Steven M. Frank, MD
Medical Director, Center for Bloodless Medicine and Surgery
Medical Director, Johns Hopkins Health System Blood Management Clinical Community
Professor, Department of Anesthesiology/Critical Care Medicine
The Johns Hopkins Medical Institutions
Andrew V. Scott, BS
The Johns Hopkins Medical Institutions
Linda M. S. Resar, MD
Co-Director, Center for Bloodless Medicine and Surgery
Professor, Department of Medicine (Hematology)
Professor, Department of Oncology
Institute for Cell Engineering
The Johns Hopkins Medical Institutions
Bloodless medical care seeks to avoid the need for transfusions. The following is a review of the most important considerations for setting up a bloodless care center.
“Bloodless” medical care was first recognized in the 1970s when Denton Cooley, MD, performed cardiac surgery on hundreds of patients who were Jehovah’s Witnesses (JW).1 These patients were often turned away by other physicians because they were prohibited from receiving allogeneic transfusions. Bloodless care became more common in the 1980s, when the risks for viral infections transmitted through transfusion reached an all-time high, especially for HIV and viral hepatitis. The practice of bloodless medicine was further developed and promoted by the Society for the Advancement of Blood Management (SABM), which was founded in 2001 and continues to specialize in this area today.
Bloodless care shares many principles in common with “patient blood management” (PBM),2 which aims to prevent and manage anemia, optimize coagulation to reduce or prevent hemorrhage, and promote optimal blood conservation, and to achieve these goals in order to improve outcomes with an evidence-based, patient-centered focus.3 PBM was an outgrowth of multiple randomized clinical trials, all of which compared a restrictive with a liberal transfusion strategy based on hemoglobin (Hb) triggers of 7 to 8 versus 9 to 10 g/dL, respectively, in which every trial showed either no benefit from or increased adverse outcomes with the liberal strategy.4-11 Perhaps these trigger trials were a natural progression from the high prevalence of viral risk that emerged in the blood supply during the 1980s or were efforts to reduce other transfusion-related risks and complications. Nonetheless, it is now generally accepted that “less is more” when it comes to transfusion, with the exception of ischemic brain and ischemic heart syndromes, for which the ideal Hb trigger is yet to be determined.12 Bloodless care can be thought of as extreme PBM, in which the goal is to avoid rather than reduce the need for transfusions.
In this article, we will review the top 10 issues to consider when setting up a bloodless program, which are summarized in Table 1.
Issue 1 is the evidence to support giving less blood, as referenced in the previous paragraph, as well as the evidence supporting the advantages of bloodless care. Although a randomized trial may never be performed involving bloodless care, case-control and propensity-matched studies clearly demonstrate either the same or better outcomes, at the same or lower costs, compared with conventional care using transfusion.13-15
The primary findings in one such study from our institution are summarized in Figure 1. The overall costs of providing bloodless care were 12% to 14% lower, with morbid events occurring with no higher incidence and mortality occurring with a lower incidence in the bloodless patients. It should be carefully noted, however, that these patients were given specialized bloodless care, which is not the same as simply withholding transfusions. Regarding anemia tolerance, it is generally recognized that, with regard to symptoms, chronic anemia is much better tolerated than acute anemia. We have seen, for example, chronically anemic patients who decrease their Hb levels from 6 to 4 g/dL, and have surprisingly few symptoms. Along these lines, we have recently shown that a perioperative “delta Hb” of a 50% or greater decrease from the preoperative baseline level was a strong predictor of perioperative morbidity.16
Clinical outcomes (A) and overall hospital charges and costs (B) in patients receiving bloodless care compared with matched control patients who accept transfusion. Major morbidity was similar, with a trend toward less hospital-acquired infections; in-hospital mortality was lower in the bloodless patient group. Total hospital charges and costs were 12% to 14% lower in the patients receiving bloodless care than in patients accepting transfusion.
Adapted from reference 13.
