Can RBCs Be Given Through an Infusion Pump?
Whether there is an optimal method of red blood cell transfusion administration has been a point of discussion. Studies evaluating the effect of various administration methods on the integrity of blood cells exist, focused on the in vitro effect of infusion pumps, measuring the degree of free RBC content (free hemoglobin, potassium, lactate dehydrogenase, bilirubin) and osmotic fragility. The results vary from observing significant increases to insignificant increase in values, while transfusions with red cells with longer storage time resulting in a larger increase of hemolysis markers than those with shorter storage times. The variability in results, in addition to the anecdotal evidence of patients benefiting from RBC transfusions administered with infusion pumps, are a cause for varying opinions.
A study assessing in vivo survival time of RBCs infused with various infusion methods, compared the use of gravity flow, volumetric peristaltic pump, and syringe pump in autologous transfusions in dogs. Blood was collected from 9 healthy dogs, washed, and separated into 3 portions labeled with different densities of biotin. These labeled red cells were transfused through either gravity flow with a 170–260 µm filter, volumetric peristaltic infusion pump with a 170–260 µm filter, or a syringe infusion pump with an 18 µm aggregate filter at 2 mL/kg/h. Blood was sampled from test subjects at day 1, and every 7 days until day 49, measuring the proportion of red cells with biotin labels through flow cytometry. Additional in vitro testing was conducted, measuring plasma hemoglobin and osmotic fragility testing.
Labeled RBCs infused through gravity flow, volumetric pump, and syringe pump were detectable in 100% (8/8), 50% (4/8), and 14.3% (1/7) samples, respectively post-transfusion. The quantity and half-life between RBCs infused by gravity flow and volumetric pump that were detectable (4/8) were not different. The RBCs infused via syringe pump detected at 24 hours post-transfusion was no longer detectable at 7 days, indicating complete removal of those cells from circulation sometime between 24 hours and 7 days post-transfusion. No differences were seen in in vitro values examined.
The study concluded that delivery of RBCs with a syringe pump and microaggregate filter is associated with significant decrease in in vivo survival time. Volumetric pump delivery was associated with a 50% probability of loss of transfused RBCs within the first 24 hours, and gravity flow allowed for highest chance of RBC survival. The reason behind this difference is speculated to be the mechanical shear damage to the RBC membranes when transfused through the microaggregate filter, causing preferential removal of damaged cells upon entry into the circulation and exposure to the mononuclear phagocytic system. Though unconfirmed, there is a potential for microclots to have formed in the blood during resuspension in sub-room temperature plasma, which placed a higher degree of shearing stress on the RBCs going through the filter, causing this effect. Early denaturation and oxidation of hemoglobin due to the mechanical stress induced by syringe pump and volumetric pump methods, leading to IgG binding to the red cell surface and removal from circulation, is another possible cause for early removal.
Small sample size limiting the power of the results is a common limitation in the veterinary field, and this study is no exception. The results are most relevant to exact methods used in the study, and we can only make speculations on alternate setups to remove the use of microaggregate filters with the syringe pump (use of an in-line pediatric 170–260 µm filter or extraction of blood through a 170–260 µm filter administration set into a syringe, for example).
The authors of the study recommended against using a syringe pump with 18 µm aggregate filters in the light of the results of their study, though considering the limitations, drastic changes to clinical protocols was not stated to be necessary. The current best practice considering this evidence would be to administer blood products via gravity flow for larger volume, higher flow rate transfusions, as long as consistency in flow rate is monitored closely (as it can be influenced by catheter patency, positioning and motion by the patient, and amount of blood left in the bag). The syringe pump method is particularly useful when performing small volume transfusions such as in felines. A similar study performed with feline blood stated their observation of RBC survival time being unaffected by the syringe pump method.
There are a couple of infusion pumps approved for blood product, one of which is an internal approval, and the other of FDA approval for human blood products. These pumps could be the next best solution and validation with veterinary blood products is warranted.
PRBC Has an Expiration Date of 42 Days?
Current practices in blood banking involve the usage of APS and additive nutrient solution which are labeled for 42 days of storage. Other studies have observed significant changes in degree of hemolysis, ATP level, and 2,3 DPG concentrations by 31 days. More recent evidence gathered over the past decade indicates stored red blood cells to have impaired RBC survival, reduced efficacy as an oxygen carrier, and even incite adverse effects in the recipient causing mortality and morbidity. These changes are seen as early as 7 to 14 days into storage, and involve a collection of biochemical, biomechanical, and oxidative changes to the RBC and storage solution, all collectively referred to as “storage lesions.”
