Correspondence

Goal-Directed Therapy for Severe Sepsis

N Engl J Med 2002; 346:1025-1026March 28, 2002

Article

To the Editor:

Rivers et al. (Nov. 8 issue)1 report on goal-directed therapy for severe sepsis and septic shock. Although their findings are interesting and provocative, they should be interpreted with caution. The end points of therapy and the treatment approaches used are somewhat troubling. The central venous pressure is a poor indicator of intravascular volume.2 Furthermore, mixed venous oxygen saturation (SmvO₂), and, by inference, central venous oxygen saturation (ScvO₂), are poorly correlated with cardiac output and indexes of tissue oxygenation.2,3 The use of packed cells as first-line therapy to increase the ScvO₂ in the patients assigned to early goal-directed therapy is worrisome. There is good evidence that packed red cells do not increase oxygen consumption (at least in the first 24 hours) in patients with sepsis.4 Paradoxically, “old” units of packed red cells may cause tissue dysoxia in patients with sepsis.4 Furthermore, transfusions of packed red cells may increase mortality in critically ill patients with sepsis.5,6

How, then, does one reconcile these facts with the impressive results of the study by Rivers et al.? Clearly, early, aggressive resuscitation of patients with sepsis improves the outcome. The patients in the early-therapy group received, on average, approximately 1500 ml more in total fluids in the first six hours of treatment than did the standard-therapy group and had a significantly higher mean arterial pressure (mean [±SD], 95±19 vs. 81±18 mm Hg; P<0.001). These findings may be important in explaining the difference in outcome between the two groups. We wholeheartedly endorse the concept of early, aggressive volume resuscitation in patients with sepsis, but please do not transfuse blood and do not be misled by the SmvO₂ or ScvO₂.

Paul E. Marik, M.D.
University of Pittsburgh Medical School, Pittsburgh, PA 15261
pmarik@zbzoom.net

Joseph Varon, M.D.
Baylor College of Medicine, Houston, TX 77030

6 References

1. 1

   Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377
   Full Text | Web of Science | Medline

2. 2

   Marik PE, Varon J. The hemodynamic derangements in sepsis: implications for treatment strategies. Chest 1998;114:854-860
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   Marik PE. Sublingual capnography: a clinical validation study. Chest 2001;120:923-927
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   Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993;269:3024-3029
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5. 5

   Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-417
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   Purdy FR, Tweeddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997;44:1256-1261
   CrossRef | Web of Science | Medline

To the Editor:

Rivers et al. report an impressive reduction in in-hospital mortality in the group of patients with sepsis who received early goal-directed therapy, as compared with those who received standard therapy (absolute reduction, 16 percent). We are concerned, however, that the elevated mortality rate in the standard-therapy group (46.5 percent) may account for these results. In two recent trials of the treatment of severe sepsis, reported by Bernard et al.1 and Warren et al.,2 the mortality rate at 28 days was 30.8 percent and 38.7 percent, respectively, in the placebo groups. These studies involved 1690 and 2314 patients, respectively, with scores for disease severity in the control groups that were similar to the scores in the standard-therapy group in the study by Rivers et al. (Acute Physiology and Chronic Health Evaluation [APACHE II] score, 25.0±7.8 and 20.4±7.4 in the studies by Bernard et al. and Rivers et al., respectively; Simplified Acute Physiology Score II, 49±16 and 48.8±11.1 in the studies by Warren et al. and Rivers et al., respectively).

Fekri Abroug, M.D.
Lamia Besbes, M.D.
Semir Nouira, M.D.
Centre Hospitalier Universitaire Fatouma Bourguiba, 5000 Monastir, Tunisia
f.abroug@rns.tn

2 References

1. 1

   Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
   Full Text | Web of Science | Medline

2. 2

   Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-1878
   CrossRef | Web of Science | Medline

To the Editor:

Rivers et al. report that early goal-directed therapy provided in the emergency department to patients with severe sepsis and septic shock resulted in a significantly lower mortality than that associated with standard therapy. However, there was a statistically significant difference between the two groups in the rate of achievement of the stated hemodynamic goals. The goals were achieved in 86.1 percent of the patients assigned to standard therapy and in 99.2 percent of those assigned to early goal-directed therapy (P<0.001). A potentially major bias in this study is that it was unblinded, since blinding was not feasible, given the study design. Knowledge of the treatment assignments may have led to a difference in the intensity of bedside care between the two groups. A lower level of intensity in the care given to the standard-therapy group would have resulted in an inability to achieve the investigators' stated goals in this group. This explanation may account for the difference in the incidence of sudden cardiovascular collapse between the two groups and, therefore, the decreased survival in the standard-therapy group.

We agree with the authors' conclusion that “benefits arise from the early identification of patients at high risk for cardiovascular collapse” but believe that these tasks of identification and prevention are best served by intensive bedside care and treatment rather than by the use of additional costly monitoring devices of unproved efficacy.