Issue 2 is that bloodless care is patient-centered, and thus it is important to define who are bloodless patients. Historically, they have been JW patients for whom allogeneic transfusion of red blood cells, plasma, and platelets is not an option. Many JW patients, however, will accept what they call the “minor fractions” of blood, such as albumin, immunoglobulins, cryoprecipitate, and other blood-derived fractions. JW patients will often accept intraoperative autologous salvaged (ie, Cell Saver) blood, and autologous normovolemic hemodilution (ANH), but these are considered to be a personal choice that each JW patient must make (see discussion, below).17,18 In addition, there are a growing number of patients who are not JWs who will choose bloodless care when offered for reasons of avoiding the risks and complications associated with transfusion. Very often, however, this option is never discussed or offered, and physicians simply ask the patient to “sign here (on the consent) in case you need a transfusion.”
Issue 3 to consider is that providing bloodless care is akin to a team sport, with many different specialties and provider types included, some of which are listed in Table 1. The bloodless clinical coordinator is invaluable for coordinating care among all the specialists and other personnel on the team. Often this coordinator is a nurse with PBM experience, and sometimes coordinators are JWs themselves, who have a unique perspective and passion for optimizing bloodless management. Anesthesiologists and intensivists are involved when patients come for surgery or require ongoing care in the ICU. These physicians must be familiar with all the methods discussed in this review. Talented surgeons are critical to any bloodless program, and must be experienced enough to know their limits in terms of what procedures can be done and when to say no if something cannot be done without allogeneic transfusion. Other specialists from hematology, transfusion medicine, nursing, and pharmacy are all important members of the bloodless care team, offering their own unique contribution to managing these patients.17
Issue 4 is the preoperative preparation for surgery with the primary aim of avoiding the need for transfusion. Although medical patients are often treated in a bloodless fashion, the focus is often on surgical patients for whom blood loss is a primary concern. Perhaps the most important factor is knowing at least 4 weeks prior to the scheduled procedure what surgery is planned, as well as a baseline Hb level in order to assess the target Hb and to allow time to manage and treat anemia before surgery.
We use our institution-specific maximum surgical blood order schedule (MSBOS),19 as described below, to decide whether the planned surgery is one with a high, medium, or low degree of blood loss. Then we account for the experience of the particular surgeon, and also the patient’s ideal body mass (based on height and weight), which is proportional to his or her total blood volume. For example, 1 L of blood loss in a 40-kg patient could be about 30% of total blood volume, whereas in an 80-kg patient 1 L represents only about 15% of total blood volume.20 The expected drop in Hb level would therefore be at least these percentages or slightly higher, since there is postoperative downward Hb drift by as much as 1 to 2 g/dL after more invasive surgical procedures.21 Thus, in smaller-sized patients having larger blood loss procedures, we generally aim for a higher preoperative Hb level in preparing the patient for surgery.
Often we see mild anemia (Hb, 10-11 g/dL) in patients having very low blood loss procedures (eg, thyroidectomy or mastectomy), for whom no preoperative tune-up is needed. An anemia workup is still warranted, at some point, for all anemic patients, especially to rule out gastrointestinal malignancy or other important treatable causes, which should not be overlooked. We often start the anemia workup with an iron panel, as iron deficiency is commonly seen and easily treated. For mildly anemic patients having low to moderate blood loss procedures, oral iron may be all that is needed, but absorption is slow and incomplete.
For more severe anemia or for patients having higher blood loss procedures, we use IV iron treatments,22 sometimes combined with erythropoiesis-stimulating agents (ESAs).23 At least 3 to 4 weeks are needed to achieve a 1 to 2 g/dL rise in Hb levels with this aggressive approach. When ESAs are given, the risks for tumor promotion in cancer patients and thrombotic complications in those at risk must be weighed against the benefits of treating preoperative anemia.24Another important preoperative concern is discontinuation of anticoagulant medications or herbal supplements that may promote bleeding. Coordination is often required with internists or cardiologists to implement “bridging” therapy for patients who cannot tolerate days off anticoagulants.
