Several e-network blood bankers have recently submitted queries about the use of whole blood in various clinical scenarios.

Scenario #1: A blood banker at a children's hospital reports that their cardiovascular surgical program requires fresh (< 48 hours old) heparinized whole blood for transfusion of pediatric heart surgery patients. The laboratory had to open a donor center for the collection of heparinized whole blood donations, which is the only product that they collect; the number of units collected averages one to two per week. The donor center must 'make' their own blood bags, as they cannot purchase bags pre-filled with heparin. The surgeon is willing to waive disease marker testing in order to have the blood less than < 24 hours old for some patients.

Scenario #2: A blood banker in the San Diego area reports that a cardiac surgeon has requested CPD-A1 whole blood (not heparinized) for pediatric surgery citing two references that appeared in the medical literature in 1991 and 1992. Specifically, the articles cited were by Manno et al., Blood, vol 77, No. 5 (March 1), 1991: pp 930-936, entitled "Comparison of the Hemostatic Effects of Fresh Whole Blood, Stored Whole Blood and Components after Open Heart Surgery in Children AND Mohr et al., Ann Thorac Surg 1992;53:650-4 entitled Fresh Blood Units contain Large Potent Platelets that Improve Hemostasis after Open Heart Operations. The surgeon is willing to waive required disease marker testing so that the blood can be delivered in less than 48 hours even if NAT testing is not complete.

Scenario #3: A blood banker in Texas comments that their OB service has been using whole blood for transfusion of their patients with a justification that since patients are losing whole blood during delivery/surgery, they should be given whole blood. Also, OB patients who are merely anemic but not actively bleeding are transfused with whole blood. The commonest transfusion reaction reported by that service is "volume overload". Last year 120 units of whole blood were transfused by the service. However, they had to convert about 700 units of whole blood into packed cells when they could not be used by that service. The whole blood units are usually group O and A. Group B and AB whole blood units are generally not available, so group B and AB obstetric patients are transfused with packed cells.

The following questions were posed to the e-network for discussion:

• Who supplies whole blood as a routine for pediatric cardiac surgery rather than RBCs or leukoreduced RBCs?
• If so, how old is the blood upon receipt by the hospital?
• How "young" does the blood need to be?
• Are requests for whole blood <48 hours old for pediatric cardiac surgery patients a reasonable request?
• Is the use of whole blood for an OB service a reasonable practice?

The following replies were submitted in response to the above. I think it is safe to say the NO consensus is obvious from the replies that were submitted. Strong opinions were expressed on both sides of the issue. I have attempted to group the responses in a PRO versus CON format:

CON positions regarding use of whole blood for the indications described above:

CON #1: A physician blood banker in Michigan expressed a strong opinion that the use of heparinized whole blood is an irrational request that places the patient, the Transfusion Medicine physician and the blood bank at undue risk. According to the responding physician, the "science" of using "fresh" heparinized whole blood for pediatric cardiovascular surgery is questionable and the risk of serious disease transmission is significant, especially since the donors are more likely to be first-time directed donors for the patient population in question. The responding blood banker predicts that a lawyer could have a field day whether informed consent was truly obtained from the parents in these cases. The responding blood banker had equally critical comments for the practice of CPD and CPD-A1 whole blood transfusion to OB patients. In his opinion there is absolutely no justification for use of whole blood (regardless of the preservative system) for OB patients. He believes that bleeding OB patients can be managed like the thousands of trauma patients who are successfully resuscitated every day in the US using appropriately chosen components. Since most OB patients have significantly increased vascular volumes approaching term, it is not a surprise that whole blood transfusions result in volume overload postpartum. The responding blood banker says that his hospital successfully manages OB patient hemorrhage (a very rare event at his institution despite the largest OB service in Michigan) using routine Transfusion Medicine principles. He finds it hard to believe that the obstetricians in the inquiring hospital in Texas are of lower skill and knowledge than their counterparts in Michigan. Finally, he commented that perhaps all the stake-holders at the inquiring hospital where obstetricians are ordering whole blood for their patients should look at the outcomes in the women who only get packed cells because of their blood group, to see if their outcomes are different. The responding blood banker predicts that the RBC transfusion group will have fewer episodes of volume overload per delivery than the whole blood transfusion group.

