- Email: [email protected]
Better pale than yellow
October 1999
A phase I trial has been completed using a synthetic 105–amino acid polypeptide derived from a mucin designated MUC-1 as a vaccination to stimulate ASI ( J Surg Res 1996;63:298–304). The synthetic peptide contained 5 copies of a conserved tandem repeat observed in MUC-1. Sixty-three patients with adenocarcinoma (24 pancreatic, 9 breast, and 30 colon) were tested for baseline delayedtype hypersensitivity to the 105–amino acid polypeptide by intradermal injection. Only 3 patients had a strong skin response to this vaccination, but 37 patients had injection site biopsy specimens showing an intense T-cell infiltration. After a brief series of injections over a 6-week period, 7 of 22 patients tested had a 2–4-fold increase in peripheral blood lymphocyte antibody production to mucin. Other potential sources of tumor-specific antigens may come from the very oncogenes that gave rise to neoplasia in the first place. The products of mutated proto-oncogenes, such as the Ras gene product, may be consistently found in a range of human adenocarcinomas. Studies are under way examining the effects of treatment with vaccines against specific mutated Ras peptides (Proc Annu Meet Am Soc Clin Oncol 1996;15:A1813). This particular strategy would strike specifically at malignant cells leaving normal cells unharmed. Maximizing T-cell activation requires more than the presence of a specific antigen recognized by a specific T-cell receptor. There are costimulatory signals that are necessary to enhance cytolytic T-cell responses. Some of these signals naturally come from T-helper cells and their repertoire of cytokines. Other signals come in the form of accessory molecules expressed on the surface of a target cell. One approach to improving immunity against a tumor burden might be to increase the presence of these costimulatory factors. Genes for the production of various cytokines such as granulocytemacrophage colony–stimulating factor (GM-CSF), IL-2, or IFN-␣ may be introduced into stable cultured cell lines. These cell lines may then be used to accompany the tumor cells in a vaccination, similar to the way BCG was used in the current study. For instance, an immortalized fibroblast cell line transfected with an IL-2–encoding plasmid has been used in a phase I clinical trial of patients with various solid and hematologic tumors (Int J Cancer 1997;70:269–277). These patients received vaccinations with irradiated autologous tumor cells coupled with the IL-2–expressing fibroblasts. Although the clinical responses were not particularly promising, the investigators were able to isolate and culture lymphocytes from skin biopsy specimens of the patients’ injection sites. The sites contained a mix of T-cell populations, although in most cases the number of CD4⫹ cells exceeded the number of CD8⫹ cells. A very important aspect of that study was the ability to show cytotoxicity against isolated tumor cells by the isolated T cells. This supports the theory that ASI can work. Isolated tumor cells themselves may be transfected with various cytokines before use as a vaccine. Melanoma and renal cell cancer cells have been engineered to secrete IL-2 or TNF, and renal cancer cells have been altered to secrete GM-CSF (Hum Gene Ther 1992;3:75–90, Proc Annu Meet Am Soc Clin Oncol 1996;15:A585). In the latter, delayed-type hypersensitivity reactions to innoculation with GM-CSF– secreting autologous tumor cells was 4-fold greater than to innoculation with control autologous tumor cells. The clinical utility of this technique has not been established, but represents another approach to the development of ASI. In addition to the proper mix of cytokines, T-cell activation may require the presence of certain molecules on the T-cell target other than the T-cell receptor antigen. Such surface molecules act synergistically with the T-cell receptor target antigen to heighten the T-cell response. Some of these molecules include B7, CD40L, intercellular adhesion molecule (ICAM)-1, -2, -3, and VCAM-1 (Cancer Immunol
SELECTED SUMMARIES 1017
Immunother 1996;43:165–173). In a number of murine cancer models, tumor cells have been genetically altered to constitutively express B7. This expression resulted in both CD8⫹- and CD4⫹dependent rejection of subsequent challenges with wild-type tumor cells (Science 1993;259:368–370, Proc Natl Acad Sci USA 1993;90: 5687–5690). Although the study by Vermorken et al. reported fewer recurrences of colon cancer with the use of a tumor vaccination, the clinical effect was not overwhelming. The vaccines used contained a collection of antigens with varying levels of immunogenicity and tumor specificity. As the techniques for improving ASI described evolve, more phase III trials will undoubtedly be reported. The use of immunologic therapies to fight malignancy shows promise but will require more precise antigen targeting and more specific uses of cell-mediated immunity before widespread applications are likely. For now, the use of experimental ASI protocols may provide the more standard chemotherapeutic protocols a needed ‘‘shot in the arm.’’ BRIAN C. JACOBSON, M.D. JACQUES VAN DAM, M.D., Ph.D.
