Editorial Views  |   October 2002
Hemodilution and Candles
Author Notes
  • Professor, Department of Anesthesia, and Staff Member, Cardiovascular Research Institute, University of California, San Francisco, California.
Article Information
Editorial Views
Editorial Views   |   October 2002
Hemodilution and Candles
Anesthesiology 10 2002, Vol.97, 773-775. doi:
Anesthesiology 10 2002, Vol.97, 773-775. doi:
THE impetus for the development of transfusion-sparing pharmaceuticals or techniques has been the risks associated with transfusion (infectious disease, transfusion-associated lung injury, transfusion reactions [hemolytic, anaphylactic], immunomodulation) and the need for augmenting oxygen delivery when compatible blood is not available or cannot be used. The blood supply of North America and Western Europe is now safer than ever; however, the need for blood and blood components at times is greater than their availability. 1 
Acute normovolemic hemodilution (ANH), withdrawal of blood while maintaining isovolemia, was originally introduced to return coagulation factors to the patient after cardiopulmonary bypass. 2 The concept that hemodilution might save erythrocytes per se  appears to have been first envisioned by Messmer et al  . 3 The basis of this notion is that ANH reduces the circulating concentration of erythrocytes, thus, following ANH, the blood lost during surgery contains a lesser concentration of erythrocytes than if ANH had not been performed, resulting in a conservation of erythrocytes. ANH is one of the few procedures in medicine that lends itself to mathematical modeling. Analyses have shown that efficacy of hemodilution requires high initial hematocrits, 4,5 low hematocrits after ANH (“target”), 4,5 and a surgical blood loss that exceeds a specific minimum value 4,5 and is also within a specific range. 5 Recently, a more detailed analysis concluded that for ANH to be efficacious (conserve at least one unit of erythrocytes), surgical blood loss should be more than approximately 70% of the patient's blood volume. 6 
Although the use of ANH to conserve erythrocytes and transfusion has been advocated by several organizations 7–9 and transfusion experts, 10,11 its use has remained controversial because of its uncertain efficacy and safety. The authors of a recent meta-analysis noted that their findings were inconclusive. 12 The expected inconclusive nature of the totality of all publications rests on several important issues. Studies have failed to fulfill one or more of these critical criteria, all of which are required to provide a valid test of hemodilution: a relatively homogeneous population of patients so that blood loss is reasonably uniform; prospective random allocation of patients to groups with or without ANH; sufficiently high initial hematocrit; sufficiently low hematocrit (“target”) after ANH; withdrawal of a sufficient volume of blood; prospective transfusion criteria, uniformly and consistently applied; surgical blood loss that is within the range of potential efficacy; and a sample size sufficiently large to have a reasonable expectation of detecting a difference, should one exist. Indeed, of the publications analyzed, it appears that none satisfied these criteria.
In this issue of Anesthesiology, Matot et al.  13 report the results of their study, which was uniquely designed to meet all criteria to provide an adequate test of the efficacy of ANH. They removed approximately 2 l of blood during ANH, reducing the patients’ hematocrit from 41% to 24%, and found the technique to be efficacious, significantly decreasing the fraction of patients requiring allogeneic transfusion (from 36% to 10%). Their findings are in accord with the prediction that more than 70% of a patient's blood volume must be lost for ANH to be efficacious, 6 and that there is a range of blood loss, above and below which ANH will not result in avoidance of allogeneic transfusion. 5,6 Also, as predicted by mathematical analysis, 6 in the study conducted by Matot et al.  13, when blood loss was within the range of potential efficacy (70–90% of the estimated blood volume), ANH was exceedingly efficacious: none of the nine patients in whom ANH was performed required allogeneic blood, whereas all 10 patients in the control group did (P  < 0.0001); and the groups had an equal incidence (100%) of allogeneic transfusion when blood loss exceeded 90% of the patient's estimated blood volume (numbers of patients not transfused supplied by personal communication with I. Matot, June 21, 2002). When surgical blood loss is exceedingly high, ANH can reduce the number of allogeneic units of blood transfused but not the fraction of patients requiring allogeneic transfusion. 5,6 It is important to note that the efficacy of ANH depends not only on the amount of surgical blood loss but also on a sufficiently high initial hematocrit and the removal of a sufficient quantity of blood to achieve a sufficiently low “target” hematocrit. 4–6 