CON #2: A blood bank physician, whose hospital is not too far from the Mall of the Americas, wonders about flawed logic of the argument that "the patient is losing whole blood and thus requires whole blood". He is also troubled by the fact that certain clinicians are being acceded to for political or economic reasons (the surgeons bring in a steady revenue stream for the hospital), while compliance with FDA-defined GMPs in the "manufacturing" process are overridden. He wonders why no Transfusion Committee or other responsible quality management group has stepped in to stop unsafe practices, such as 'manufacturing' heparinized whole blood. Also, he is concerned about the routine use of pathogen-untested blood products merely to obtain some potential relatively small functional benefit from "fresh blood". He feels this is breathtakingly cavalier, irresponsible and highly dangerous. He asks if the risk managers have evaluated the practice for legal risks. It would seem from these scenarios that the mere fact that there is some paper published somewhere which advocates some practice or other is taken as sufficient grounds for all sorts of dangerous modifications to what might generally be considered safe and prudent management of blood resources. He concluded by saying that it is truly amazing that such short-sightedness exists in a time of greatly increased scrutiny of transfusion practices (by FDA and others) and of increased awareness of legal jeopardy.

CON #3: A blood banker who does inspections for the JCAHO said that the data concerning fresh whole blood in open heart pediatric surgery is suggestive for an advantage, but (in his opinion) not enough to outweigh waiving conventional testing. If one believes the data, then one could make an argument for pre-testing fresh whole blood donors. With regard to OB patients needing whole blood, he says that this is an old story, and the response is that by similar logic, one would give patients with cholera their diarrhea fluids p.o. to restore hydration.

CON #4: A blood bank physician in North Carolina wrote that the original basis for providing whole blood <48 hours was based on one study from Children's Hospital of Philadelphia (CHOP) which showed a statistically significant difference in blood usage for a subgroup of complex congenital heart surgery. The reference was provided above in scenario #2. In this study it was concluded that the transfusion of <48 hours old whole blood was associated with significantly less post-op blood loss than the transfusion of packed red blood cells, FFP, and platelets in children under 2 years of age who underwent complex cardiac surgery. However, while statistically significant, critical review of this paper raises the question of whether these differences were clinically significant (resulting in additional allogeneic exposure). Complex cases were defined by Manno as 'arterial switch, Fontan, Glenn, truncus arteriosus repair and stage I palliation for hypoplastic left heart syndrome'. This study, to the best of the responding blood banker's knowledge has never been confirmed at any other center in the USA. He comments that he is also not aware of any studies that have shown a benefit with older units of whole blood. Therefore, his hospital does not know what point in the storage process (i.e., duration) the benefits of fresh whole blood fail to exceed those of RBCs and FFP. Given the inability to provide fully tested whole blood (NAT tested) in his institution, the Transfusion Committee decided the liability exceeded the benefit (a small fraction of a unit of RBCs) in selected complicated cases, and the practice of using fresh whole blood (<48 hours) for congenital heart cases was abandoned.

CON #5: A New York physician blood banker does not believe there is sufficient information in the literature to justify any of the three approaches described in the scenarios under discussion, particularly when fully tested components for hemostasis are available. The medicolegal ramifications alone seem daunting.