Reply. We agree with the reviewer’s conclusion that the future of active specific immunotherapy involves potential sources of tumorspecific antigens from various molecular biological approaches. We are disappointed that they felt that our study demonstrated fewer recurrences in the autologous tumor cell vaccine group and that the clinical effect was not overwhelming. The vaccine regimen decreased the recurrence rate by 44% of that in nontreated patients by the intention-to-treat analysis. Because the randomization was stratified by stage, the prospective subgroup analysis showed that in stage II disease there was significantly longer recurrence-free periods and a 61% risk reduction for recurrences. Also, the recurrence-free survival was significantly longer with vaccine treatment in stage II disease, with a 42% risk reduction for recurrence or death. We acknolwedge that there was a proportional, but not significant, difference in overall survival in the intention-to-treat analysis as well as in stage II subset analysis. This clinical trial resulted in the conclusion that (1) the comparison performed in this trial is no longer of interest for patients with stage III colon cancer because of the proven efficacy of adjuvant chemotherapy: (2) many clinicians are reluctant to use cytotoxic therapy in patients with stage II colon cancer because of lack of proven clinical efficacy; and (3) active specific immunotherapy with autologous cell vaccine, as performed in our study, has little, if any, side effects. The clinical implication of this study is that active specific immunotherapy with autologous tumor cell vaccines is a treatment option for patients with stage II colon cancer. We feel that this study fills an unmet clinical need. A. J. M. VAN DEN EERTWEGH, M.D., Ph.D. M. G. HANNA, Jr., Ph.D. H. M. PINEDO, M.D., Ph.D.
BETTER PALE THAN YELLOW Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yitisir E, and the Transfusion Requirements in Critical Care Investigators for the Canadian Critical Care Trials Group (Critical Care Program and Clinical Epidemiology Unit, University of Ottawa, Ottawa; Department of Pathology, McMaster University, Hamilton, Ontario; Critical Care Program, University of Toronto, Toronto;
1018 SELECTED SUMMARIES
Critical Care Program, University of Western Ontario, London; Critical Care Program, University of British Columbia, Vancouver, Canada). A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–417. Hebert et al. note that some observational studies show an association between anemia and increased mortality in critically ill patients. On the other hand, they cite some theoretical reasons why transfusions might be detrimental, e.g., because of immunosuppressive and microcirculatory complications. To determine if the potential benefits outweighed the potential risks, they undertook a multicenter, randomized controlled trial. A total of 838 euvolemic critically ill patients with hemoglobin levels of ⱕ9 g/dL were assigned to 1 of 2 groups. Those treated with a liberal strategy received enough blood transfusions to maintain their hemoglobin levels at 10–12 g/dL. The patients assigned to a restrictive strategy received transfusions to maintain a lower hemoglobin level, 7–9 g/dL. The primary outcome measure was the 30-day all-cause mortality. The other outcomes evaluated were the 60-day all-cause mortality, mortality rates in the intensive care unit (ICU) and in the hospital, and survival curves during the first 30 days. In addition, the lengths of stay (LOSs) in the ICU and hospital, as well as measurements of organ dysfunction, were assessed. The investigators initially calculated that they would need to enroll 2300 patients in the trial to detect a 4% difference in the 30-day mortality rate. As the study progressed, the anticipated mortality rate was found to have been too low, and the power calculation was redone. This new computation suggested that only 1620 patients would be required. However, because of a slow enrollment of subjects, the study was terminated after the 838 patients were accessed. The committee that decided to stop the trial had no knowledge of the data that had been accumulated to date. The average hemoglobin levels in the 2 groups were 8.5 g/dL (restrictive) and 10.7 g/dL (liberal) (P ⬍ 0.01). Patients in the restrictive group received an average of 2.6 U of blood; those in the liberal