Correspondence

Treating Patients with Severe Sepsis

N Engl J Med 1999; 341:56-57July 1, 1999

Article

To the Editor:

Drs. Wheeler and Bernard (Jan. 21 issue)1 provide an informative overview of the treatment of patients with severe sepsis. Their comments on the use of catecholamines for severe sepsis, especially as listed in Table 2, seem to reflect the effects observed under physiologic (nonseptic) conditions. In patients with sepsis, catecholamines may have different effects. Epinephrine decreases splanchnic blood flow, gastric mucosal pH, and splanchnic oxygen consumption and increases blood lactate concentrations in patients with sepsis.2,3 A group of specialists in sepsis has concluded that epinephrine should be avoided in the treatment of septic shock, leaving norepinephrine as the more suitable drug.4

As Wheeler and Bernard point out, there is no evidence that dopamine can prevent renal failure or otherwise protect the kidneys. In fact, dopamine may decrease intestinal mucosal perfusion.5 Furthermore, when infused for several days, dopamine may influence pituitary function, suggesting that it may participate in the endocrine response in patients with sepsis.6 For these reasons, we believe that dopamine should not be the catecholamine of first choice in the treatment of severe sepsis.

Andreas Meier-Hellmann, M.D.
Friedrich Schiller University, 07745 Jena, Germany

Donald L. Bredle, Ph.D.
University of Wisconsin–Eau Claire, Eau Claire, WI 54701

Konrad Reinhart, M.D.
Friedrich Schiller University, 07745 Jena, Germany

6 References

1
Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999;340:207-214
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2
Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, Spies CD, Hannemann L. Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med 1997;25:399-404
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3
Levy B, Bollaert PE, Charpentier C, et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med 1997;23:282-287
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4
Sibbald WJ, Vincent JL. Round table conference on clinical trials for the treatment of sepsis. Crit Care Med 1995;23:394-399
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5
Giraud GD, MacCannell KL. Decreased nutrient blood flow during dopamine- and epinephrine-induced intestinal vasodilation. J Pharmacol Exp Ther 1984;230:214-220
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6
Van den Berghe G, de Zegher F. Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med 1996;24:1580-1590
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To the Editor:

In their discussion of treatment for severe sepsis, Wheeler and Bernard state, “septic shock is initially characterized by a low capillary wedge pressure, a low cardiac index, and normal or elevated systemic vascular resistance.” This is not true in most cases of early sepsis, according to our current understanding.1 Septic shock, as defined by the American College of Chest Physicians and the Society of Critial Care Medicine, is sepsis with hypotension, despite adequate fluid resuscitation, along with perfusion-related abnormalities that may include, but are not limited to, lactic acidosis, oliguria, and an acute alteration of mental status.2 Septic shock, at least in its earliest phase, is a hyperdynamic state with high cardiac output, low systemic vascular resistance, and normal-to-low filling pressure. The decrease in vascular resistance seems to be directly related to various mediators, such as cytokines and nitric oxide, produced by the body in response to sepsis.

Volume deficiency, whether absolute or relative, is always a feature of septic shock, in part because of increased vascular permeability, as well as an altered distribution pattern. Thus, volume replacement is an important part of the treatment of septic shock, though by itself, it would never be sufficient to correct hypotension. Otherwise, septic shock would not be present.

Although cardiac output is high in the early phase of septic shock, cardiac function has already been compromised as a direct consequence of sepsis. This problem ultimately leads to a deterioration of cardiac function, in the absence of prompt treatment.

Fu Lung Luan, M.D.
Coney Island Hospital, Brooklyn, NY 11235

2 References

1
Jimenez EJ. Shock. In: Civetta JM, Taylor RW, Kirby RR, eds. Critical care. 3rd ed. Philadelphia: Lippincott-Raven, 1997:367-8.

2
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-874
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To the Editor:

In their comprehensive review of the treatment of patients with severe sepsis, Wheeler and Bernard point out that specific immunonutritional components have not been proved to diminish gastrointestinal dysfunction. This statement has to be questioned.

