Correspondence

Pathogenetic Mechanisms of Septic Shock

N Engl J Med 1993; 329:1427-1428November 4, 1993

Article

To the Editor:

Dr. Parrillo (May 20 issue)1 raises an important issue concerning the use of inhibitors of nitric oxide synthase in septic shock in his article “Pathogenetic Mechanisms of Septic Shock.” The view that these inhibitors may be harmful in the treatment of septic shock is based on experiments in animals given 2 to 4 mg of endotoxin per kilogram of body weight. These amounts of endotoxin are 1 million times greater than those that cause cardiovascular changes in humans2. In contrast, only concentrations of endotoxin measurable in picograms per milliliter have been detected in the serum of patients with septic shock. Although the administration of very high doses of endotoxin to animals results in marked cardiac decompensation that is not influenced by or attributable to nitric oxide synthase inhibitors,3 in animals given lower doses of endotoxin or cytokines that are known to mediate septic shock, these inhibitors are potent and potentially useful pressor agents4. In preliminary studies of patients with septic shock, the administration of N^G-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, resulted in a prompt increase in blood pressure5. Although inhibitors of nitric oxide synthase are a novel class of drugs and specific compounds may have unexpected toxic effects, they may be useful for a condition that is difficult to treat and associated with a high mortality.

Robert G. Kilbourn, M.D., Ph.D.
University of Texas, Houston, TX 77030

Owen W. Griffith, Ph.D.
Medical College of Wisconsin, Milwaukee, WI 53226

Steven S. Gross, Ph.D.
Cornell University Medical College, New York, NY 10021

5 References

1. 1

   Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993;328:1471-1477
   Full Text | Web of Science | Medline

2. 2

   Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321:280-287
   Full Text | Web of Science | Medline

3. 3

   Klabunde RE, Helgren CM. Cardiovascular actions of N^G-methyl-L-arginine are abolished in a canine shock model using high-dose endotoxin. Res Commun Chem Pathol Pharmacol 1992;78:57-68
   Medline

4. 4

   Kilbourn RG, Jubran A, Gross SS, et al. Reversal of endotoxin-mediated shock by N^G-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 1990;172:1132-1138
   CrossRef | Web of Science | Medline

5. 5

   Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991;338:1557-1558
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Parrillo replies:

To the Editor: Kilbourn and colleagues argue that very high doses of endotoxin may account for the lack of beneficial effect of nitric oxide synthase inhibitors in some experimental models. The dose response to endotoxin varies widely among species; humans are relatively sensitive. In evaluating these experiments, the main issue concerns how closely any model mimics the cardiovascular and multiorgan responses typical of septic shock in humans. In general, models using large animals, live infecting microorganisms, a nidus of infection, no anesthesia, and an evaluation period of several days (the usual time course of septic shock) are preferred because they provide lessons that can be extrapolated to human disease. The animals should have refractory hypotension and failure of multiple organ systems, the problems that lead to morbidity and mortality in humans1.

Inhibitors of nitric oxide synthesis reversed hypotension transiently in dogs given endotoxin, but no animals were given endotoxin alone2. In dogs given endotoxin that had the cardiac and vascular changes of sepsis and measurable mortality, inhibition of nitric oxide synthesis increased systemic and pulmonary vascular resistance, decreased cardiac output and oxygen delivery, did not change blood pressure, and increased mortality3. One can hypothesize that nitric oxide is needed to ensure adequate microcirculatory flow and that the inhibition of its action leads to worsened tissue perfusion, although systemic blood pressure may be increased.

Kilbourn et al. note that the administration of N^G-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, to patients with “refractory” septic shock promptly increased blood pressure4. However, these reports were anecdotal, did not use a standard definition of “refractory,” and did not compare the ability of the inhibitors to maintain blood pressure with that of conventional vasopressor drugs. Since this report concerned only blood pressure, one worries that inhibition may worsen microvascular perfusion and increase morbidity and mortality.

Many of the pathogenetic mechanisms in septic shock represent the body's compensatory response to the toxins of sepsis and therefore have salutary effects. We must tailor our mediator inhibitors to interrupt harmful pathways and not interfere with the beneficial compensatory mechanisms. At present, studies in animals suggest that the inhibition of nitric oxide synthesis may have a harmful effect on outcome; therefore, more investigation is needed before one can advocate this method of managing septic shock.

Joseph E. Parrillo, M.D.
Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612

4 References

1. 1

   Parrillo JE, moderator. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990;113:227-242
   Web of Science | Medline

2. 2

   Kilbourn RG, Jubran A, Gross SS, et al. Reversal of endotoxin-mediated shock by N^G-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 1990;172:1132-1138
   CrossRef | Web of Science | Medline

3. 3

   Cobb JP, Natanson C, Hoffman WD, et al. N^ω-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 1992;176:1175-1182
   CrossRef | Web of Science | Medline

4. 4

   Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991;338:1557-1558
   CrossRef | Web of Science | Medline

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   Hafida Bentala, Willem R. Verweij, Ali Huizinga-Van der Vlag, Annemiek M. van Loenen-Weemaes, Dirk K. F. Meijer, Klaas Poelstra. (2002) Removal of Phosphate from Lipid A as a Strategy to Detoxify Lipopolysaccharide. Shock 18:6, 561-566
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   C. Erik Hack, Sacha Zeerleder. (2001) The endothelium in sepsis: Source of and a target for inflammation. Critical Care Medicine 29, S21-S27
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   Bradley D. Freeman, Fabrice Zeni, Steven M. Banks, Peter Q. Eichacker, John D. Bacher, Edward P. Garvey, Joel V. Tuttle, Cynthia H. Jurgensen, Charles Natanson, Robert L. Danner. (1998) Response of the septic vasculature to prolonged vasopressor therapy with N (omega-monomethyl-L-arginine) and epinephrine in canines. Critical Care Medicine 26:5, 877-886
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