group received 5.6 U (P ⬍ 0.01). The 30-day mortality rate was 18.7% in the restrictive group and 23.3% in the liberal one (P ⫽ 0.11). Similarly, the 60-day, ICU, and hospital mortality rates were 2%–6% lower in the restrictive group; the hospital rate (22.2% vs. 28.1%) achieved a borderline statistical significance (P ⫽ 0.05). No differences were seen in the LOSs. The organ dysfunction scores were lower in the restrictive group. Both pulmonary edema and myocardial infarction were more common events in the liberal group (P ⫽ 0.02). Fourteen other categories of complications were assessed; no other statistically significant differences were observed. Patients who were younger (⬍55 years) and had lower APACHE II scores had significantly better 30-day survival curves if they had been treated restrictively. In their discussion, the investigators cited 5 earlier and smaller randomized trials comparing transfusion strategies ( J Thor Cardiovasc Surg 1984;88:26–38 and 1992;104:307–314,
GASTROENTEROLOGY Vol. 117, No. 4
Br J Surg 1986;73:783–785, N Engl J Med 1995;333:206– 213, JAMA 1995;273:1439–1444). None of them showed any benefit associated with the use of more aggressive transfusion practices, but 4 of them were so small (27–69 patients in each trial) that they would not have had sufficient power to identify anything less than very dramatic differences. Of note, in 1 of the studies (Br J Surg 1986;73:783–785), the recipients of the more aggressive transfusion therapy had an adverse effect, a coagulopathy. The fifth trial (N Engl J Med 1995;333:206– 213) was conducted in patients with sickle cell anemia who were undergoing surgery; there was no difference between the 2 groups on the incidence of postoperative sickle cell crises. The authors believe that their data could be extrapolated to most critically ill patients. They recommend a restrictive strategy for all such individuals, with the possible exception of patients with acute myocardial infarctions or unstable angina. Comment. During my days of medical training (1963–1974), I was taught that patients with gastrointestinal bleeding should have hematocrit levels maintained at least at 30%. The rationale provided to me was that, if a patient rebled, one wanted a safe zone from which to start. I wondered about this advice even then, because it seemed to me that the mortality from bleeding was an issue of hypovolemia, not one of anemia. During my gastroenterology fellowship, I participated in a prospective study of posttransfusion hepatitis. Because of the design of the trial, we tended to follow up patients who had received large numbers of units of blood. Nevertheless, I was surprised that more than 40% of them developed this disease (Am J Med 1975;59:754–760). When I joined the faculty in the mid-1970s, I began to wonder how we could reduce this incidence, and it occurred to me that there was not a single case report of a patient who had not been exposed to blood products developing posttransfusion hepatitis. This observation led me to calculate what minimum hemoglobin level would be required to meet the oxygen demands of a person who was just lying in bed. (In my experience, the issue of transfusion usually arose in patients who had had gastrointestinal bleeding; after the acute episode, these individuals were just lying in bed.) From some standard physiology texts, I learned that every gram of saturated hemoglobin contains 1.34 mL of oxygen, and that there are 3 mL of oxygen dissolved in every liter of blood that leaves the lungs of a person without pulmonary disease. A resting 70-kg male burns 250 mL of oxygen per minute. Using these numbers, and assuming that a 70-kg male has a normal cardiac output of 6 L/min and can increase that to 18 L/min if necessary, I solved the following equation for X (the necessary hemoglobin concentration): 250 mL O2 ⫽ 3 mL O2/L (18 L/min) ⫹ (0.25*) (X g/100 mL) (1.34 mL O2/g) (18 L/min) (1000 mL/L). X ⫽ 3.3 This number clearly depends on the cardiopulmonary status of the patient. For example, if the patient has a limited cardiac reserve, and 6 L/min is the maximal cardiac output he or she can achieve, X ⫽ 11.6. This calculation was subsequently validated in an animal experiment ( J Surg Res 1987;42:629–634). Primates underwent phlebotomies
*Only 25% of the hemoglobin-bound oxygen is extracted at the tissue level under normal circumstances.
