner medullary collecting duct is dependent on V2 receptor activation of the phosphoinositide pathway. Am J Physiol Renal Physiol 2007; 293:F526–32 [Article] [PubMed]
Rudichenko, VM, Beierwaltes, WH Arginine vasopressin-induced renal vasodilation mediated by nitric oxide. J Vasc Res 1995; 32:100–5 [Article] [PubMed]
Russell, JA, Walley, KR, Singer, J, Gordon, AC, Hébert, PC, Cooper, DJ, Holmes, CL, Mehta, S, Granton, JT, Storms, MM, Cook, DJ, Presneill, JJ, Ayers, D VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–87 [Article] [PubMed]
Argenziano, M, Chen, JM, Choudhri, AF, Cullinane, S, Garfein, E, Weinberg, AD, Smith, CRJr, Rose, EA, Landry, DW, Oz, MC Management of vasodilatory shock after cardiac surgery: Identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998; 116:973–80 [Article] [PubMed]
Morales, D, Madigan, J, Cullinane, S, Chen, J, Heath, M, Oz, M, Oliver, JA, Landry, DW Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock. Circulation 1999; 100:226–9 [Article] [PubMed]
Morales, DL, Garrido, MJ, Madigan, JD, Helman, DN, Faber, J, Williams, MR, Landry, DW, Oz, MC A double-blind randomized trial: Prophylactic vasopressin reduces hypotension after cardiopulmonary bypass. Ann Thorac Surg 2003; 75:926–30 [Article] [PubMed]
Morales, DL, Gregg, D, Helman, DN, Williams, MR, Naka, Y, Landry, DW, Oz, MC Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac Surg 2000; 69:102–6 [Article] [PubMed]
Elgebaly, AS, Sabry, M Infusion of low-dose vasopressin improves left ventricular function during separation from cardiopulmonary bypass: A double-blind randomized study. Ann Card Anaesth 2012; 15:128–33 [Article] [PubMed]
Russell, JA VJ, Kjolbye, A, Olsson, H, Blemings, A, Grundemar, L Selepressin, a novel selective V1a agonist, reduces norepinephrine requirements and shortens duration of organ dysfunction in septic shock patients. Crit Care Med 2012; 40:1 [PubMed]
He, X, Su, F, Taccone, FS, Laporte, R, Kjølbye, AL, Zhang, J, Xie, K, Moussa, MD, Reinheimer, TM, Vincent, JL A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit Care Med 2016; 44:23–31 [Article] [PubMed]
Khanna, A, English, SW, Wang, XS, Ham, K, Tumlin, J, Szerlip, H, Busse, LW, Altaweel, L, Albertson, TE, Mackey, C, McCurdy, MT, Boldt, DW, Chock, S, Young, PJ, Krell, K, Wunderink, RG, Ostermann, M, Murugan, R, Gong, MN, Panwar, R, Hästbacka, J, Favory, R, Venkatesh, B, Thompson, BT, Bellomo, R, Jensen, J, Kroll, S, Chawla, LS, Tidmarsh, GF, Deane, AM ATHOS-3 Investigators: Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017; 377:419–30 [Article] [PubMed]