CON #6: The Medical Director of the Blood Bank and Transfusion Medicine services at Hershey Medical Center (Penn State) submitted the following: "I do not see the issue of whole blood so much here at Penn State, but when I was at The Cleveland Clinic our pediatric cardiac surgeon insisted on 48 hour or less (preferably no more than 24 hour old) whole blood collected in heparin (and irradiated). We were able to provide it since we had 4-6 hour turn-around infectious disease testing in place for our organ transplantation program, but we were not dealing with NAT at the time. Since most of these cases were electively scheduled we were able to test the donors ahead of time, if necessary (to minimize unexpected findings), or to recruit repeat donors. In fact, we had a special donor club - "Cardiac Kids", or some such name - that was a list of "dedicated" repeat donors who could be called at a moment's notice. Yes, the data to support such a program is thin, but the surgeon had great operating statistics (Who can argue with that?), brought in a lot of patients and money to the hospital, and we (in transfusion medicine) were basically told to give him whatever he wanted. We did run into trouble with the FDA during one of our inspections because our heparin formulation did not follow exactly what was published in the CFR (I think we added some dextrose, or something, as it was the surgeon's formula from wherever he originally came from). We eventually reformulated the heparin solution to everyone's satisfaction but a lot of time and energy was put into making it work. Part of the reason that we were able to make it work was that we had a full-service hospital-based donor program and dedicated people, as such a program is very labor intensive. Our regional blood supplier would never have had the energy or the initiative to support such a specialized blood component request. The question remains, however, whether or not heparinized whole blood was clinically necessary in the first place but the surgeon was not very interested in doing any randomized studies."

CON #7: A blood banker in Los Angeles was very concerned about assuring sterility of the heparinized whole blood, since the inquiring donor center must 'make' their own blood bags, as they cannot purchase bags pre-filled with heparin.

SEVERAL additional CON comments were submitted, stating similar concerns as expressed above.

PRO positions regarding use of whole blood for the indications described below:

PRO #1: The Associate Director of the transfusion service at the Children's Hospital of Philadelphia submitted the following response. "The study quoted (Manno et al) was carried out at our institution and Dr. Manno is the director of the blood bank. A few points to be made: Fresh whole blood was studied specifically for the bleeding diathesis associated with cardiopulmonary bypass, and it was used specifically for the transfusions given as the child comes off bypass. We believe that the hemostatic advantage of fresh whole blood is related to supplying functional platelets to a patient whose own platelets have been affected by the bypass circuit, and that the freshness, defined as <48 hours old, preserves the platelet function in whole blood stored at 4 degrees. So it does not in general make sense to use fresh whole blood for all cardiothoracic surgery patients - we supply it only for bypass cases and intend for it to be used only post-bypass. We supply packed red cells for priming the bypass pump, and packed red cells for post-operative care in the intensive care unit. There are times when our cardiothoracic anesthesiologists and critical care MDs will use the fresh whole blood in other settings, but it is generally intended to restrict the patient's blood exposure to only the whole blood. For example, if they think they can get through the post bypass period using only a quarter or a half of the fresh whole blood unit, then they may use the other half to prime the bypass machine. Or if the patient has received only half of the whole blood unit post-bypass, they may want to use more of the same whole blood unit for postop bleeding within the next 24 hours. These decisions are very individualized, depending on the patient's hematocrit, the size of the patient and bypass circuit, the target for post-bypass hematocrit, the type of surgery and the degree of bleeding, and complications. We have not been willing to waive standard, federally mandated testing for transmissible diseases in the interest of this fresh blood program. Our blood supplier has worked out collection, testing, and distribution strategies to provide the fresh whole blood fully tested such that it is transfused before it is 48 hours old. The only current exception to that has been NAT testing, which cannot always be turned around within the time frame, and we have asked the cardiothoracic surgery program to sign a written statement about their decision to forgo NAT testing and their willingness to inform the families about this deviation from usual practice (all other blood products in our region are NAT tested). The whole blood we get is in CPD, and we do NOT use heparinized blood.

