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The Efficacy and Utility of Acute Normovolemic Hemodilution

Grant, Michael C. MD*; Resar, Linda M. S. MD; Frank, Steven M. MD*

doi: 10.1213/ANE.0000000000000935
Editorials: Editorial
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From the *Department of Anesthesiology/Critical Care Medicine and Department of Medicine (Hematology), Oncology, and the Institute for Cellular Engineering, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Accepted for publication July 14, 2015.

Funding: None.

Conflict of Interests: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Steven M. Frank, MD, Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, 1800 Zayed, Room 6208, Baltimore, MD 21287. Address e-mail to Sfrank3@jhmi.edu.

Acute normovolemic hemodilution (ANH) is a blood conservation technique that was first described in the early 1970s in the setting of cardiac surgery.1,2 The principle behind this procedure is to reduce the patient’s hematocrit by phlebotomy along with infusing crystalloid and/or colloid before the onset of surgical blood loss such that for a given amount of bleeding, a smaller red blood cell (RBC) mass will be lost. The maximum benefit from ANH is achieved when a low, but physiologically adequate, hematocrit is maintained during the blood loss phase of the surgical procedure, after which the fresh whole blood that was removed is given back to the patient near the end of the surgical procedure. Ideally, for ANH to be effective in reducing allogeneic transfusion requirements, the patient should: (1) have a relatively high preoperative hematocrit; (2) undergo the maximum allowable phlebotomy; and (3) lose a substantial amount of blood during surgery. If any of these 3 parameters is not present, the potential benefit of ANH in reducing allogeneic transfusions will be limited.3

Whether ANH is effective in reducing transfusion requirements has been a point of controversy. Multiple controlled trials evaluating ANH in patients who underwent a variety of surgical procedures have been published, which allows for meta-analysis to determine efficacy. In fact, 2 previous meta-analyses, including 1 in 1998 with 24 trials4 and 1 in 2004 with 42 trials,5 did not show conclusive evidence to support the widespread use of ANH.

Now 11 years later, in the current issue of Anesthesia & Analgesia, Zhou et al.6 report an updated systematic review and meta-analysis that includes additional recent studies (63 studies in total) in an attempt to answer the question of whether ANH is efficacious in reducing allogeneic transfusion. The authors should be commended for conducting the largest and most rigorous analysis of ANH studies to date. Despite their comprehensive meta-analysis, high-quality evidence to support the routine use of ANH is still lacking. Although ANH decreased both the likelihood of any allogeneic transfusion (by 26%) and the volume of allogeneic transfusion (by approximately 1 unit), there was evidence for publication bias leading to an overestimation of benefit from ANH. The primary limitations of this study were the inclusion of small trials, some with as few as 10 patients per group, and the absence of transfusion protocols with a designated hemoglobin trigger or target, which introduces bias when blinding is not possible in such studies. As expected, the type of surgery, the volume of blood withdrawn, the presence or absence of other blood management methods, and even the year of publication all influenced the beneficial impact of ANH. The secondary outcomes were adverse (morbid) events. The only morbid event for which the incidence differed between groups was “any infection,” which unfortunately was reported in only 10 of the 63 studies but occurred with less frequency in the ANH group (relative risk, 0.64; P = 0.037). Because allogeneic transfusion is known to be associated with hospital-acquired infection,7 this finding is plausible, interesting, and perhaps understated in the current study. In addition, the inability to assess such outcomes in a blinded fashion is problematic. The authors go on to conclude that based on their findings, in combination with previous mathematical modeling studies,8 surgical procedures with blood loss of 1 L or greater are the cases in which the benefits of ANH are most likely to be recognized.

Assessing the efficacy of ANH is no simple task. For example, what is the primary outcome that should be measured? Is it the percentage of patients exposed to allogeneic transfusion or the volume of blood transfused? What about other important outcomes that are often not reported in these studies such as length of stay, morbid events, mortality, and overall costs? Is ANH being compared with no blood conservation measures at all? Should ANH be used in combination with other blood management methods, which are now commonly used, such as preoperative anemia management, autologous blood salvage, antifibrinolytic medications, controlled hypotension, new methods of surgical cautery, and hemostatic agents and sealants?9–11 Many of these measures have now become routine care, given the widespread adoption of patient blood management, with the resulting improved outcomes, as well as reduced costs and risks by avoiding unnecessary transfusions.12 Although ANH has been touted as easy to perform, it remains labor-intensive and time-consuming. In addition, it frequently requires invasive intravascular access that may not otherwise be needed simply to remove the volume of blood required to make a difference.