The removal of such substantial quantities of blood and the reduction of the hemoglobin concentration to values sufficient to produce efficacy has the potential to threaten patient safety. Normovolemia must be maintained (to preserve oxygen delivery to and oxygenation of critical organs) not only during but also after performing ANH of a substantial fraction of the patient's blood, as the administered fluids leave the vascular space at different rates. 14,15 Although the reduction of the hemoglobin concentration to a value as low as 5 g/dl does not produce systemic evidence of inadequate oxygenation in healthy, conscious humans, 16 it does produce subtle, reversible deficits of cognitive function. 17,18 Anesthetized patients can withstand hemodilution to hemoglobin concentrations at least as low as 8 g/dl (and likely substantially lower) without systemic evidence of inadequate oxygenation. 19,20 It has been recommended that anesthetized healthy patients not be transfused until the hemoglobin concentration decreases to 7 g/dl 21 or 6 g/dl. 8 The safe limits of hemodilution for patients who cannot increase blood flow sufficiently to critical organs (e.g.  , because of arterial stenosis, vasculitis, or impaired cardiac function) are not known. Hemodilution has not been associated with systemic or cardiac markers of inadequate oxygenation in patients undergoing coronary artery surgery. 22,23 The coronary vasculature has a reserve dilatory capacity, which, in response to acute anemia, can increase blood flow by several fold. 24 However, data from laboratory studies clearly demonstrate that at very low hemoglobin concentrations (below 3–5 g/dl), the myocardium becomes hypoxic, 25 with decreased contractility, 26 and that the hemoglobin value at which this occurs is higher when coronary artery blood flow is limited by a stenosis. 27 
As other studies before it, the present study did not evaluate a sufficient number of patients to document the safety of ANH. For example, it would not have been expected to be able to detect an increase in myocardial infarction rate in this group of American Society of Anesthesiologists physical status I and II patients. Even in patients with or at high risk for coronary artery disease undergoing abdominal aortic surgery, the incidence of myocardial infarction is only approximately 4%. A study with an 80% likelihood of detecting a 25% increase of this incidence, to 5%, would require approximately 14,000 patients. Detection of a doubling of this rate, to 8%, would require a study population of approximately 1,200 patients.
Thanks to Matot et al.  13, we now have appropriate evidence that ANH, as predicted, can be efficacious if used correctly for the appropriate patient population. Unfortunately, its safety is unknown and must be weighed against the risks of the procedure and those of allogeneic transfusion. In addition to the potential risks of not maintaining normovolemia (hypovolemia or hypervolemia), theoretically, ANH could cause an increase in surgical blood loss because of increased blood flow (owing to increased cardiac output 16,28,29 and lower blood viscosity 30); decreased concentrations of clotting factors 31 (they are removed together with the erythrocytes); the effect of the fluid, such as hetastarch (on coagulation factors and platelet function 32), infused to replace the withdrawn blood; and perhaps because of altered margination or function of platelets. 33,34 Although some investigators have reported increased surgical blood loss with ANH, Matot et al.  13 did not. In addition, ANH requires expertise, takes time, and potentially could also divert the attention of the anesthesiologist from other patient care issues.
The potential for blood components to transmit viral disease is at an all-time low in Western Europe and North America, with the risk for transmission of human immunodeficiency virus (HIV), hepatitis C virus, and hepatitis B virus each being estimated as approximately 1 per 1,900,000, 1 per 1,600,000, and 1 per 180,000 units transfused, respectively. 35,36 The risk of fatal hemolytic transfusion reactions (the majority occur in the operating room) exceeds that of transmission of HIV or hepatitis B virus. 37 However, the incidence of transfusion-induced serious bacterial infection is at least as high as that of either HIV or hepatitis C virus, and it has been suggested that the incidence may be substantially underestimated. 38 In some areas of the world, the incidence of transmission of parasitic disease is substantially higher than that of viral disease. 39 New vectors of transmissible disease may, and likely will, appear. In addition to the infectious risk, the consequences of potential immunomodulation 40 and the incidence of transfusion-associated lung injury 41 are not clearly defined.
Thus, we are left with a not unusual clinical circumstance. We can quantify the efficacy of a technique or therapy, but its full risks are not clear. Is it worth the candle? 42 It is better to light a single candle than to curse the darkness (attributed to Confucius): with the efficacy having been shown, perhaps someone will now address safety.
