Megan Marquez, DVM, DACVECC
Emergency and Critical Care Specialist
Anemia is defined as a decrease in red blood cell volume and, therefore, hemoglobin concentration. This results in a reduction of oxygen carrying capacity within the blood, which yields decreased oxygen delivery and negatively affected end organ health/function.
Anemia is a very common finding on an emergency visit, and often requires immediate supportive care, even if the anemia is not acute. Causes of anemia include decreased red cell production, increased red cell loss, and destruction of red cells. The most common causes in veterinary patients are listed below.
DECREASED RED CELL PRODUCTION:
- Chronic disease (organ diseases- renal, liver, thyroid, chronic infections, cancer)
- Bone Marrow dysfunction (drugs, cancer, immune mediated, radiation therapy, infectious, idiopathic)
INCREASED RED CELL LOSS:
- Trauma, Surgery
- Parasites (GI loss, fleas)
- Drugs (NSAIDS, Steroids)
- Cancer (GI, spleen, liver, renal)
- Thrombocytopathia (von Willebrand disease)
- Hereditary coagulopathy (Hemophilia A, B)
- Acquired coagulopathy (DIC, liver failure, rodenticide, dilutional)
DESTRUCTION OF RED CELLS:
- Hemolytic injury
- Immune mediated (IMHA, Evans)
- Infectious (Rickettsial, Mycoplasma/Bartonella, Babesia)
- Drugs (zinc, copper, sulfa reaction)
- Deficiencies (phosphorus, vitamin, potassium)
- Oxidative damage (onions, garlic, snake bite envenomation, propofol-cats, hepatic lipidosis)
- DIC- mechanical
Cancer (hemangiosarcoma, histiocytosis)
WHO NEEDS A TRANSFUSION?
The goal of an allogenic red cell transfusion is to meet oxygen demands and help prevent tissue/organ hypoxia. The question stands, what is the Hemoglobin (Hb) level needed for adequate oxygen delivery (DO2). Keep in mind that Hb x 3 approximates Hematocrit (Hct). The answer to this question depends entirely on the cause, speed and chronicity of anemia.
In patients with slow or chronic anemia, the body has many ways to compensate, and often succeeds, in providing adequate DO2. As blood viscosity decreases, vasomotor tone is augmented to increase venous return and decrease left ventricular afterload. This results in increased cardiac output (CO).
DO2 = CO x CaO2 (arterial oxygen content), therefore, increases in CO can improve DO2. Since CO = SV (stroke volume) x HR (heart rate), another adaptive mechanism is to increase the HR. This protective mechanism can become detrimental when tachycardia occurs due to decreased diastole and coronary flow, resulting in decreased CO and myocardial ischemia. Another protective mechanism, in dogs only, is a right shift in the oxyhemoglobin saturation curve, which decreased oxygen affinity to Hb, resulting in increased release of oxygen to the tissues.
Optimal DO2 has been shown to be achieved with HCT>20%, however, this does not mean that a Hct <20% is considered an automatic “transfusion trigger.” There is much controversy in the term “transfusion trigger” as it has been proven that there is not a single clinical sign or laboratory value that should “trigger” a transfusion. Several studies in human medicine have show that adequate DO2 can be achieved at varying Hb deficiencies, depending on volume status (hypovolemia vs euvolemia), cardiovascular health and speed of red cell loss.
Since improving DO2 is the goal of allogenic red cell transfusions, the time to consider giving a transfusion is when there are concerns for decreased DO2. In patients with chronic anemia, we typically wait for signs of decreased DO2. These signs include weakness, tachycardia, tachypnea and hypotension. These signs vary by the individual and many patients will not show all of these signs and may only show one, such as tachycardia alone.
Patients with acute red cell loss, such as trauma related hemorrhage, will also show the same signs for decreased DO2, however, it is more acceptable to give a red cell transfusion even prior to signs of decreased DO2, depending on severity of acute loss. For example, a dog with substantial peritoneal hemorrhage secondary to vehicular trauma, will likely present with signs of tachycardia and hypotension from acute hypovolemia related to blood/volume loss, but not from acute tissue hypoxia related to blood loss. This is shown to be true when that patient’s heart rate and blood pressure can be stabilized with crystalloid fluid boluses alone. What is important to recognize in these cases of acute blood loss, is that if their HCT confirms substantial blood loss, such as a drop in HCT of 20 or greater (e.g. HCT drop from 45% to 25%) then this patient is very likely to experience shock from tissue hypoxia as this is a large loss of Hb that the body has to compensate for in a very short period of time, and is often unsuccessful in providing adequate DO2. For this reason, even if the patient stabilized with crystalloids, consider that this patient will become clinical soon for tissue hypoxia due to anemia, therefore, it is reasonable to consider giving a transfusion prior to when the clinical signs of decreased DO2 are present. Keep in mind that signs of decreased DO2 is the body compensating for a state of shock. If we can prevent this state of shock by preemptively giving blood, then this may be advantageous for the patient in preventing organ dysfunction such as myocardial ischemia (often seen as VPCs and depressed ST segments), which is often seen after acute severe blood loss. It can be hard to know what was the patient’s HCT prior to the trauma; however, it is safe to assume that if the HCT is in the 20s, there is most likely a 20 or greater decrease in HCT.
HOW MUCH SHOULD BE GIVEN?
Once it has been determined that a patient needs a transfusion, the next question is how much should be given. Average rule of thumb is a packed red blood cell (pRBC) dose of 10mls/kg will likely increase the PCV (packed cell volume) by about 10 %. This is not always the case in patients with active/continued red cell loss or when hypovolemia is present and being corrected. The most accurate calculation to determine how much pRBC is needed to improve PCV to a specific goal is:
VT (mL) = kg BW × blood volume (90 mL) × ([desired PCV–recipient PCV]/donor PCV).