Issue 5 to consider is the MSBOS, as noted above, which is used as a guide to indicate the amount of bleeding associated with individual surgical procedures.19We have described methods for using data acquired from electronic anesthesia records to create an MSBOS that categorizes each procedure as no blood orders needed, Type and screen, and Type and crossmatch, and if so, how many units are to be crossmatched.25 These group assignments are roughly equivalent to low, medium, and high blood loss groups, respectively. Using data from electronic anesthesia records allows the MSBOS to be specific to your own institution, and such information is used to determine a target Hb level to attain before a given surgical procedure. If a database is maintained, the transfusion rates and average number of units per patient can be assessed for each individual surgeon, which may also be helpful in choosing a target preoperative Hb level.
Issue 6 is intraoperative management from the perspective of anesthesia care. Simply avoiding hypothermia can reduce bleeding risk because core temperatures of 35∞C or lower can promote bleeding. In addition, avoiding hypertension can reduce bleeding, and for some cases (eg, orthopedic procedures), controlled hypotension can be very effective in reducing bleeding, as long as care is taken to stay within the autoregulation threshold for vital organ perfusion.
Other methods of reducing red cell loss include ANH, by which autologous blood is removed from the patient into citrated blood bags (to prevent coagulation) before incision, and hemodilution is achieved with colloid and/or crystalloid solutions. The concept is that blood loss occurs at a lower Hb level, the patient loses less red cell mass, and then the fresh whole blood is returned to the patient at the end of surgery.
ANH is most useful in reducing transfusion requirements under the following three conditions:
- The preoperative Hb is relatively high,
- The blood loss of the surgical procedure is relatively high, and
- A large enough volume of blood is phlebotomized from the patient to achieve a low Hb during the bleeding phase of surgery.26
We primarily use ANH for cardiac surgery patients, who also benefit from the fresh whole blood with functional clotting factors and platelets given after separation from cardiopulmonary bypass.
Intraoperative methods of reducing blood loss also include the use of antifibrinolytics such as tranexamic acid (TXA).27 This drug has recently gained great popularity in orthopedic hip and knee arthroplasty and in major spine surgery. By preventing clot breakdown, TXA has been reported to reduce blood loss and transfusion requirements by about 30%, without any measurable increase in thrombotic complications. The primary concern, however, is the lack of evidence to support an ideal dose for TXA, which has been reported in studies to vary up to 10-fold.
Issue 7 to consider is a combination of surgical methods and adjuncts to reduce bleeding. For example, minimally invasive approaches have dramatically reduced blood loss. Robotic hysterectomies and prostatectomies have an exceedingly low blood loss potential compared with historical open techniques. At our institution, just 1 of the last 1,000 robotic prostate surgery patients required a transfusion, whereas in the 1990s with open prostate surgery we transfused the majority of patients. Bloodless centers always mention meticulous surgical technique as an important method of reducing blood loss. Although one might believe all patients should have meticulous surgical technique, we have noticed that whatever the expected blood loss is for a given surgery, the blood loss is often half as much in JW patients, which suggests that intentional, focused efforts to reduce bleeding make a difference. JW patients sometimes say the decreased blood loss is due to the “Jehovah factor,” which implies that either divine intervention or greater attention to achieving hemostasis is beneficial and effective.
Other methods of reducing blood loss include hemostatic agents and sealants,28as well as newer variations of electrocautery, such as the saline-irrigated bipolar cautery that seals blood vessels rather than burns them by employing a lower temperature.29 A wide variety of hemostatic agents are now available, some derived from human blood (eg, thrombin-based products), which makes acceptance by JW patients a personal choice.18
Issue 8 to consider in a bloodless program is autologous blood salvage, which is often referred to as Cell Saver. Cell Saver technology was first introduced in the late 1970s and became very popular in the 1980s and 1990s, when the risk for viral transmission with transfusion was exceedingly high. The method uses a suction tip irrigated with anticoagulant (heparin or citrate) and collects shed blood into a reservoir. When a sufficient amount of blood is collected (500-1,000 mL), the blood is processed in a specialized bowl and then centrifuged and washed to remove the anticoagulant and any surgical debris. Using a pediatric-sized bowl (70 mL) is often desirable in bloodless cases since smaller volumes of shed blood can be processed. With larger bowls (eg, 125-250 mL), such small volumes are often discarded because of inadequate bowl filling and washing.