Mature RBCs lack mitochondria and rely on glycolysis for ATP production, leading to a lowered pH. ATP production is reduced by the acidic environment, combined with depletion, leads to decreased RBC membrane integrity. Lowered pH also affects 2,3 diphosphoglycerate (2,3 DPG) level reducing hemoglobin’s effectiveness as oxygen carrier, though this effect is reversible and not significant in cats. Hemoglobin in longer stored RBC products contains free hemoglobin and microparticles that scavenge nitrous oxide (NO) upon transfusion and cause a vasoconstrictive effect impairing blood flow, stimulate coagulation, induce oxidative damage, and cause proinflammatory effects. Microparticles, which are vesicles that have budded off of cellular components, induce proinflammatory and procoagulant effects. Stored RBCs show morphologic changes to echinocytes and spheroechinocytes leading to a loss of deformability and impairment in normal flow through capillaries. Oxidative damage leads to increased hemolysis and methemoglobin formation, decreasing viable RBC count and oxygen-carrying capacity.
There are many complicated mechanisms in play during RBC storage. To summarize the effects, storage lesions can lead to impaired RBC survival, reduce the efficacy of RBCs as oxygen carriers, and induce adverse effects such as arrhythmias, thrombosis, systemic inflammation, transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (ARDS), hypotension, and multiple organ dysfunctions. These changes occur as early as 7–14 days into storage, making supplying our patients with safe transfusion products a realistic challenge. Clinical impact of storage lesions is a topic of ongoing investigation while blood banks strive to balance provision of fresher products and minimize wasting.
First Transfusions Are “Free”?
Compatibility testing for canine blood transfusions has traditionally been omitted in the interest of swift transfusions and financial considerations. This comes from the widespread notion that the “first transfusions are free for dogs,” intended to state that canine RBC transfusions can be given without blood type matching (without typing the donor or recipient) or crossmatching, yet be performed without signs of immunologic complications, namely acute hemolytic transfusion reactions or anaphylaxis. This statement is made with the understanding that the most clinically significant dog erythrocyte antigen (DEA) is DEA 1, responsible for inciting acute hemolytic transfusion reactions when preexisting alloantibodies for the antigen is present. In 98% of the population, these antibodies are not present, so the first mismatched transfusion will only result in sensitization of the immune system to the antigen, leading to the development of antibodies over a course of approximately 4 days. This leads to a delayed hemolytic transfusion reaction, often asymptomatic as long as the patient has overcome the initial incident of anemia, or clinical symptoms of anemia as well as bilirubinemia and bilirubinuria may arise.
Given the asymptomatic or mild nature of clinical signs, many have accepted this reason to forgo compatibility testing. However, the sensitization will lead to an acute hemolytic transfusion reaction in subsequent mismatched transfusions, resulting in hemolysis of transfused cells and likeliness of anaphylaxis. By omitting compatibility testing, we run the risk of priming a patient for such reaction in the next transfusion which may be handled similarly if the patient’s transfusion status is not noticed. A medical team may be placed in a situation where the transfusion status of the patient may be unknown (pet brought in by pet sitter who thinks there had been no transfusions, or adopted dog who “probably” has not had a transfusion). In the case a patient presents with risk of imminent death from anemia, this practice may be justified with the knowledge of the risk. Blood typing of all blood donors and stocking of DEA 1-negative blood is highly recommended for use in these situations to avoid sensitization of the patient to DEA 1. If there is any uncertainty in the transfusion history of the patient, crossmatching is appropriate as erythrocyte antigens aside from DEA 1 exist with limited knowledge on consequences from patients sensitized for these miscellaneous antigens (some reports of AHTR exist). Transfusions of canine RBCs without compatibility testing are not “free,” and certainly have the hidden costs of DHTR and sensitization. Cats possess alloantibodies for the RBC antigens foreign to them (aside from the very rare type AB cats), leading to hemolytic transfusion reaction, even with first exposure.
DEA 1 Negative is the Universal Blood Type?