PRO #2: A pediatric blood banker in Washington DC says that her transfusion service will supply whole blood or reconstituted whole blood, prestorage leukodepleted for their baby open heart cases for the pump prime. The units administered post-operatively are leukocyte-reduced RBC. They draw their whole blood units in house; serology and NAT are done by a reference lab. Since Sept 11, they have had to release units without NAT due to logistics problems. Older infants and children may get a packed cell prime or colloid prime. They try to give blood as fresh as possible. This usually means units that are 5-7 days old. They have not had issues of hyperkalemia with units collected in this fashion. In addition, using cell-saver blood is a practice that aids in decreasing the blood needs in these babies. They give FFP and platelets as needed and not prophylactically. The older child who is a "re-do" is a different story as to blood component needs. Finally, she comments that in her opinion, the data by Manno et al. are compelling in regard to postoperative blood loss and component need in the infant open heart case that is complex with a long pump run. The same postoperative losses do not hold for the older child. That study did NOT use heparinized blood. In fact, the responding blood banker has not ever seen a study that has compared heparinized whole blood to reconstituted blood in the pediatric surgery literature. She also comments that there are two similar studies from Israel from the same set of investigators, but one is a less well done study. The use of heparinized blood is common among the Australian and New Zealand trained pediatric open-heart surgeons. The responding blood banker comments that the Cleveland Clinic provides heparinized whole blood for the patients of one of their surgeons

PRO #3: A pediatric blood banker in Palo Alto wrote that "the paper by Manno, cited in the query, suggests that fresh whole blood (< 48 hr) given at the end of surgery will decrease post-operative blood loss in a select group of patients (< 2 yr. old with complex cardiac surgery). We have one surgeon who believes strongly that this product makes a difference in preventing post-op blood loss, and we make the product available to his infant patients. The product must be ordered on a patient-specific basis and is not guaranteed with less than a one week notice. We have other surgeons who operate on the same category of patient who do not feel that fresh whole blood is necessary. They use packed cells, FFP, and platelets as needed. Several of our pediatric surgeons and anesthesiologists like "freshness" and "wholeness" for reasons other than hemostatic properties. With regard to freshness, our anesthesiologists are concerned about the total dose of free potassium in the setting of massive transfusion (which is one unit or more in a neonate). When massive amounts of blood are used and/or the patient has other risk factors for hyperkalemia or acidosis, some of the anesthesiologists have requested various types of "reduced potassium" products, such as relatively fresh cells, washed cells, or non-irradiated cells. Given adequate notice, we agree to provide washed cells. We do not guarantee "fresh cells". With regard to "wholeness", the anesthesiologists who work with small infants say that it is difficult to keep the baby's hematocrit stable when they infuse packed cells and FFP separately. We provide them with separate units of packed cells and FFP, and allow them to mix the products together in the O.R. prior to infusion. Whole blood can be ordered, but we require 1 week notice and discourage the practice because it requires patient-specific recruiting."

ADDENDUM Nov. 7, 20

PRO #4: The Medical Director of a large Regional Blood Center reports that "Until recently, I was the director of the transfusion service at a pediatric hospital that performs a large number of cardiac surgeries, mostly for congenital heart defects. When a new surgeon came (trained at the Cleveland Clinic), he wanted type-specific heparinized whole blood, less than 48 hours old. Working with our very cooperative local blood center, we were able to provide this. All normal testing was performed, and all blood was CMV-negative. Many of our patients came from out of town. While some of the donors were first-time, the center was willing to call in specifically some of its regular donors for this program, and they were more than glad to help. It took a great deal of effort on the part of the blood center and cooperation with the hospital. The surgeon had designated a key member of his nursing support team to be on call to coordinate, 24/7. Unfortunately, a fair number of units were wasted, as surgery for these kids will often be cancelled at the last minute, if they have a fever or show any signs of an impending respiratory infection. The blood center eventually stopped the program, as it became too difficult to obtain the necessary samples for NAT testing, which cannot be done on heparinized samples. Of course you could draw the samples separately, but that would have required major changes for the blood center, and the program was already extremely expensive for them (and the hospital).