After processing, the “Cell Saver blood” consists of red blood cells and saline, and all clotting factors and platelets are removed in the process. A limitation of this method is that after a certain volume of transfusion (≥5 units), a dilutional coagulopathy will begin to develop from factor and platelet deficiency. Another limitation is the relative contraindication with cancer surgery, cesarean delivery, and surgeries where bacterial contamination may occur. In these cases, the risk–benefit balance in patients who will not accept transfusion must be weighed. The risk for contamination can be reduced using a leukoreduction filter placed in line when the Cell Saver blood is transfused back into the patient.30-32 Often we use a “standby” approach, in which the device is in the room, set up and ready to use, in case of major bleeding, which very often does not occur, but the device adds a level of comfort for the providers and the patient, even when the chance of bleeding is very low. We have seen the Cell Saver provide lifesaving blood for transfusion in a few difficult surgeries, in which unanticipated but large blood loss occurred.
An additional factor supporting the use of Cell Saver blood is that these red blood cells are fresh, not having been stored in the blood bank for up to 6 weeks, and thus have normal amounts of 2,3-DPG and a normal Hb–oxygen dissociation curve (Figure 2).33 Cell Saver blood–transfused patients also have circulating red blood cells with normal cell membrane deformability, as opposed to patients who received banked blood, which has decreased red cell deformability.34 All these findings suggest that Cell Saver blood may be better suited for delivering oxygen than banked blood.
Autologous salvaged (Cell Saver) red blood cells (RBCs) are not depleted in 2,3-DPG and are similar to fresh blood, whereas banked blood is depleted in 2,3-DPG and has a left-shifted Hb-oxygen dissociation curve. Cell Saver RBCs therefore are higher quality than banked RBCs and more likely to unload oxygen at the tissue level.
P<0.05 vs fresh and Cell Saver RBCs.
Used with permission, from Scott A, Nagababu E, Johnson D, et al. 2,3-Diphosphoglycerate Concentrations in Autologous Salvaged Versus Stored Red Blood Cells and in Surgical Patients After Transfusion. Anesth Analg. 2016;122(3):616-623.
Issue 9 with providing bloodless care is minimizing blood loss secondary to phlebotomy for lab tests. It has long been recognized that frequent lab testing, especially in ICU patients for whom more tests are ordered, can lead to substantial blood loss.35 We surveyed 5 ICUs at our own institution and determined that the average daily blood loss was about 60 mL from routine lab testing (Figure 3). This amount of blood represents just over 1% of total blood volume in a normal-sized adult patient, or perhaps 2% in a small adult, or even more in pediatric patients. Since the body destroys and creates about 1% of red blood cells each day through erythropoiesis, routine phlebotomy for lab tests essentially cancels out the positive effects of erythropoiesis. In a recent study, cardiac surgery patients were found to lose between 1 and 2 units of blood over the course of an ICU stay, simply from lab testing, and the authors called this “astonishing.”36 We found that in one particular ICU, where an in-line blood return device was routinely used for indwelling arterial and central venous catheters, the blood loss per day was halved by eliminating the wasted discard used to clear the saline from the IV tubing during blood draws.
Volume of blood removed from a patient in a 24-hour period in 5 different ICUs at Johns Hopkins Hospital. The blue portion is the wasted discard for clearing indwelling catheters of saline to provide an undiluted sample. The red portion is the volume of blood sent to the laboratory for the ordered tests. Just over 1% of total blood volume is removed each day from a typically adult-sized patient, which is the same amount of red blood cells destroyed and replaced each day by normal erythropoiesis. In one ICU (the NCCU), an in-line blood return device is routinely used, which reduces the blood volume lost to wasted discard.
These data are from the Johns Hopkins Hospital ICUs, and are previously unpublished.