The concept of “universal” blood type indicates a blood type that can be given to any member of the same species without expectation of an immunologic reaction related to blood type mismatches. Because DEA 1 is the one antigen we know most about and leads to AHTR when mismatched for the second time, blood from DEA 1-negative dogs can be given without sensitization of DEA 1-negative and DEA 1-positive recipients, and often is considered as “universal.” There are, however, other RBC antigens such as DEA 3 through 8, dal, and other less known antigens confirmed to exist, which can lead to sensitization when mismatched transfusions occur. Therefore, a donor should be tested negative for every RBC antigen we are capable of testing in order to truly considering it “universal.” This creates a challenge as 98% of the canine population is positive for DEA 4, and a donor negative in DEA 4 is virtually impossible to find. Fortunately, this is not a clinical issue since the recipient is likely DEA 4 positive as well, allowing the blood types to match. Another challenge lies in our current inability to routinely test for DEA other than 1, 4, and 7 through a reference lab due to a lack of testing anti-sera (and anything aside from DEA 1 not available as in-house kits), preventing complete typing of our donors and timely testing of our recipients. Given our knowledge of additional RBC antigens, we should consider DEA 1 negative, 4 positive, 7 negative blood type as the “least antigenic,” and type our donors for all DEAs we are capable of, given finances permit it. DEA 1 negative can be considered safe blood to use from anecdotal evidence as reports of hemolytic transfusion reactions are rare, and crossmatches should detect incompatibility issues arising from repeated exposure to the less known erythrocyte antigens. Cats have no universal donors, though type AB cats may receive transfusions from both type A and B donors.
Are Blood Transfusions Between Different Species Possible?
Despite common knowledge that blood product transfusions should be between members of the same species to prevent immunologic consequences, there is ongoing research to test interspecies transfusions, or xenotransfusions. Early experiments in blood transfusion in the 1600s document a human patient receiving sheep blood, and showing no signs of reaction (at least on first exposure). Porcine red blood cells with modified antigens have been a topic of research in compatibility as human blood substitute. In the veterinary field, feline blood is consistently in short supply, especially for patients with the rare blood type of B. Type B cats can only be transfused with type B blood as introduction of a small volume of type A blood will result in an acute hemolytic reaction and anaphylaxis. In addition, even for type A patients, blood supply may be short causing delays or inability to obtain blood products in a timely manner as the patient suffers life-threatening anemia. In these situations, veterinarians have attempted to use canine blood as a source of blood as it is more readily available, and can easily tolerate the small volume donations.
There is limited amount of evidence available from a few studies conducted on canine to feline transfusions. The results of the studies concluded felines do not possess naturally occurring alloantibodies against canine erythrocytes. Compatibility testing methods such as slide agglutination test and crossmatching only revealed agglutination on the minor crossmatch. Of the total of 62 transfusions performed between the various studies, 5 cats showed signs of mild reactions, with tachypnea and pyrexia within 24 hours of the start of transfusion. Development of antibodies against canine RBCs were seen 4 to 7 days after the transfusion, indicating the transfusion led to sensitization of the immune system to the foreign antigens. Because of this, the life span of the transfused RBCs was approximately 4 days due to delayed hemolytic transfusion reactions while feline to feline transfusions allow RBCs to last 30 days. Subsequent transfusions resulted in anaphylaxis and were fatal in 66% of documented cases.
While transfusion of dog blood to a feline patient is not the best solution to supplementing oxygen-carrying capacity, it may be justifiable when faced with imminent death of the feline patient and without blood. A responsible medical team would discourage dog to cat transfusion and consider the method only when the patient 1) has no source of compatible cat blood (Type B cat with no stocked blood, donor, or nearby hospital with stock, for example) or hemoglobin based oxygen carrier solutions, 2) is imminently going to pass away without a transfusion or compatible blood will not be obtained soon enough (truly dying animal), 3) is expected to benefit from a short-term oxygen-carrying capacity gain, and 4) the owner understands risks and consequences. Xenotransfusions should not become a common practice and maintaining a good source of cat blood should always be pursued without considering canine blood as “backup.”
Premedicating Reduces Chances of Reactions?
Premedication, or administration of antihistamines, glucocorticoids, or antipyretics in anticipation of immunologic complications to counter histamine and inflammatory mediators and suppress the effects, have been a traditional practice in transfusion medicine. There are a number of human studies observing no difference in incidence of type I hypersensitivity reactions (allergic reaction) or febrile non-hemolytic transfusion reactions (FNHTR). Some clinicians reason that administration of premedication potentially masks early symptoms of immunologic complications delaying required interventions for treatment, advocating against it. Evaluation of the difference in severity between recipients with premedication or without premedication has not been performed, and remains a question whether this reasoning is valid. Human evidence is unfortunately not always directly translatable into veterinary practice, though expectations of similar physiological mechanisms exist. A recent veterinary retrospective study evaluating the effect of premedication on acute transfusion-related reactions saw no beneficial effect. There might be a beneficial effect to administration of diphenhydramine in decreasing chances of acute allergic reactions, though further studies were recommended by the authors since the incidence of allergic reaction in the non-premedicated group was already low (2.6%). Studies evaluating effects of premedication and efficacy in prevention of hemolytic transfusion reactions are not apparently available, and the theoretical benefit is no justification for forgoing proper compatibility testing.