Data from 12 of the 13 prospective, randomized clinical trials discussed by Zaloga1 showed that the use of immunonutritional components could reduce the risk of septic complications and even shorten the hospital stay. Glutamine, especially, has been shown in experimental studies and in subsequent clinical studies to preserve the integrity of the gut. The increased synthesis of glutamine under the conditions of critical illness is not sufficient to meet the increased energy demands,2 and during severe sepsis, plasma levels and intracellular concentrations of glutamine are decreased. Thus, glutamine becomes an essential source of energy under these circumstances. Indeed, as a treatment for sepsis, the administration of glutamine has been shown to maintain mucosal weight and villous height.3 Preserving the structure of the gut by this mechanism may prevent bacterial translocation and septic complications.

More important, these findings were associated with an improved outcome. In experimental studies of sepsis, the administration of glutamine increased the rate of survival. With regard to clinical trials, Griffiths et al. reported a decreased mortality rate at six months among critically ill patients receiving glutamine-enriched parenteral nutrition.4 Data from multicenter, prospective clinical trials show that the rate of survival among patients with sepsis is increased even when other immunonutritional components are used.5

Glutamine is safe and does not have severe side effects when used for the treatment of sepsis. Nutrients, especially glutamine, should be considered as potentially valuable for the treatment of severe sepsis.

Thomas W. Felbinger, M.D.
Ulrich Suchner, M.D.
Alwin E. Goetz, M.D., Ph.D.
Ludwig-Maximilians University Medical Center, 81377 Munich, Germany

5 References

1
Zaloga GP. Immune-enhancing enteral diets: where's the beef? Crit Care Med 1998;26:1143-1146
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2
Noguchi Y, James JH, Fischer JE, Hasselgren PO. Increased glutamine consumption in small intestine epithelial cells during sepsis in rats. Am J Surg 1997;173:199-205
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3
van der Hulst RR, van Kreel BK, von Meyenfeldt MF, et al. Glutamine and the preservation of gut integrity. Lancet 1993;341:1363-1365
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4
Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295-302
Web of Science | Medline

5
Galban C, Celaya S, Marco P, Mesejo A, Montejo JC, Sanchez-Segura JM. An immune-enhancing enteral diet reduces mortality and episodes of bacteremia in septic ICU patients. JPEN 1998;22:S13-S13 abstract.

Author/Editor Response

The authors reply:

To the Editor: Dr. Luan points out the difficulty in defining septic shock. Hypotension in severe sepsis is associated with inadequate intravascular volume, vasomotor tone, and cardiac performance, all of which vary over time.1 Hence, fluid administration, a low-risk treatment that is rapidly accomplished, usually effective, and inexpensive, should be the initial means of resuscitation for any patient with hypotension and sepsis who does not already have clinically significant volume overload.

Felbinger et al. note the salutary effect of feeding on nutritional indexes, in vitro immune function, and the architecture of the gut. However, we do not believe there are compelling, reproducible data that support the recommendation of a particular enteral or parenteral formula.2 In the editorial cited by Felbinger et al., Zaloga discussed only one small study of patients with sepsis and specifically acknowledged that in the studies reviewed, there were numerous methodologic problems, overall mortality remained unaffected, and the essential active ingredient in the formulas used was unknown or unclear, making it impossible to recommend a single formula as the best one.3

Meier-Hellmann et al. point out that the pharmacologic effects of catecholamines in normal hosts may differ from the effects in patients with severe sepsis. Although we agree that epinephrine may have an adverse effect on splanchnic perfusion, the same effect can be observed with norepinephrine or dopamine. Until a large, appropriately designed trial directly compares the benefits of various vasoactive substances, physicians will have to determine the benefits in each individual patient.

We recognize the limitations of current definitions of sepsis and its subtypes, but without consensus definitions, even if they are flawed, we will have no common ground for investigation. Additional large, well-designed, randomized clinical trials are clearly needed to answer important questions about the support of critically ill patients.

Arthur P. Wheeler, M.D.
Gordon R. Bernard, M.D.
Vanderbilt University School of Medicine, Nashville, TN 37232-2650

3 References

1
Rackow EC, Falk JL, Fein IA, et al. Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crit Care Med 1983;11:839-850
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2
Heyland DK. Nutritional support in the critically ill patients: a critical review of the evidence. Crit Care Clin 1998;14:423-440
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