Another method of reducing blood loss from lab testing is the use of “microtainers” or smaller phlebotomy tubes. While some adult-size tubes hold 7 to 10 mL, the pediatric-size tubes hold 2 to 5 mL, and the neonatal tubes hold as little as 0.5 mL. Blood loss can be reduced by up to 90% using these super-small neonatal tubes. The lab, however, and the phlebotomists dislike these smaller tubes because they require uncapping to squirt the blood into the tube (with a splash risk), and the machines in the lab often cannot accommodate the tubes, necessitating manual testing. Nonetheless, when we are concerned about optimizing blood conservation in many of our bloodless patients, we use these smaller tubes. In many hospitals, lab tests are routinely done every morning, so changing practice to test by indication only will improve care. It has been said that the most common indication for lab tests is the sun rising in the morning, and this knee-jerk test ordering should be thought of as creating avoidable waste and excess in our health care system.
Issue 10 to consider is the availability and potential use of hemoglobin-based oxygen carriers (HBOCs). These compounds at times are referred to as blood substitutes or artificial blood. About 15 years ago, these were tested in multiple clinical trials, but were not approved by the FDA because of concern about safety compared with conventional banked blood transfusions. The HBOC products are polymerized or cross-linked bovine or human hemoglobin molecules, with a half-life of about 24 hours. The concern in previous studies was mainly about nitric oxide scavenging and unwanted vasoconstriction, and the potential for vital organ ischemia. Recently, the products have made a resurgence in a second round of FDA approval attempts, since it was realized that the control comparison group should have been no transfusion instead of banked blood, because the HBOC compounds are being targeted for those patients in whom transfusion is not an option due to red cell antibodies or unwillingness to accept allogeneic blood.
Although acceptance of HBOCs by JW patients is considered a personal choice, in our experience many have considered these to be a minor fraction and will accept them. The only way to obtain HBOCs at this time is through single patient emergency compassionate use protocols, requiring FDA and institutional review board approval each time the HBOC is needed. Hopefully, in the near future HBOCs will be made available for specialized indications, when blood is not an option.
We have outlined what we consider to be the 10 most important issues when setting up a program for providing bloodless care to patients. Not only does the evidence support giving less blood to patients than we usually give, but studies have also shown that providing the whole package of bloodless care—not simply withholding transfusions—can improve the care we provide to our patients. By assembling a team of providers, diagnosing and treating preoperative anemia, reducing blood loss during surgery and from phlebotomy, and using anesthesia care methods to conserve red cell mass, we can provide a higher quality of care and avoid allogeneic transfusion. By providing bloodless care to our patients, we can not only help JW patients receive the care they need, but we can also reduce or eliminate transfusions in the other 99% of patients. Bloodless care is an example of how we can reduce risks, improve outcomes and save costs, thus increasing the value of health care we provide.
- Ott DA, Cooley DA. Cardiovascular surgery in Jehovah’s Witnesses. Report of 542 operations without blood transfusion.JAMA. 1977;238:1256-1258.
- Shander A, Javidroozi M, Perelman S, et al. From bloodless surgery to patient blood management.Mt Sinai J Med. 2012;79:56-65.
- Goodnough LT, Shander A. Patient blood management.Anesthesiology. 2012;116:1367-1376.
- Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group.N Engl J Med. 1999;340:409-417.
- Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial.JAMA. 2010;304:1559-1567.
- Lacroix J, Hebert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units.N Engl J Med. 2007;356:1609-1619.
- Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery.N Engl J Med. 2011;365:2453-2462.
- Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding.N Engl J Med. 2013;368:11-21.
- Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery.N Engl J Med. 2015;372:997-1008.
- Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial.JAMA. 2014;312:36-47.
- Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock.N Engl J Med. 2014;371:1381-1391.
- Frank SM, Ejaz A, Pawlik TM. Optimal transfusion trigger in surgical patients with coronary artery disease.JAMA Surg. 2016;151:146.
- Frank SM, Wick EC, Dezern AE, et al. Risk-adjusted clinical outcomes in patients enrolled in a bloodless program.Transfusion. 2014;54:2668-2677.