October 1999
(with isovolemic replacement of the blood with plasma) to establish the hematocrit level at which the oxygen extraction ratio (the percentage of hemoglobin that is desaturated at the tissue level, a number comparable with the 0.25 used in my equation) increased and/or myocardial lactate excretion started to increase. The hematocrit level at which the oxygen extraction ratio started to increase was 10%, and that ratio had to reach 0.50 before excess myocardial lactate was produced. This minimum hemoglobin level was far lower than I had expected, but it did provide a physiological explanation for the ability of patients who refuse to accept blood transfusions (such as Jehovah’s Witnesses) to tolerate episodes of acute anemia. I then began to try to convince my colleagues to use less blood when they cared for patients with gastrointestinal bleeding. In one instance, a young man with a bleeding duodenal ulcer was transferred to our hospital because of a lack of insurance; when he was discharged, his hematocrit was 15%. He returned to the care of his regular gastroenterologist, who called me in a panic the next day because the patient looked so pale. My comment back to my colleague was that it was probably better to be pale than to be yellow. During the late 1970s and early 1980s, our anesthesiologists were unwilling to anesthetize patients undergoing elective surgery if the hematocrit was ⬍30% (or hemoglobin level ⬍10 g/dL). This standard dogmatic principle stood until the mid-1980s, when the minimum hematocrit was reduced to 25%. When I inquired as to what new finding had changed the standard, I was told that there had been none. Rather, because of fear about the contraction of acquired immunodeficiency syndrome, patients were refusing to be transfused. If hematocrit values between 25 and 30 were not going to be accepted, the elective surgery was not going to get done. Pragmatism produced a change in dogmatism. Perhaps the most striking example of my confidence in this calculation occurred when my own 17-year-old son needed emergency surgery for a traumatic laceration of his liver. When he was taken to the operating room, his hematocrit was 20% and the surgeon wanted to transfuse him. Believing that the anemia could be tolerated, I declined that therapeutic intervention. Although I was unaware of the previous randomized trials that Hebert et al. cited, I did know of another small one that was much more narrowly focused (maintaining surgical patients at 9 vs. 10 g/dL) (Am J Surg 1997;174:143–148). This trial with 99 patients also failed to show any advantage derived from the extra transfusions. Thus, I was not surprised at the results of this study. In fact, my question is whether hemoglobin levels of 7 g/dL are still more than what is actually required. This trial by Hebert et al. is, by far, the largest study that has evaluated this question, and it does support the data derived from the smaller trials. However, some attention should be paid to the possibility that it was still underpowered. Only about one third of the number of patients initially planned actually were accrued. It is possible that a difference favoring the liberal strategy was missed. On the other hand, the trends favored the restrictive group; it is more likely that if a type II error was present, it failed to detect another difference in that direction. Another lesson from this study relates to our tendency to routinely adopt magic hematocrit values that we then apply to all patients. It is time to stop this practice, which was the editorial warning of Ely and Bernard (N Engl J Med 1999;340:468–469) that accompanied this paper.
SELECTED SUMMARIES 1019
Perhaps most importantly, this trial serves as a reminder that we should not routinely accept dogmatic statements. Rather, it behooves us to find out what data led to that dogma. Only if the data are convincing does it become reasonable to adopt the dogma. Of course, we can still practice the dogma even if the data are not persuasive. However, we will then be aware of the limitations of our actions. This is not the first, nor will it be the last, time that a dogmatic precept failed the test of a prospective randomized controlled trial. RONALD L. KORETZ, M.D.
Reply. Dr. Koretz provides a very detailed summary of our recently published multicenter randomized clinical trial evaluating transfusion practices in critically ill patients. We welcome the opportunity to clarify a few points made in his commentary. Although the equation for global oxygen transport is correct in theory, we caution readers that a large number of assumptions must be made when extrapolating these values to humans. The assumption that the average global oxygen consumption is 250 mL/min is a major limitation of his thesis. More specifically, the critical level of oxygen delivery varies significantly from patient to patient because of variations in the basal metabolic rate (i.e., oxygen consumption) modified by disease processes; anesthetic agents; patient characteristics such as body composition, age, and gender; variations in the distribution of blood flow between organs; and a host of other factors (Can Med Assoc J 1997;151:S27–S40, Anesth Analg 1994;78:1000–1021). It is quite clear from laboratory studies that extreme levels of anemia may be tolerated but it is also equally obvious that once the anaerobic threshold is reached, death soon ensues. Cardiac output is also quite variable from patient to patient and is inversely related to the degree of anemia (Anesth Analg 1994;78:1000–1021). In young patients without coronary artery disease, it is possible that more extreme levels of anemia may be tolerated because of compensatory increases in cardiac output, but this was not the subject of our investigation ( JAMA 1998;279:217–221). We should also emphasize that our study was conducted in critically ill patients who were not bleeding actively (N Engl J Med 1999;340:409–417). Therefore, our results should not be used as justification for modifying the criteria for transfusions in acute gastrointestinal hemorrhage. However, once a patient has stopped bleeding, we suggest that a transfusion threshold as low as 7 g/dL is safe under most circumstances. We agree with Dr. Koretz that there is nothing magical about 7 g/dL, no more than the previous threshold of 10 g/dL. We strongly advocate that clinicians use their clinical judgment in determining the appropriateness of a transfusion rather than using a fixed number. However, there are few high-quality clinical data to support a threshold much lower than 7 g/dL under most clinical conditions. Once the reader has critically appraised our study and found the results to be internally valid (as we hope they should), the most important question is to whom should the results of this study apply (external validity). Quite clearly, our results will apply to most critically ill patients who have gastrointestinal disease with major medical or surgical complications. There were 218 patients in the trial with either a primary or secondary diagnosis of a gastrointestinal disease and 121 patients with a gastrointestinal disease most responsible for their ICU admission including gastrointestinal hemorrhage and intra-abdominal infection. PAUL C. HEBERT, M.D.