If the donor PCV is a known 60% (most commercial products), then a short cut approximation is 1.5ml/kg of pRBC will increase the patient’s PCV by 1%.
THE RISK WITH ALLOGENIC RED CELL TRANSFUSION:
There are several studies in both human and veterinary literature that have shown a correlation with allogenic red cell transfusion and increased mortality rates. Although illness severity factor is a variable in most of these studies to some degree, there are studies that look at “restricted” versus “liberal” transfusion protocols in critical patients and have shown increased mortality in the “liberal” transfusion group. These studies include the TRICC trial (Transfusion Requirements in Critical Care), CRIT study (Anemia and blood transfusion in the critically ill – Current clinical practice in the United States), ABC study (Anemia and blood transfusion in the critically ill trial). The general consensus for concerns of increased morbidity correlating with allogenic blood transfusions is likely in part related to red cell storage lesion, Transfusion-Associated Immunomodulation (TRIM) and Transfusion-Related Acute Lung Injury (TRALI).
Red cell storage lesion is the “injury” the red cells undergo while being stored, due to storage media and time, which negatively affect red cell function and survival. Over time, insufficient ATP in the storage media leads to RBC membrane instability, resulting in lose of biconcave shape and formation of spherocytosis, which result in decreased oxygen carrying capacity, increased fragility and difficulty navigating small vessels. This lack in ATP also leads to decreased 2,3 DPG (2,3-diphosphoglycerate), which inhibits oxygen release from the Hb to the tissues. There is also a build up of storage byproducts within the media such as hydrogen ions, potassium, pro-inflammatory cytokines, histamine, complement factors, and lipid which are released by white blood cells. These white blood cells and their activating factors can lead to an inflammatory state once in the patient, increasing risk for organ damage/dysfunction. Studies in both humans and animals have been performed to help determine if this storage lesion truly inhibits oxygen delivery once transfused. These studies concluded that RBCs stored in citrate-phosphate-dextrose-adenine-1 for 28 days were ineffective at improving tissue oxygenation when compared with fresh RBCs.
Transfusion-Associated Immunomodulation (TRIM) is not fully understood and is multifactorial due to the patient’s immune system. TRIM is a transfusion related complication that is unlikely related to storage time, but instead immunomodulation and inflammatory up-regulation. Immunosuppression post allogenic blood transfusions have been shown through down regulation of natural killer cells, macrophages, suppression of Tcells and increase in human leukocyte antibody (HLA). Tissue injury and organ failure has also been documented post allogenic red cell transfusion, and has been correlated with the release of inflammatory mediators within the storage media that results in neutrophil priming and endothelial cell activation. TRIM has been thought to be the reason why there is an increased incidence of post-surgical infections in critical patients receiving allogenic red cell transfusions. To help confirm clinical impact from inflammatory activation, there are several studies using leukoreduction filters at the time of pRBC collection. These studies have shown that the use of leukoreduction filters significantly reduces morbidity and mortality. Leukoreduction filters have been proven to remove >99% of WBC in pRBC products.
Transfusion-Related Acute Lung Injury (TRALI) is a potentially life-threatening complication, which leads to severe clinical signs of tachypnea, dyspnea, hypoxemia and bilateral pulmonary infiltrates on thoracic radiographs. TRALI can be either acute (within 6hrs) or delayed (>24hrs). The acute form typically shows signs within 1-2hrs of the transfusion. In humans, about 70% of acute TRALI victims require mechanical ventilation, however, most survive and have complete recovery of respiratory signs. Delayed TRALI leads to ARDS (acute respiratory distress syndrome) and is typically fatal. There are two theories for the pathophysiology of TRALI. One theory is that anti-neutrophil antibodies from the donor, results in an antigen-antibody response (Type III hypersensitivity) in the recipient. This hypersensitivity reaction leads to WBC activation, and that these activated WBCs eventually reach the lungs, which causes pulmonary damage, capillary leakage and pulmonary edema. The second theory is the “2 hit mechanism.” This theory is based on the idea that WBCs are already sequestered in the lungs due to the patient’s primary disease process and that when an allogenic transfusion is given, then those WBCs are activated via the inflammatory mediators that accumulate over time in storage media. TRALI has been proven to be a higher risk with fresh-frozen plasma.
Ways to help mitigate transfusion related complications (such as these explained above, which are not dose dependent), includes using leukoreduced blood products, storing blood products appropriately, handing/delivering appropriately (blood safe pumps only), discarding products at 28days, using new products when there is concern for primary inflammatory (IMHA, DIC, SIRS), and only giving blood products when needed and not more than is needed.
Allogenic red cell products plays a very important role in treating our critical patients and its use is substantially increasing in veterinary medicine. It is important to understand the need, the delivery and the risks with these products in order to provide the safest and most effective treatment possible for our veterinary patients.
Prottie et al. Controversies related to red blood cell transfusion in critically ill patients . Journal of Veterinary Emergency and Critical Care 20(2) 2010, pp 167–176
Obrador et al. Red blood cell storage lesion. Journal of Veterinary Emergency and Critical Care 25(2) 2015, pp 187–199
Short et al. Accuracy of formulas used to predict post-transfusion packed cell volume rise in anemic dogs. Journal of Veterinary Emergency and Critical Care 22(4) 2012, pp 428–434
Holowaychuck et al. Risk factors for transfusion-associated complications and nonsurvival in dogs receiving packed red blood cell transfusions: 211 cases (2008–2011). JAVMA, Vol 244, No. 4, Feb 2014 pp431-437