Samir Sarkar, M.D.
Yizhak Kupfer, M.D.
Sidney Tessler, M.D.
Maimonides Medical Center, Brooklyn, NY 11219
stessler@maimonidesmed.org

Author/Editor Response

The authors reply:

To the Editor: In response to Drs. Marik and Varon: our protocol was derived from the guidelines for hemodynamic support in adults with sepsis issued by the Society of Critical Care Medicine,1 which discuss the variables that Marik and Varon believe warrant caution (central venous pressure and venous oxygen saturation),2,3 including red-cell transfusion. A decreased value for SmvO₂ or ScvO₂ and an increased lactate level (as in our patients), at any given cardiac index, indicate supply dependency, necessitating further resuscitation.1 Furthermore, in high-risk elderly patients with cardiovascular disease (such as those in our study), a hematocrit of 30 percent is associated with improved survival.1,4

In response to Sarkar et al.: all patients in both treatment groups met the protocol goals for central venous pressure and mean arterial pressure during the first six hours. In 13.7 percent of the patients in the early-therapy group, ScvO₂ was low after the central venous pressure, mean arterial pressure, and hematocrit had been normalized, indicating myocardial suppression and necessitating inotropic therapy.1 With improved myocardial contractility and compliance, the central venous pressure subsequently decreases, triggering additional administration of fluids. This conversion of pressure to a volume interpretation of central venous pressure was not apparent in the control group in the absence of continuous monitoring of ScvO₂. This early recognition of myocardial dysfunction is important because it approximates the mortality benefit.

Venous oximetry is not new and has been extensively studied for more than two decades. Our early use of it as an adjunct in the resuscitation of patients with sepsis is novel. Contrary to the claim by Sarkar et al. that our approach is costly and unproved, it resulted in four fewer days of hospitalization among survivors and decreased the rate of use of pulmonary-artery catheterization by 13.9 percentage points.

In response to Abroug et al.: the APACHE II scores, when used to predict mortality, are computed on the basis of the most abnormal variables in a 24-hour period after admission to the intensive care unit. Our intent was to assess and compare the severity of illness (not mortality) at “nontraditional” time points for scoring (starting within one hour after arrival at the hospital). Because a significant cause of early death was sudden cardiovascular collapse in seemingly stable patients before the onset of serious organ failure, the scores in our study were similar to those in the two cited at base line, but in our study, in-hospital mortality was higher. To reflect mortality adequately, scoring systems must be recalibrated to better weigh coexisting conditions, assess the severity of shock, and reflect events before admission to the intensive care unit. As another reference population, the control group in the study by Gattinoni et al. had a mortality rate of 48.4 percent.3

Emanuel P. Rivers, M.D., M.P.H.
H. Bryant Nguyen, M.D.
Henry Ford Hospital, Detroit, MI 48202
erivers1@hfhs.org

4 References

1. 1

   Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 1999;27:639-660
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2. 2

   Cohn JN. Central venous pressure as a guide to volume expansion. Ann Intern Med 1967;66:1283-1287
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3. 3

   Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995;333:1025-1032
   Full Text | Web of Science | Medline

4. 4

   Hebert PC, Wells G, Tweeddale M, et al. Does transfusion practice affect mortality in critically ill patients? Am J Respir Crit Care Med 1997;155:1618-1623
   Web of Science | Medline

Citing Articles (11)

Citing Articles

1. 1

   Rory O’Neill, Javier Morales, Michael Jule. (2011) Early Goal-directed Therapy (EGDT) for Severe Sepsis/Septic Shock: Which Components of Treatment are More Difficult to Implement in a Community-based Emergency Department?. The Journal of Emergency Medicine
   CrossRef

2. 2

   Andre C. Kalil. (2010) Wanted: early goal-directed therapy for septic shock—dead or alive, but not critically ill!. Intensive Care Medicine 36:1, 1-3
   CrossRef

3. 3

   Maryn McKenna. (2008) Controversy Swirls Around Early Goal-Directed Therapy in Sepsis: Pioneer Defends Ground-Breaking Approach to Deadly Disease. Annals of Emergency Medicine 52:6, 651-654
   CrossRef

4. 4

   Alan E. Jones, Michael D. Brown, Stephen Trzeciak, Nathan I. Shapiro, John S. Garrett, Alan C. Heffner, Jeffrey A. Kline. (2008) The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis*. Critical Care Medicine 36:10, 2734-2739
   CrossRef

5. 5

   David A. Talan, Gregory J. Moran, Fredrick M. Abrahamian. (2008) Severe Sepsis and Septic Shock in the Emergency Department. Infectious Disease Clinics of North America 22:1, 1-31
   CrossRef

6. 6

   Michael W. Donnino, Peter Clardy, Daniel Talmor. (2007) A central venous pressure goal of 8???12 mm Hg for all patients in septic shock. Critical Care Medicine 35:5, 1441
   CrossRef

7. 7

   (2007) Management of Sepsis. New England Journal of Medicine 356:11, 1178-1182
   Full Text

8. 8

   Mercedes Palomar, Rafael Canton, Juan de Dios Colmenero, Emili Díaz, Pilar Marco, Pedro Olaechea, Miguel Sánchez, Jordi Vila, Rafael Zaragoza, Francisco Gudiol. (2007) Update: sepsis and septic shock. Enfermedades Infecciosas y Microbiología Clínica 25, 58-66
   CrossRef

9. 9

   Ian Jenkins. (2006) Evidence-based sepsis therapy: A hospitalist perspective. Journal of Hospital Medicine 1:5, 285-295
   CrossRef

10. 10

    Michael H. Dueck, Markus Klimek, Stefan Appenrodt, Christoph Weigand, Ulf Boerner. (2005) Trends but Not Individual Values of Central Venous Oxygen Saturation Agree with Mixed Venous Oxygen Saturation during Varying Hemodynamic Conditions. Anesthesiology 103:2, 249-257
    CrossRef

11. 11

    Paul E Marik. (2005) Regional carbon dioxide monitoring to assess the adequacy of tissue perfusion. Current Opinion in Critical Care 11:3, 245-251
    CrossRef