Why was the surgeon so insistent on heparinized whole blood? Partly it is history. Many of the pediatric cardiac surgeons in this country trained at the Cleveland Clinic (see above), with McNee. He came from Australia, and brought heparinized whole blood with him. At least this is my understanding. So a whole lineage of surgeons has been trained using this product. Is it better? Our primary surgeon, who has wonderful outcomes statistics and whom I all respect, says that a part of his success (and what he learned at Cleveland) is the absolutely meticulous management of electrolytes and other metabolic parameters. They use on-site testing in the OR to help them manage this. Heparinized whole blood made the babies easier to stabilize after putting on the pump. When you read the literature on metabolic effects of citrate (and most of it is quite old now), it is not hard to see the problems it might cause in these tiny, already stressed babies. Notice that some people doing apheresis procedures with small children prefer to use heparin as anticoagulant for the same reason. There is a European literature on using heparinized FFP for reconstituting cells in similar circumstances. So, using heparin in these cardiac cases does not seem so unreasonable. I tried to get some studies and comparisons done, but failed because we could never figure out appropriate parameters to measure, and he felt so strongly about heparin's superiority that he did not feel a controlled clinical trial would be ethical. So we have several years of experience of its safety, but not its superiority. I might point out that we may be talking about apples and oranges here. We used this blood most of the time at 18-36 hours after collection - donated in the afternoon, tested at night, used in the next morning. We did some basic studies showing red cells in heparin are as well preserved as older CPD cells, just to establish for ourselves its safety, and had an abstract at the 1998 AABB. There is some ancient literature too, some of Mollison's work and others in the 1940's and 50's. But there is no evidence the platelets are any good then, and our surgeon never claimed it helped particularly with bleeding, although of course heparin effect can be rapidly reversed. If platelets were needed post-pump, he gave them separately. So it's interesting that the Manno study, often cited, talked about bleeding but not metabolic consequences. With heparin, we use the blood fresh because the red cells aren't well enough preserved to use for long. Finally, the heparinized bags were made by the hospital pharmacy under the same conditions they make other IV solutions. We never had a problem with sterility."

ADDENDUM Nov. 9, 2001

Partly PRO (#5) and partly CON (#8): A blood banker who used to work at the Web Master's cross-town rival university wrote the following: "Some investigators have suggested that transfusion of fresh whole blood is optimal for minimizing bleeding after cardiopulmonary bypass (CPB) surgery. Mohr et al (J Cardiovasc Surg 96:530, 1988) compared the effectiveness of fresh blood with that of platelet transfusions in adults having CPB surgery and reported no statistical difference in postoperative blood loss after a transfusion of 1 unit of fresh whole blood compared with transfusion of 10 units of platelets. This is readily understandable as there is no evidence that either product should affect postoperative blood loss in uncomplicated CPB surgery. The most detailed study to compare the hemostatic effects of fresh whole blood, stored whole blood, and components after open-heart surgery was conducted by Manno and colleagues (Blood 77;930: 1991). They compared postoperative blood loss in 161 children undergoing open-heart surgery with CPB whose immediate postoperative transfusion requirements were met with either very fresh whole blood (VFWB), 24- to 48-hour-old whole blood, or "reconstituted whole blood" (packed RBC, FFP, and platelets). Comparison of mean 24-hour blood loss for the 68 children older than 2 years did not show a significant difference among the treatment groups. In the 93 children younger than 2 years of age, mean blood loss in ml/kg was statistically significantly higher in the patients receiving reconstituted whole blood compared with the other two groups. They concluded that the lesser blood loss associated with the transfusion of VFWB and 24- and 48-hour old blood compared to reconstituted whole blood was not explained by postoperative coagulation tests, and may have been due to better functioning platelets.

Manno et al discussed the fact that platelet function in blood refrigerated for up to 48 hours is presumably significantly impaired, and they did not compare the use of fresh platelet products with the other types of blood products. In particular, their "reconstituted whole blood" contained platelets stored up to 5 days and it was this product that was compared with VFWB and 24- and 48-hour old blood.

Optimal platelet preservation is provided by storage of platelet concentrates at room temperature rather than in whole blood at 4C under conditions established for preservation of RBC. Accordingly, it is much more scientifically sound to provide optimally stored platelets rather than platelets as part of whole blood that has been stored at 4C for replacement therapy for children of any age. As far as coagulation factors are concerned, it is difficult to conceive of factors that would be in VFWB that are not in FFP. Accordingly, the use of VFWB appears to be a triumph of dogma over science.

However, this is not to say that whole blood has no place in transfusion medicine. In instances of large blood loss, such as trauma, extensive surgery, and liver transplantation, the transfusion of whole blood rather than the combination of red blood cells (RBCs) and fresh frozen plasma (FFP), is rational and may be preferred.