A phase I trial has been completed using a synthetic 105–amino acid polypeptide derived from a mucin designated MUC-1 as a vaccination to stimulate ASI ( J Surg Res 1996;63:298–304). The synthetic peptide contained 5 copies of a conserved tandem repeat observed in MUC-1. Sixty-three patients with adenocarcinoma (24 pancreatic, 9 breast, and 30 colon) were tested for baseline delayedtype hypersensitivity to the 105–amino acid polypeptide by intradermal injection. Only 3 patients had a strong skin response to this vaccination, but 37 patients had injection site biopsy specimens showing an intense T-cell infiltration. After a brief series of injections over a 6-week period, 7 of 22 patients tested had a 2–4-fold increase in peripheral blood lymphocyte antibody production to mucin. Other potential sources of tumor-specific antigens may come from the very oncogenes that gave rise to neoplasia in the first place. The products of mutated proto-oncogenes, such as the Ras gene product, may be consistently found in a range of human adenocarcinomas. Studies are under way examining the effects of treatment with vaccines against specific mutated Ras peptides (Proc Annu Meet Am Soc Clin Oncol 1996;15:A1813). This particular strategy would strike specifically at malignant cells leaving normal cells unharmed. Maximizing T-cell activation requires more than the presence of a specific antigen recognized by a specific T-cell receptor. There are costimulatory signals that are necessary to enhance cytolytic T-cell responses. Some of these signals naturally come from T-helper cells and their repertoire of cytokines. Other signals come in the form of accessory molecules expressed on the surface of a target cell. One approach to improving immunity against a tumor burden might be to increase the presence of these costimulatory factors. Genes for the production of various cytokines such as granulocytemacrophage colony–stimulating factor (GM-CSF), IL-2, or IFN-␣ may be introduced into stable cultured cell lines. These cell lines may then be used to accompany the tumor cells in a vaccination, similar to the way BCG was used in the current study. For instance, an immortalized fibroblast cell line transfected with an IL-2–encoding plasmid has been used in a phase I clinical trial of patients with various solid and hematologic tumors (Int J Cancer 1997;70:269–277). These patients received vaccinations with irradiated autologous tumor cells coupled with the IL-2–expressing fibroblasts. Although the clinical responses were not particularly promising, the investigators were able to isolate and culture lymphocytes from skin biopsy specimens of the patients’ injection sites. The sites contained a mix of T-cell populations, although in most cases the number of CD4⫹ cells exceeded the number of CD8⫹ cells. A very important aspect of that study was the ability to show cytotoxicity against isolated tumor cells by the isolated T cells. This supports the theory that ASI can work. Isolated tumor cells themselves may be transfected with various cytokines before use as a vaccine. Melanoma and renal cell cancer cells have been engineered to secrete IL-2 or TNF, and renal cancer cells have been altered to secrete GM-CSF (Hum Gene Ther 1992;3:75–90, Proc Annu Meet Am Soc Clin Oncol 1996;15:A585). In the latter, delayed-type hypersensitivity reactions to innoculation with GM-CSF– secreting autologous tumor cells was 4-fold greater than to innoculation with control autologous tumor cells. The clinical utility of this technique has not been established, but represents another approach to the development of ASI. In addition to the proper mix of cytokines, T-cell activation may require the presence of certain molecules on the T-cell target other than the T-cell receptor antigen. Such surface molecules act synergistically with the T-cell receptor target antigen to heighten the T-cell response. Some of these molecules include B7, CD40L, intercellular adhesion molecule (ICAM)-1, -2, -3, and VCAM-1 (Cancer Immunol
SELECTED SUMMARIES 1017
Immunother 1996;43:165–173). In a number of murine cancer models, tumor cells have been genetically altered to constitutively express B7. This expression resulted in both CD8⫹- and CD4⫹dependent rejection of subsequent challenges with wild-type tumor cells (Science 1993;259:368–370, Proc Natl Acad Sci USA 1993;90: 5687–5690). Although the study by Vermorken et al. reported fewer recurrences of colon cancer with the use of a tumor vaccination, the clinical effect was not overwhelming. The vaccines used contained a collection of antigens with varying levels of immunogenicity and tumor specificity. As the techniques for improving ASI described evolve, more phase III trials will undoubtedly be reported. The use of immunologic therapies to fight malignancy shows promise but will require more precise antigen targeting and more specific uses of cell-mediated immunity before widespread applications are likely. For now, the use of experimental ASI protocols may provide the more standard chemotherapeutic protocols a needed ‘‘shot in the arm.’’ BRIAN C. JACOBSON, M.D. JACQUES VAN DAM, M.D., Ph.D.