Nightingale SD: Summary of Meeting of the DHSS Advisory Committee on Blood Safety and Availability of 29–30 May 1999. Washington, DC, US Department of Health and Human Services, Office of the Secretary, 1999
Buckley MJ, Austen G, Goldblatt A, Laver MB: Severe hemodilution and autotransfusion for surgery of congenital heart disease. Surg Forum 1971; 22: 160–2Buckley, MJ Austen, G Goldblatt, A Laver, MB
Klövekorn WP, Pichlmaier H, Ott E, Bauer H, Sunder-Plassmann L, Messmer K: Akute praeoperative Haemodilution eine Moeglichkeit zu autologen Bluttransfusion. Chirurg 1974; 45: 452–8Klövekorn, WP Pichlmaier, H Ott, E Bauer, H Sunder-Plassmann, L Messmer, K
Brecher ME, Rosenfeld M: Mathematical and computer modeling of acute normovolemic hemodilution. Transfusion 1994; 34: 176–9Brecher, ME Rosenfeld, M
Weiskopf RB: Mathematical analysis of isovolemic hemodilution indicates that it can decrease the need for allogeneic blood transfusion. Transfusion 1995; 35: 37–41Weiskopf, RB
Weiskopf R: Efficacy of acute normovolemic hemodilution assessed as a function of fraction of blood volume lost. A nesthesiology 2001; 94: 439–46Weiskopf, R
National Heart, Lung, and Blood Institute Expert Panel on the use of Autologous Blood: Transfusion alert: Use of autologous blood. Transfusion 1995; 35: 703–11NA,
American Society of Anesthesiologists Task Force on Blood Component Therapy: Practice guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy.. Anesthesiology 1996; 84: 732–47NA,
Napier JF, Bruce M, Chapman J, Duguid JKM, Kelsey PR, Knowles SM, Murphy MF, Williamson LM, Wood JK, Lee D, Contreras M, Cross N, Desmond NJ, Gillon J, Lardy A, Williams FG: Guidelines for autologous transfusion. II. Perioperative haemodilution and cell salvage British Committee for Standards in Haematology Blood Transfusion Task Force. Autologous Transfusion Working Party.. Br J Anaesth 1997; 78: 768–71Napier, JF Bruce, M Chapman, J Duguid, JKM Kelsey, PR Knowles, SM Murphy, MF Williamson, LM Wood, JK Lee, D Contreras, M Cross, N Desmond, NJ Gillon, J Lardy, A Williams, FG
Stehling L, Zauder HL: Controversies in transfusion medicine. Perioperative hemodilution: Pro. Transfusion 1994; 34: 265–8Stehling, L Zauder, HL
Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP: Transfusion medicine. Second of two parts—blood conservation. N Engl J Med 1999; 340: 525–33Goodnough, LT Brecher, ME Kanter, MH AuBuchon, JP
Bryson GL, Laupacis A, Wells GA: Does acute normovolemic hemodilution reduce perioperative allogeneic transfusion? A meta-analysis. The international study of perioperative transfusion. Anesth Analg 1998; 86: 9–15Bryson, GL Laupacis, A Wells, GA
Matot I, Scheinin O, Jurim O, Eid A: Effectiveness of acute normovolemic hemodilution to minimize allogeneic blood transfusion in major liver resections. A nesthesiology 2003; 98: in press
Svensén C, Hahn R: Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers. A nesthesiology 1997; 87: 204–12Svensén, C Hahn, R
Payen J-F, Vuillez J-P, Geoffray B, Lafond J-L, Comet M, Stieglitz P, Jacquot C: Effects of preoperative intentional hemodilution on the extravasation rate of albumin and fluid. Crit Care Med 1997; 25: 243–8Payen, J-F Vuillez, J-P Geoffray, B Lafond, J-L Comet, M Stieglitz, P Jacquot, C
Weiskopf RB, Viele M, Feiner J, Kelley S, Lieberman J, Noorani M, Leung J, Fisher D, Murray W, Toy P, Moore M: Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998; 279: 217–21Weiskopf, RB Viele, M Feiner, J Kelley, S Lieberman, J Noorani, M Leung, J Fisher, D Murray, W Toy, P Moore, M
Weiskopf RB, Kramer JH, Viele M, Neumann M, Feiner J, Watson JJ, Hopf H, Toy P: Acute severe isovolemic anemia impairs cognitive function and memory and humans. A nesthesiology 2000; 92: 1646–52Weiskopf, RB Kramer, JH Viele, M Neumann, M Feiner, J Watson, JJ Hopf, H Toy, P
Weiskopf R, Feiner J, Hopf HW, Viele M, Watson J, Kramer JH, Ho R, Toy P: Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia. A nesthesiology 2002; 96: 871–7Weiskopf, R Feiner, J Hopf, HW Viele, M Watson, J Kramer, JH Ho, R Toy, P
