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European Heart Journal Advance Access originally published online on April 25, 2007
European Heart Journal 2007 28(9):1109-1116; doi:10.1093/eurheartj/ehm075
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study

Vladimir Dzavík1,*, Gad Cotter2, Harmony R. Reynolds3, John H. Alexander2, Krishnan Ramanathan3, Amanda L. Stebbins2, David Hathaway4, Michael E. Farkouh3, E. Magnus Ohman5, David A. Baran6, Roland Prondzinsky7, Julio A. Panza8, Warren J. Cantor9, Zvi Vered10, Christopher E. Buller11, Neal S. Kleiman12, John G. Webb13, David R. Holmes14, Joseph E. Parrillo15, Stanley L. Hazen17, Steven S. Gross16, Robert A. Harrington2, Judith S. Hochman for the SHould we inhibit nitric Oxide synthase in Cardiogenic shocK 2 (SHOCK-2) Investigators3,*

1 University Health Network, Toronto General Hospital, 6-246, 200 Elizabeth Street, Toronto M5G 2C4, Ontario, Canada
2 Duke Clinical Research Institute, Durham, NC, USA
3 New York University, New York, NY, USA
4 Arginox Pharmaceuticals, Redwood Shores, CA, USA
5 University of North Carolina, Chapel Hill, NC, USA
6 Newark Beth Israel Medical Center, Newark, NJ, USA
7 Martin Luther University, Halle, Germany
8 Washington Hospital, Washington, DC, USA
9 St Michael's Hospital, Toronto, Ontario, Canada
10 Assaf Harofeh Medical Center, Zerifin, Israel
11 Vancouver General Hospital, Vancouver, British Columbia, Canada
12 Baylor College of Medicine, Houston, TX, USA
13 St Paul's Hospital, Vancouver, British Columbia, Canada
14 Mayo Clinic, Rochester, MN, USA
15 Cooper University Hospital, Camden, NJ, USA
16 Cornell University, New York, NY, USA
17 Cleveland Clinic Foundation, Cleveland, OH, USA

Received 20 December 2006; accepted 7 March 2007; online publish-ahead-of-print 25 April 2007.

* Corresponding authors. Tel: +1 416 340 4800 (extension 6265); fax: +1 416 340 3390; or Tel: +1 212 263 2697; fax: +1 212 263 7129 E-mail address: vlad.dzavik{at}uhn.on.ca or Judith.Hochman{at}med.nyu.edu

Aims: Previous studies suggested haemodynamic benefits and, possibly, mortality reduction with the use of nitric oxide synthase (NOS) inhibition in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). We assessed preliminary efficacy and safety of four doses of L-N-monomethyl-arginine (L-NMMA), a non-selective NOS inhibitor, in patients with AMI complicated by CS despite an open infarct-related artery.

Methods and results: Patients (n = 79) were randomly assigned to a bolus and 5 h infusion of placebo or 0.15, 0.5, 1.0, or 1.5 mg/kg of L-NMMA. The primary outcome measure was absolute change in mean arterial pressure (MAP) at 2 h. Fifteen minutes after study drug initiation, mean change in MAP was –4.0 mmHg in the placebo group and 5.8 (P = 0.02), 4.8 (P = 0.02), 5.1 (P = 0.07), and 11.6 (P < 0.001) mmHg in the four L-NMMA groups, respectively (all vs. placebo). Mean change in MAP at 2 h was –0.4, 4.4, 1.8, –4.1, and 6.8 mmHg in the placebo and four L-NMMA groups, respectively (all P = NS).

Conclusion: L-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h.

Key Words: Acute myocardial infarction • Cardiogenic shock • Inflammation • Nitric oxide synthase • L-N-monomethyl-arginine (L-NMMA)


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