Is Warming of Blood Products Necessary?
Warming of blood products in the interest of preventing hypothermia in the recipient is a consideration during blood product administration. Concerns for hemolysis of erythrocytes when warming during transfusion exist, and studies point towards little to no difference in markers for hemolysis in vitro when blood is warmed to typical body temperature. However, at non-emergent administration rates, blood reaching the patient through the line placed in a room temperature environment is easily at room temperature upon reaching the patient, and will not contribute to a significant decrease in body temperature. In the case of rapid transfusions of large volumes into small patients, warming of the blood may be indicated with care taken to be evenly warmed to 35–37°C and not exceed 42°C close to the patient to minimize loss of heat. Hypothermia is also a documented complication related to massive transfusions. Aside from these situations, in many cases warming effort directed at the patient is most effective in treating hypothermia.
Is Plasma Indicated for Use in Hypoproteinemia? Parvoviral Enteritis?
Plasma contains many proteins of interest, namely hemostatic proteins, albumin, and immunoglobulins. Hypoproteinemia, specifically hypoalbuminemia, occurs in many critically ill patients with protein-losing disorders including protein-losing enteropathies, protein-losing nephropathies, liver failure, trauma, burn wounds, etc. This leads to a loss of intravascular colloid osmotic pressure (COP), and subsequent consequences. Administration of plasma products (fresh frozen plasma, frozen plasma, or cryosupernatant) has been used as a method in supplementing albumin for COP. However, the amount of plasma required to raise the patient’s albumin level by 1 g/dL is approximately 40–50 mL/kg. This is equivalent to 1.1 L of plasma (9.5 units) for a 50# patient. The amount of plasma required to make a significant difference in the measurable level of albumin is both cost prohibitive and poses a large immunologic risk to the patient. Whether increasing the albumin level to a normal value (>2 g/dL) will lead to increased chances of a positive outcome is still unclear, and difficult to advocate.
Similar concepts can be applied to the usage of plasma products derived from survivors of parvovirus infection. Clinicians have theorized that transfusion of plasma containing antibodies against canine parvovirus (CPV) will aid in recovery from CPV infections. A study evaluating use of a single dose of plasma containing CPV antibodies in its efficacy versus saline placebo saw no significant difference in reducing clinical signs, viremia, or speeding recovery. The volume used in this study (12 mL) may be a limitation to the efficacy of the compared treatment, though the amount of plasma required for an adequate dosage of antibodies is unknown, and is likely to be at similar or higher levels of dosage for albumin supplementation. Thus, same concerns prevent use of plasma in this manner.
References
1. Blais MC, Berman L, Oakley DA, Giger U. Canine Dal blood type: a red cell antigen lacking in some Dalmatians. J Vet Intern Med. 2007;21(2):281–286.
2. Bovens C, Gruffydd-Jones T. Xenotransfusion with canine blood in the feline species: review of the literature. J Feline Med Surg. 2013;15(2):62–67.
3. Bragg RF, Duffy AL, DeCecco FA, et al. Clinical evaluation of a single dose of immune plasma for treatment of canine parvovirus infection. J Am Vet Med Assoc. 2012;240(6):700–704.
4. Bruce JA, Kriese-Anderson L, Bruce AM, Pittman JR. Effect of premedication and other factors on the occurrence of acute transfusion reactions in dogs. J Vet Emerg Crit Care (San Antonio). 2015;25(5):620–630.
5. Chiang V, Hopper K, Mellema MS. In vitro evaluation of the efficacy of a veterinary dry heat fluid warmer. J Vet Emerg Crit Care. 2011;21(6):639–647.
6. Heikes BW, Ruaux CG. Effect of syringe and aggregate filter administration on survival of transfused autologous fresh feline red blood cells. J Vet Emerg Crit Care. 2014;24(2):162–167.
7. Kisielewicz C, Self IA. Canine and feline blood transfusions: controversies and recent advances in administration practices. Vet Anaesth Analg. 2014;41(3):233–42.
8. Lacerda LA, Hlavac NR, Terra SR, et al. Effects of four additive solutions on canine leukoreduced red cell concentrate quality during storage. Vet Clin Pathol. 2014;43(3):362–370.
9. Marti-Carvaial AJ, Sola I, Gonzalez LE, et al. Pharmacological interventions for the prevention of allergic and febrile non-haemolytic transfusion reactions. Cochrane Database Syst Rev. 2010;2010(6):CD007539.
10. McDevitt RI, Ruaux CG, Baltzer WI. Influence of transfusion technique on survival of autologous red blood cells in the dog. J Vet Emerg Crit Care. 2011;21(3):209–216.