Van Der Linden P, Wathieu M, Gilbart E, Engelman E, Wautrecht J-C, Lenaers A, Vincent J-L: Cardiovascular effects of moderate normovolaemic haemodilution during enflurane-nitrous oxide anaesthesia in man. Acta Anaesthesiol Scand 1994; 38: 490–8Van Der Linden, P Wathieu, M Gilbart, E Engelman, E Wautrecht, J-C Lenaers, A Vincent, J-L
Ickx BE, Rigolet M, Van der Linden PJ: Cardiovascular and metabolic response to acute normovolemic anemia. A nesthesiology 2000; 93: 1001–16Ickx, BE Rigolet, M Van der Linden, PJ
Consensus conference: Perioperative red blood cell transfusion. JAMA 1988; 260: 2700–3NA,
Spahn DR, Schmid ER, Seifert B, Pasch T: Hemodilution tolerance in patients with coronary artery disease who are receiving chronic beta-adrenergic blocker therapy. Anesth Analg 1996; 82: 687–94Spahn, DR Schmid, ER Seifert, B Pasch, T
Doak GJ, Hall RI: Does hemoglobin concentration affect perioperative myocardial lactate flux in patients undergoing coronary artery bypass surgery? Anesth Analg 1995; 80: 910–6Doak, GJ Hall, RI
Von Restorff W, Höfling B, Holtz J, Bassenge E: Effect of increased blood fluidity through hemodilution on coronary circulation at rest and during exercise in dogs. Pflugers Arch 1975; 357: 15–24Von Restorff, W Höfling, B Holtz, J Bassenge, E
Jan KM, Chien S: Effect of hematocrit variations on coronary hemodynamics and oxygen utilization. Am J Physiol 1977; 233: H106–13Jan, KM Chien, S
Crystal GJ, Salem MR: Myocardial oxygen consumption and segmental shortening during selective coronary hemodilution in dogs. Anesth Analg 1988; 67: 500–8Crystal, GJ Salem, MR
Levy P, Kim S, Eckel P, Chavez R, Ezz F, Gould S, Salem M, Crystal G: Limit to cardiac compensation during acute isovolemic hemodilution: Influence of coronary stenosis. Am J Physiol 1993; 265: H340–9Levy, P Kim, S Eckel, P Chavez, R Ezz, F Gould, S Salem, M Crystal, G
Laks H, Pilon RN, Klövekorn WP, Anderson W, MacCallum JR, O'Connor NE: Acute hemodilution: Its effects on hemodynamics and oxygen transport in anesthetized man. Ann Surg 1974; 180: 103–9Laks, H Pilon, RN Klövekorn, WP Anderson, W MacCallum, JR O'Connor, NE
Von Restorff W, Höfling B, Holtz J, Bassenge E: Effect of increased blood fluidity through hemodilution on general circulation at rest and during exercise in dogs. Pflugers Arch 1975; 357: 25–34Von Restorff, W Höfling, B Holtz, J Bassenge, E
Murray JF, Escobar E, Rapaport E: Effects of blood viscosity on hemodynamic responses in acute normovolemic anemia. Am J Physiol 1969; 216: 638–42Murray, JF Escobar, E Rapaport, E
Rosberg B: Blood coagulation during and after normovolemic hemodilution in elective surgery. Ann Clin Res 1981; 13(suppl 33): 84–8Rosberg, B
Strauss RG, Pennell BJ, Stump DC: A randomized, blinded trial comparing the hemostatic effects of pentastarch versus hetastarch. Transfusion 2002; 42: 27–36Strauss, RG Pennell, BJ Stump, DC
Valeri C, Crowley J, Loscalzo J: The red cell transfusion trigger: Has a sin of commission now become a sin of omission? Transfusion 1998; 38: 602–10Valeri, C Crowley, J Loscalzo, J
Valeri CR, Cassidy G, Pivacek LE, Ragno G, Lieberthal W, Crowley JP, Khuri SF, Loscalzo J: Anemia-induced increase in the bleeding time: Implications for treatment of nonsurgical blood loss. Transfusion 2001; 41: 977–83Valeri, CR Cassidy, G Pivacek, LE Ragno, G Lieberthal, W Crowley, JP Khuri, SF Loscalzo, J
Kleinman SH, Busch MP: The risks of transfusion-transmitted infection: Direct estimation and mathematical modelling. Baillieres Best Pract Res Clin Haematol 2000; 13: 631–49Kleinman, SH Busch, MP
Busch MP, Kleinman SH, Nemo GJ: Current and emerging infectious risks of blood transfusions. JAMA 2002; (in press)
Sazama K: Reports of 355 transfusion-associated deaths: 1976 through 1985. Transfusion 1990; 30: 583–90Sazama, K
Blajchman M, Goldman M: Bacterial contamination of platelet concentrates: Incidence, significance, and prevention. Semin Hematol 2001; 38: 20–6Blajchman, M Goldman, M
Dodd RY: Transmission of parasites by blood transfusion. Vox Sang 1998; 74: 161–3Dodd, RY
Klein HG: Immunomodulatory aspects of transfusion: A once and future risk? A nesthesiology 1999; 91: 861–5Klein, HG
Popovsky M: Transfusion-related acute lung injury [letter]. Transfusion 1995; 35: 180–1Popovsky, M
De Montaigne ME: Essays, Book II,Chapter 27. 1580.