Reply. We agree with the reviewer’s conclusion that the future of active specific immunotherapy involves potential sources of tumorspecific antigens from various molecular biological approaches. We are disappointed that they felt that our study demonstrated fewer recurrences in the autologous tumor cell vaccine group and that the clinical effect was not overwhelming. The vaccine regimen decreased the recurrence rate by 44% of that in nontreated patients by the intention-to-treat analysis. Because the randomization was stratified by stage, the prospective subgroup analysis showed that in stage II disease there was significantly longer recurrence-free periods and a 61% risk reduction for recurrences. Also, the recurrence-free survival was significantly longer with vaccine treatment in stage II disease, with a 42% risk reduction for recurrence or death. We acknolwedge that there was a proportional, but not significant, difference in overall survival in the intention-to-treat analysis as well as in stage II subset analysis. This clinical trial resulted in the conclusion that (1) the comparison performed in this trial is no longer of interest for patients with stage III colon cancer because of the proven efficacy of adjuvant chemotherapy: (2) many clinicians are reluctant to use cytotoxic therapy in patients with stage II colon cancer because of lack of proven clinical efficacy; and (3) active specific immunotherapy with autologous cell vaccine, as performed in our study, has little, if any, side effects. The clinical implication of this study is that active specific immunotherapy with autologous tumor cell vaccines is a treatment option for patients with stage II colon cancer. We feel that this study fills an unmet clinical need. A. J. M. VAN DEN EERTWEGH, M.D., Ph.D. M. G. HANNA, Jr., Ph.D. H. M. PINEDO, M.D., Ph.D.
BETTER PALE THAN YELLOW Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yitisir E, and the Transfusion Requirements in Critical Care Investigators for the Canadian Critical Care Trials Group (Critical Care Program and Clinical Epidemiology Unit, University of Ottawa, Ottawa; Department of Pathology, McMaster University, Hamilton, Ontario; Critical Care Program, University of Toronto, Toronto;
1018 SELECTED SUMMARIES
Critical Care Program, University of Western Ontario, London; Critical Care Program, University of British Columbia, Vancouver, Canada). A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–417. Hebert et al. note that some observational studies show an association between anemia and increased mortality in critically ill patients. On the other hand, they cite some theoretical reasons why transfusions might be detrimental, e.g., because of immunosuppressive and microcirculatory complications. To determine if the potential benefits outweighed the potential risks, they undertook a multicenter, randomized controlled trial. A total of 838 euvolemic critically ill patients with hemoglobin levels of ⱕ9 g/dL were assigned to 1 of 2 groups. Those treated with a liberal strategy received enough blood transfusions to maintain their hemoglobin levels at 10–12 g/dL. The patients assigned to a restrictive strategy received transfusions to maintain a lower hemoglobin level, 7–9 g/dL. The primary outcome measure was the 30-day all-cause mortality. The other outcomes evaluated were the 60-day all-cause mortality, mortality rates in the intensive care unit (ICU) and in the hospital, and survival curves during the first 30 days. In addition, the lengths of stay (LOSs) in the ICU and hospital, as well as measurements of organ dysfunction, were assessed. The investigators initially calculated that they would need to enroll 2300 patients in the trial to detect a 4% difference in the 30-day mortality rate. As the study progressed, the anticipated mortality rate was found to have been too low, and the power calculation was redone. This new computation suggested that only 1620 patients would be required. However, because of a slow enrollment of subjects, the study was terminated after the 838 patients were accessed. The committee that decided to stop the trial had no knowledge of the data that had been accumulated to date. The average hemoglobin levels in the 2 groups were 8.5 g/dL (restrictive) and 10.7 g/dL (liberal) (P ⬍ 0.01). Patients in the restrictive group received an average of 2.6 U of blood; those in the liberal group received 5.6 U (P ⬍ 0.01). The 30-day mortality rate was 18.7% in the restrictive group and 23.3% in the liberal one (P ⫽ 0.11). Similarly, the 60-day, ICU, and hospital mortality rates were 2%–6% lower in the restrictive group; the hospital rate (22.2% vs. 28.1%) achieved a borderline statistical significance (P ⫽ 0.05). No differences were seen in the LOSs. The organ dysfunction scores were lower in the restrictive group. Both pulmonary edema and myocardial infarction were more common events in the liberal group (P ⫽ 0.02). Fourteen other categories of complications were assessed; no other statistically significant differences were observed. Patients who were younger (⬍55 years) and had lower APACHE II scores had significantly better 30-day survival curves if they had been treated restrictively. In their discussion, the investigators cited 5 earlier and smaller randomized trials comparing transfusion strategies ( J Thor Cardiovasc Surg 1984;88:26–38 and 1992;104:307–314,
GASTROENTEROLOGY Vol. 117, No. 4
Br J Surg 1986;73:783–785, N Engl J Med 1995;333:206– 213, JAMA 1995;273:1439–1444). None of them showed any benefit associated with the use of more aggressive transfusion practices, but 4 of them were so small (27–69 patients in each trial) that they would not have had sufficient power to identify anything less than very dramatic differences. Of note, in 1 of the studies (Br J Surg 1986;73:783–785), the recipients of the more aggressive transfusion therapy had an adverse effect, a coagulopathy. The fifth trial (N Engl J Med 1995;333:206– 213) was conducted in patients with sickle cell anemia who were undergoing surgery; there was no difference between the 2 groups on the incidence of postoperative sickle cell crises. The authors believe that their data could be extrapolated to most critically ill patients. They recommend a restrictive strategy for all such individuals, with the possible exception of patients with acute myocardial infarctions or unstable angina. Comment. During my days of medical training (1963–1974), I was taught that patients with gastrointestinal bleeding should have hematocrit levels maintained at least at 30%. The rationale provided to me was that, if a patient rebled, one wanted a safe zone from which to start. I wondered about this advice even then, because it seemed to me that the mortality from bleeding was an issue of hypovolemia, not one of anemia. During my gastroenterology fellowship, I participated in a prospective study of posttransfusion hepatitis. Because of the design of the trial, we tended to follow up patients who had received large numbers of units of blood. Nevertheless, I was surprised that more than 40% of them developed this disease (Am J Med 1975;59:754–760). When I joined the faculty in the mid-1970s, I began to wonder how we could reduce this incidence, and it occurred to me that there was not a single case report of a patient who had not been exposed to blood products developing posttransfusion hepatitis. This observation led me to calculate what minimum hemoglobin level would be required to meet the oxygen demands of a person who was just lying in bed. (In my experience, the issue of transfusion usually arose in patients who had had gastrointestinal bleeding; after the acute episode, these individuals were just lying in bed.) From some standard physiology texts, I learned that every gram of saturated hemoglobin contains 1.34 mL of oxygen, and that there are 3 mL of oxygen dissolved in every liter of blood that leaves the lungs of a person without pulmonary disease. A resting 70-kg male burns 250 mL of oxygen per minute. Using these numbers, and assuming that a 70-kg male has a normal cardiac output of 6 L/min and can increase that to 18 L/min if necessary, I solved the following equation for X (the necessary hemoglobin concentration): 250 mL O2 ⫽ 3 mL O2/L (18 L/min) ⫹ (0.25*) (X g/100 mL) (1.34 mL O2/g) (18 L/min) (1000 mL/L). X ⫽ 3.3 This number clearly depends on the cardiopulmonary status of the patient. For example, if the patient has a limited cardiac reserve, and 6 L/min is the maximal cardiac output he or she can achieve, X ⫽ 11.6. This calculation was subsequently validated in an animal experiment ( J Surg Res 1987;42:629–634). Primates underwent phlebotomies
*Only 25% of the hemoglobin-bound oxygen is extracted at the tissue level under normal circumstances.
October 1999
(with isovolemic replacement of the blood with plasma) to establish the hematocrit level at which the oxygen extraction ratio (the percentage of hemoglobin that is desaturated at the tissue level, a number comparable with the 0.25 used in my equation) increased and/or myocardial lactate excretion started to increase. The hematocrit level at which the oxygen extraction ratio started to increase was 10%, and that ratio had to reach 0.50 before excess myocardial lactate was produced. This minimum hemoglobin level was far lower than I had expected, but it did provide a physiological explanation for the ability of patients who refuse to accept blood transfusions (such as Jehovah’s Witnesses) to tolerate episodes of acute anemia. I then began to try to convince my colleagues to use less blood when they cared for patients with gastrointestinal bleeding. In one instance, a young man with a bleeding duodenal ulcer was transferred to our hospital because of a lack of insurance; when he was discharged, his hematocrit was 15%. He returned to the care of his regular gastroenterologist, who called me in a panic the next day because the patient looked so pale. My comment back to my colleague was that it was probably better to be pale than to be yellow. During the late 1970s and early 1980s, our anesthesiologists were unwilling to anesthetize patients undergoing elective surgery if the hematocrit was ⬍30% (or hemoglobin level ⬍10 g/dL). This standard dogmatic principle stood until the mid-1980s, when the minimum hematocrit was reduced to 25%. When I inquired as to what new finding had changed the standard, I was told that there had been none. Rather, because of fear about the contraction of acquired immunodeficiency syndrome, patients were refusing to be transfused. If hematocrit values between 25 and 30 were not going to be accepted, the elective surgery was not going to get done. Pragmatism produced a change in dogmatism. Perhaps the most striking example of my confidence in this calculation occurred when my own 17-year-old son needed emergency surgery for a traumatic laceration of his liver. When he was taken to the operating room, his hematocrit was 20% and the surgeon wanted to transfuse him. Believing that the anemia could be tolerated, I declined that therapeutic intervention. Although I was unaware of the previous randomized trials that Hebert et al. cited, I did know of another small one that was much more narrowly focused (maintaining surgical patients at 9 vs. 10 g/dL) (Am J Surg 1997;174:143–148). This trial with 99 patients also failed to show any advantage derived from the extra transfusions. Thus, I was not surprised at the results of this study. In fact, my question is whether hemoglobin levels of 7 g/dL are still more than what is actually required. This trial by Hebert et al. is, by far, the largest study that has evaluated this question, and it does support the data derived from the smaller trials. However, some attention should be paid to the possibility that it was still underpowered. Only about one third of the number of patients initially planned actually were accrued. It is possible that a difference favoring the liberal strategy was missed. On the other hand, the trends favored the restrictive group; it is more likely that if a type II error was present, it failed to detect another difference in that direction. Another lesson from this study relates to our tendency to routinely adopt magic hematocrit values that we then apply to all patients. It is time to stop this practice, which was the editorial warning of Ely and Bernard (N Engl J Med 1999;340:468–469) that accompanied this paper.
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Perhaps most importantly, this trial serves as a reminder that we should not routinely accept dogmatic statements. Rather, it behooves us to find out what data led to that dogma. Only if the data are convincing does it become reasonable to adopt the dogma. Of course, we can still practice the dogma even if the data are not persuasive. However, we will then be aware of the limitations of our actions. This is not the first, nor will it be the last, time that a dogmatic precept failed the test of a prospective randomized controlled trial. RONALD L. KORETZ, M.D.
Reply. Dr. Koretz provides a very detailed summary of our recently published multicenter randomized clinical trial evaluating transfusion practices in critically ill patients. We welcome the opportunity to clarify a few points made in his commentary. Although the equation for global oxygen transport is correct in theory, we caution readers that a large number of assumptions must be made when extrapolating these values to humans. The assumption that the average global oxygen consumption is 250 mL/min is a major limitation of his thesis. More specifically, the critical level of oxygen delivery varies significantly from patient to patient because of variations in the basal metabolic rate (i.e., oxygen consumption) modified by disease processes; anesthetic agents; patient characteristics such as body composition, age, and gender; variations in the distribution of blood flow between organs; and a host of other factors (Can Med Assoc J 1997;151:S27–S40, Anesth Analg 1994;78:1000–1021). It is quite clear from laboratory studies that extreme levels of anemia may be tolerated but it is also equally obvious that once the anaerobic threshold is reached, death soon ensues. Cardiac output is also quite variable from patient to patient and is inversely related to the degree of anemia (Anesth Analg 1994;78:1000–1021). In young patients without coronary artery disease, it is possible that more extreme levels of anemia may be tolerated because of compensatory increases in cardiac output, but this was not the subject of our investigation ( JAMA 1998;279:217–221). We should also emphasize that our study was conducted in critically ill patients who were not bleeding actively (N Engl J Med 1999;340:409–417). Therefore, our results should not be used as justification for modifying the criteria for transfusions in acute gastrointestinal hemorrhage. However, once a patient has stopped bleeding, we suggest that a transfusion threshold as low as 7 g/dL is safe under most circumstances. We agree with Dr. Koretz that there is nothing magical about 7 g/dL, no more than the previous threshold of 10 g/dL. We strongly advocate that clinicians use their clinical judgment in determining the appropriateness of a transfusion rather than using a fixed number. However, there are few high-quality clinical data to support a threshold much lower than 7 g/dL under most clinical conditions. Once the reader has critically appraised our study and found the results to be internally valid (as we hope they should), the most important question is to whom should the results of this study apply (external validity). Quite clearly, our results will apply to most critically ill patients who have gastrointestinal disease with major medical or surgical complications. There were 218 patients in the trial with either a primary or secondary diagnosis of a gastrointestinal disease and 121 patients with a gastrointestinal disease most responsible for their ICU admission including gastrointestinal hemorrhage and intra-abdominal infection. PAUL C. HEBERT, M.D.