Another consideration is the evolution of surgery itself over the past 2 decades since the first ANH meta-analysis was published. Surgeries previously associated with high blood loss (e.g., radical prostatectomy or open aortic aneurysm repair) no longer require transfusions in most cases, thanks to minimally invasive approaches with robotic and endovascular surgery. In fact, patients undergoing radical retropubic prostatectomy, for which ANH has been shown to be efficacious in reducing transfusion,13 are now rarely or never transfused with robotic surgery. For example, only 1 in 800 patients undergoing robotic prostatectomy at our institution was transfused in the past year.14

The initial enthusiasm for ANH 20 to 30 years ago was generated when the risk of viral transmission was substantially higher than the current risk. At that time, patients only wanted their own blood for transfusion, which led to the preoperative autologous donation era. Studies from that era showed that ANH was equally efficacious as preoperative autologous donation,15,16 and less costly,17 with less chance of a wrong unit error because the blood never leaves the operating room. Of course, over time things have changed. Now the viral risk of allogeneic blood has been compared (seriously and systematically) with the risk of getting killed in an airline crash or being struck and killed by lightening!18 In addition, preoperative autologous donation has fallen out of favor because patients frequently are rendered anemic before their surgery and do not have adequate time for erythropoiesis before surgery. In addition, storing blood is associated with storage lesions, whereby the quality of RBCs decreases over time between the donation and the transfusion.19 Now that we have other methods of blood conservation, it appears that neither preoperative autologous donation nor ANH is clearly beneficial for the vast majority of cases. In fact, if forced to choose between these 2 methods, there may be more benefit from receiving 2 units of fresh whole blood at the end of surgery, with functional clotting factors and platelets, than stored preoperative autologous donated blood that is near the end of its shelf life with less hemostatic benefit. At our institution, ANH is commonly used for patients undergoing cardiac surgery, especially for those who do not accept transfusion for religious or other reasons.20 Such patients usually do not accept RBCs, plasma, or platelets, so they benefit from the hemostatic effects of fresh whole blood at the end of the procedure.21

In conclusion, the updated meta-analysis published in this issue of Anesthesia & Analgesia on the efficacy of ANH is a welcomed addition to the anesthesia literature. Although widespread adoption of this blood conservation measure is not supported by this study, there are certain clinical situations in which ANH may be beneficial. Although still controversial, cardiac surgery may be the ideal setting for ANH when patients arrive with a high hematocrit, undergo a substantial blood loss, and the hemostatic benefits of fresh whole blood may be most apparent.22 Even then, blood conservation measures such as antifibrinolytics, meticulous surgical techniques, and newer perfusion techniques (retrograde autologous priming, smaller circuit volumes, ultrafiltration) may be equally efficacious. Perhaps a combination of any or all the mentioned blood management techniques, used together for selected patients, under the right circumstances, will become the new standard of care.

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DISCLOSURES

Name: Michael C. Grant, MD.

Contribution: This author reviewed the literature and prepared the manuscript.

Attestation: Michael C. Grant approved the final manuscript and also attests to the integrity of the content reported in this manuscript.

Conflicts of Interest: Michael C. Grant has no conflicts of interest.

Name: Linda M. S. Resar, MD.

Contribution: This author reviewed the literature and prepared the manuscript.

Attestation: Linda M. S. Resar approved the final manuscript and also attests to the integrity of the content reported in this manuscript.

Conflicts of Interest: Linda M. S. Resar has no conflicts of interest.

Name: Steven M. Frank, MD.

Contribution: This author reviewed the literature and prepared the manuscript.

Attestation: Steven M. Frank approved the final manuscript, also attests to the integrity of the content reported in this manuscript, and is the archival author.

Conflicts of Interest: Steven M. Frank has received compensation for work on advisory boards for Haemonetics, Medtronic, and Biomet as well as research support from Haemonetics and the New York Community Trust.

This manuscript was handled by: Charles W. Hogue, MD.

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