A potential problem regarding the use of whole blood (WB) is the decay of plasma coagulation factors during its storage, which would seem to make necessary the transfusion of fresh frozen plasma for the prevention of dilutional coagulopathy. However, a number of studies have indicated that stored whole blood contains adequate amounts of plasma coagulation factors to prevent dilutional coagulopathy (Miller et al. Ann Surg 1971;174:794-801; Mannucci et al. Vox Sang 1982;42:113-123; Ciavarella et al. Br J Haematol 1987;67:365-368; Counts et al Ann Surg 1979;190:91-99). Counts et al pointed out that bleeding following massive transfusion is primarily due to dilutional thrombocytopenia rather than clinically significant coagulation factor deficiencies. Indeed, Reiner has stated that whole blood is the preferred blood product during massive transfusion (Reiner, IN: Perioperative Transfusion Medicine. Baltimore: Williams & Wilkins, 1998: 351-364.)

We have recently conducted a controlled, prospective, randomized study of patients undergoing orthotopic liver transplantation in which we compared the effectiveness of component therapy with the use of stored whole blood. There was no statistically significant difference between groups in coagulation profiles during any of the phases of surgery. However, there were fewer donor exposures occurring in the whole blood group compared to the component group. Perhaps even more significant is the comparative ease with which large numbers of blood products can be prepared for transfusion both in the transfusion service and in the operating room under stressful and hurried situations. By using WB rather than multiple components, the multitude of tasks both in the transfusion service and in the operating room are considerably reduced and simplified, thereby reducing the probability of transfusion error, which, of course, is one of the greatest hazards of transfusion. Our findings suggest the advisability of using whole blood rather than component therapy as replacement therapy in surgery and on trauma services."

ADDENDUM Feb. 14, 2002

CON #9: According to a blood banker from the UK, all blood in England is supplied by the National Blood Service and no whole blood is requested by any hospital that performs Paediatric Cardiac surgery in London or South East England. (The responding blood banker was not sure about what happens in Northern England) In London and SE England whole blood is supplied only for neonatal exchange transfusion when blood less than 5 days old is provided. Blood untested for the mandatory markers is never supplied. In England all blood is collected into CPD-A1 and the collection of blood in heparin ceased some 10 years or so ago.

ADDENDUM Mar. 15, 2002

CON #10: Another blood banker from the UK wrote that "In addition to the comments from London, UKabove, it should perhaps also be noted that the universal leukodepletion program in the UK takes out over 90% of the platelets from red cell components. Hence, even the freshest red cells produced by the UK services have no platelets to speak of, and as platelets are the most likely sources of the haemostatic 'virtue' in fresh whole blood, their lack in the UK product probably renders them haemostatically 'inadequate', at least in theory. Yet this red cell product is what our cardiac surgeons - pediatric and adult alike - have to prime their extracorporeal circulation."

ADDENDUM Mar. 18, 2002

CON # 11: A blood banker in Texas wrote that the use of fresh whole blood in pediatric cardiac surgery is controversial. As discussed by several discussants, when one keeps whole blood at 4C , platelets become dysfunctional. That is one reason platelets are stored at room temperature. So using fresh whole blood stored at 4C for 48 hours has less functional platelets than a platelet concentrate. Also heparin is known to interfere with platelet function. In addition, some of the leukoreduction filters reduce platelets by >90% when you filter whole blood.......which then becomes RBCs and plasma product! Such filters are used in many places where whole blood is used for pediatric cardiac surgery as an alternative to CMV negative blood for infants <4 months of age. That is what is happening in the responding Texan's institution as part of a study to compare fresh WB (<48 hrs) and reconstituted WB (RBCS+FFP) in pediatric cardiac surgery.

ADDENDA Oct 14, 2004

A recent study from U of Texas Southwestern concludes that reconsituted blood is superior to fresh whole blood for these patients. Forum members are encouraged to comment.

Please submit comments to the e-Network Forum.

Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator