Correspondence

Goal-Oriented Hemodynamic Therapy

N Engl J Med 1996; 334:799-800March 21, 1996

Article

To the Editor:

In their prospective, multicenter trial, Gattinoni and colleagues (Oct. 19 issue)1 evaluated the effects of increasing the cardiac index to a supranormal level or increasing mixed venous oxygen saturation to a normal level on the survival of critically ill patients. These resuscitative end points have been associated with increased survival in several prospective studies of critically ill patients.2-4 A popular explanation for this favorable association is that the imbalance between oxygen supply and demand in critically ill patients is minimal or absent when a supranormal level of oxygen delivery or a normal level of mixed venous oxygen saturation is achieved. However, easily obtained metabolic markers of the imbalance between oxygen supply and demand are not mentioned in the report by Gattinoni et al. When oxygen demands are not met, anaerobic metabolic pathways are activated, leading to the generation of hydrogen ions and lactic acid. The balance between the oxygen supply and the demand for oxygen, or oxygen debt, can be evaluated clinically by assessing the acid–base status of critically ill patients. Nevertheless, the blood lactate level and gastric intramucosal pH level were not assessed in this study, nor were the bicarbonate level, anion gap, and other acid–base measurements that are more commonly available but less specific.

If it is assumed that the critically ill patients in the study by Gattinoni et al. presented with a range of oxygen debt from absent to increased, the negative results of the study may be misleading. The survival benefit of increased oxygen delivery in patients with regional or systemic oxygen debt may have been obscured by the potentially negative clinical consequences of unnecessary fluid loading, blood transfusion, and administration of catecholamine inotropic medications in patients without oxygen debt and therefore without a need for increased oxygen delivery.

The authors' conclusion that achieving a supranormal cardiac index or a normal level of mixed venous oxygen saturation does not reduce morbidity or mortality among critically ill patients may indeed be true when applied to populations of patients with a wide range of disease severity. However, the authors have not reported on important subgroups of patients with signs of metabolic or lactic acidosis. Such patients can easily be identified in most clinical settings and may benefit from therapy aimed at achieving these rational goals.

Marilyn T. Haupt, M.D.
Wayne State University School of Medicine, Detroit, MI 48201

4 References

1
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

2
Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988;94:1176-1186
CrossRef | Web of Science | Medline

3
Tuchschmidt J, Fried J, Astiz M, Rackow E. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992;102:216-220
CrossRef | Web of Science | Medline

4
Yu M, Levy MM, Smith P, Takiguchi SA, Miyasaki A, Myers SA. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study. Crit Care Med 1993;21:830-838
CrossRef | Web of Science | Medline

To the Editor:

Gattinoni et al. report a failure to reduce mortality and morbidity with hemodynamic therapy in critically ill patients admitted to intensive care units with organ failure an unspecified number of days after surgery. Both the authors and Hinds and Watson, in an accompanying editorial,1 have misunderstood and misrepresented the studies that my colleagues and I performed, which were intended to prevent organ failure and death in high-risk surgical patients by optimizing oxygen transport in the first 8 to 12 hours after surgery.2,3 I find it rather disingenuous to test our regimen for preventing organ failure in patients who already had organ failure as a precondition for admission to the intensive care unit, because the reversibility of oxygen debt from circulatory deficiency is obviously related to time.

The assumption my colleagues and I made was that oxygen debt from hypovolemia with a maldistribution of the microcirculatory flow leads to tissue hypoxia, organ failure, and death, a sequence that may be preventable if corrected early according to empirically determined values for cardiac index, oxygen delivery, and oxygen consumption in survivors.3 In their randomized clinical trial, Boyd et al.4 went one step further, by optimizing oxygen delivery before surgery and then maintaining these supranormal values during the intraoperative and early postoperative periods; in their study, mortality was reduced by 75 percent. Gattinoni et al., like Hayes et al.,5 have done us a service by pointing out the limitations of our approach, which clearly does not prevent organ failure and death in patients who already have established organ failure. We concur that it is impossible to resuscitate dead cells and failed organs, even with oxygen.

An intention-to-treat analysis is a weak approach when therapeutic goals are not reached in over half the patients in a study. The high average values in this subgroup may be confounded by a small percentage of patients with late sepsis, who usually have very high cardiac indexes associated with hypermetabolism.

More important, the real message of these temporal relations has been completely missed. Despite the evidence from our studies and the study by Boyd et al.4 that organ failure and mortality can be markedly reduced by prophylactic therapy, the common practice in many centers in Europe, as well as the United States, is to admit patients to the intensive care unit only after organ failure has occurred. Treatment of late-stage disease with organ failure in the intensive care unit consumes valuable resources with limited benefit, and earlier efforts would probably achieve better results less expensively. Clearly, intensive care units give too much too late to too few.

William C. Shoemaker, M.D.
Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, CA 90059

5 References

1
Hinds C, Watson D. Manipulating hemodynamics and oxygen transport in critically ill patients. N Engl J Med 1995;333:1074-1075
Full Text | Web of Science | Medline

2
Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988;94:1176-1186
CrossRef | Web of Science | Medline

3
Shoemaker WC, Kram HB, Appel PL, Fleming AW. The efficacy of central venous and pulmonary artery catheters and therapy based upon them in reducing mortality and morbidity. Arch Surg 1990;125:1332-1339
Web of Science | Medline

4
Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993;270:2699-2707
CrossRef | Web of Science | Medline

5
Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-1722
Full Text | Web of Science | Medline

To the Editor:

. . . Since when do we ignore diagnosis in providing treatment? Since when do we treat effects rather than causes? It is time to go back to the basics. We treat massive blood loss with blood, septic shock with antibiotics, acute respiratory failure with respiratory support, and so forth. Correction of the cardiac output, oxygen delivery, oxygen consumption, and arteriovenous oxygen difference will follow automatically.

Francis J. Haddy, M.D., Ph.D.
Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799

To the Editor:

Immediate fluid resuscitation in all hypotensive and hypovolemic patients with trauma, a hitherto undisputed doctrine of critical care, has recently been challenged.1 The optimal volume and timing of fluid administration in patients with shock is under debate. Indeed, survival in animals is reduced if fluids are given for uncontrolled hemorrhage,2 and hypotensive patients with penetrating torso injuries do better when aggressive fluid resuscitation is delayed.3 Early expansion of the circulating volume is thus controversial (at least in some patients with shock), not crucial, as Hinds and Watson claim in their editorial on the wisdom of attempting to improve the outcome of critical disease by replicating the hemodynamic values found in survivors of serious disease or trauma.

Bruno Simini, M.D
Ospedale Generale Provinciale, 55100 Lucca, Italy

3 References

1
Banerjee A, Jones R. Whither immediate fluid resuscitation? Lancet 1994;344:1450-1451
CrossRef | Web of Science | Medline

2
Bickell WH, Bruttig SP, Millnamow GA, O'Benar J, Wade CE. Use of hypertonic saline/dextran versus lactated Ringer's solution as a resuscitation fluid after uncontrolled aortic hemorrhage in anesthetized swine. Ann Emerg Med 1992;21:1077-1085
CrossRef | Web of Science | Medline

3
Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331:1105-1109
Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We thank Drs. Haupt, Shoemaker, and Haddy for their comments. Dr. Haupt believes that treatment aimed at achieving supranormal hemodynamic values may be effective only in the presence of an established oxygen debt (i.e., acidosis). Dr. Shoemaker suggests that this approach is effective only before an oxygen debt is present (i.e., no acidosis); otherwise, it is too late. Dr. Haddy states that the appropriate therapy is to cure the disease, not correct the hemodynamic abnormality. These comments, which seem contradictory, explain why we needed to perform a large trial (including patients with acidosis and those without acidosis, as well as patients with various diseases).

On entry into the study, 152 of 762 patients had arterial pH values lower than 7.35, 197 had bicarbonate levels lower than 22 mmol per liter, and 202 had a base excess lower than -3 mmol per liter. When we compared the three randomized treatment groups in our study, we did not find any significant differences in mortality among the subgroups of patients with low pH, low bicarbonate values, and low base excess.

We stress in our article that the treatment approaches used by Shoemaker et al.1 and Boyd et al.2 were mainly preventive, so it is difficult to compare their results directly with ours. However, when we stratified our patients according to the number of dysfunctional organ systems at entry (none or one [392 patients], two [210], or three or more [160]), we did not find any differences in mortality among the treatment groups, even in the subgroup of patients with only one dysfunctional organ (133 patients in the control group, 123 in the cardiac-index group, and 136 in the oxygen-saturation group, with mortality rates of 43.6, 40.7, and 43.3 percent, respectively; P = 0.9). Moreover, we did not find differences in mortality among the 602 patients with a blood pH >7.35 at entry into the study (i.e., those without evidence of established oxygen debt) who were randomly assigned to the three treatment groups.

We agree with Dr. Haddy that the definitive treatment should be directed to the primary disease. However, hemodynamic therapy is also important, since it buys time for the primary treatment to work. What we have shown in every diagnostic category we studied is that therapy aimed at achieving supranormal hemodynamic values does not seem to be indicated.

Luciano Gattinoni, M.D.
Luca Brazzi, M.D.
Antonio Pesenti, M.D.
Istituto di Anestesia e Rianimazione, 20122 Milano, Italy

2 References

1
Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988;94:1176-1186
CrossRef | Web of Science | Medline

2
Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993;270:2699-2707
CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1
Ali Al-Khafaji, Emanuel Rivers, William Shoemaker. (2008) The prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients article of shoemaker et al with expert commentary by Dr. Emanuel Rivers. Journal of Critical Care 23:4, 603-606
CrossRef
2
Rivers, Emanuel, Nguyen, Bryant, Havstad, Suzanne, Ressler, Julie, Muzzin, Alexandria, Knoblich, Bernhard, Peterson, Edward, Tomlanovich, Michael, . (2001) Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine 345:19, 1368-1377
Full Text