- Pattakos G, Koch CG, Brizzio ME, et al. Outcome of patients who refuse transfusion after cardiac surgery: a natural experiment with severe blood conservation.Arch Intern Med. 2012;172:1154-1160.
- Shander A, Rijhwani TS. Clinical outcomes in cardiac surgery: conventional surgery versus bloodless surgery.Anesthesiol Clin North America. 2005;23:327-345.
- Spolverato G, Kim Y, Ejaz A, et al. Effect of relative decrease in blood hemoglobin concentrations on postoperative morbidity in patients who undergo major gastrointestinal surgery.JAMA Surg. 2015;150:949-956.
- Resar LM, Frank SM. Bloodless medicine: what to do when you can’t transfuse.Hematology Am Soc Hematol Educ Program. 2014;2014:553-558.
- Bodnaruk ZM, Wong CJ, Thomas MJ. Meeting the clinical challenge of care for Jehovah’s Witnesses.Transfus Med Rev. 2004;18:105-116.
- Frank SM, Rothschild JA, Masear CG, et al. Optimizing preoperative blood ordering with data acquired from an anesthesia information management system.Anesthesiology. 2013;118:1286-1297.
- Jassar AS, Ford PA, Haber HL, et al. Cardiac surgery in Jehovah’s Witness patients: ten-year experience.Ann Thorac Surg. 2012;93:19-25.
- Grant MC, Whitman GJ, Savage WJ, et al. Clinical predictors of postoperative hemoglobin drift.Transfusion. 2014;54:1460-1468.
- Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents?Transfusion. 2010;50:719-732.
- Goodnough LT, Shander Erythropoiesis stimulating agents, blood transfusion, and the practice of medicine.Am J Hematol. 2010;85:835-837.
- Shander A, Ozawa S, Gross I, et al. Erythropoiesis-stimulating agents: friends or foes?Transfusion. 2013;53:1867-1872.
- Frank SM, Oleyar MJ, Ness PM, et al. Reducing unnecessary preoperative blood orders and costs by implementing an updated institution-specific maximum surgical blood order schedule and a remote electronic blood release system.Anesthesiology. 2014;121:501-509.
- Grant MC, Resar LM, Frank SM. The efficacy and utility of acute normovolemic hemodilution.Anesth Analg. 2015;121:1412-1414.
- Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis.Br Med J. 2012;344:e3054.
- Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use.Ann Surg. 2010;251:217-228.
- Frank SM, Wasey JO, Dwyer IM, et al. Radiofrequency bipolar hemostatic sealer reduces blood loss, transfusion requirements, and cost for patients undergoing multilevel spinal fusion surgery: a case control study.J Orthop Surg Res. 2014;9:50.
- Waters JH, Donnenberg AD. Blood salvage and cancer surgery: should we do it?Transfusion. 2009;49:2016-2018.
- Waters JH, Biscotti C, Potter PS, et al. Amniotic fluid removal during cell salvage in the cesarean section patient.Anesthesiology. 2000;92:1531-1536.
- Waters JH, Tuohy MJ, Hobson DF, et al. Bacterial reduction by cell salvage washing and leukocyte depletion filtration.Anesthesiology. 2003;99:652-655.
- Scott AV, Nagababu E, Johnson DJ, et al. 2,3-Diphosphoglycerate concentrations in autologous salvaged and stored red blood cells and in surgical patients after transfusion.Anesth Analg. 2016;122:616-623.
- Salaria ON, Barodka VM, Hogue CW, et al. Impaired red blood cell deformability after transfusion of stored allogeneic blood but not autologous salvaged blood in cardiac surgery patients.Anesth Analg.2014;118:1179-1187.
- Chant C, Wilson G, Friedrich JO. Anemia, transfusion, and phlebotomy practices in critically ill patients with prolonged ICU length of stay: a cohort study.Crit Care. 2006;10:R140.
- Koch CG, Reineks EZ, Tang AS, et al. Contemporary bloodletting in cardiac surgical care.Ann Thorac Surg. 2015;99:779-784.