To Transfuse or not to Transfuse??? A. Schroeder, MD & S. Kache, MD

Transcription

1 To Transfuse or not to Transfuse??? A. Schroeder, MD & S. Kache, MD Introduction Critically ill children are prone to many hematologic abnormalities and often require blood products. Because blood products are a limited resource and because transfusions carry a number of risks, a thoughtful and judicious approach should be taken when deciding whether to transfuse a pediatric patient. This decision should take into account an understanding of the hematologic system, familiarity with age-specific values, a thorough assessment of the child s physiologic status, and awareness of any general and patientspecific potential side effects. Red Blood Cells (RBCs) Anemia is the most common hematologic abnormality in critically ill children. The cause of anemia should be broadly split into 2 categories: decreased production or increased destruction/loss. Causes of anemia in the ICU Decreased RBC production include o Systemic inflammatory response can suppress erythropoietin and red blood cell production similar to anemia of chronic disease o Infectious causes of bone marrow suppression o Oncologic processes o Renal insufficiency leading to decreased erythropoietin production o Malnutrition (including Fe, B12, and folate deficiency) o Medications leading to bone marrow suppression. Increased RBC destruction can result from o Active bleeding o Hemolysis, including DIC o Splenic sequestration o Phlebotomy Hematocrit equals the percentage of RBCs in the overall blood volume, and can be affected by the patient s overall volume status. Hemodilution (lower hematocrit) can occur with aggressive volume resuscitation with crystalloid or non-prbc containing colloid. Hemoconcentration (elevated hematocrit) is seen with aggressive diuresis or other sources of water-loss diarrhea, DKA/diabetes insipidus, excessive diaphoresis, etc. Although the overall RBC volume is unchanged in these situations, the changes in hematocrit may have significant effects on oxygen delivery and/or blood viscosity. To transfuse or not to transfuse 1

2 Evaluation of Anemia: An exploration of the cause of anemia in PICU patients is critical from both a diagnostic and therapeutic perspective. History and physical examination Close monitoring of daily I/O s and weights to assess for hemodilution or hemoconcentration Laboratory studies o CBC with indices (especially MCV) o DIC panel o Reticulocyte count o Other hemolysis labs (bilirubin, LDH, K+, serum haptoglobin, Coombs) o UA to look for hematuria o Chemistries to assess liver and renal function o Stool guaiac Radiographic studies: significant amounts of blood can be lost in the abdomen/retroperitoneum and thigh before physical exam evidence occurs. o Head U/S or head CT o Imaging other body compartments as indicated. When to transfuse: There is considerable practice variability between and within hospitals, and unfortunately there is minimal data in children to support any particular practice or transfusion threshold. Understanding of a simple physiologic principle can help determine if a patient requires a transfusion. Red blood cells deliver oxygen to end organs. Decreased circulating RBCs implicate other compensatory mechanisms to maintain end organ delivery. These mechanisms are: Cardiac output must increase to maintain the same oxygen delivery Certain end organs don t receive adequate oxygen delivery Both Therefore the determination of an appropriate hematocrit for the critically ill child should center on the following questions. How hard is the body working to maintain oxygen delivery and is oxygen delivery adequate? In order to determine if a patient requires a transfusion, follow a standardized approach with a checklist of questions: 1.) What is the hematocrit? 2.) What are the vital signs? 3.) Are there other signs of impaired oxygen delivery? 4.) Is there ongoing blood loss? 5.) What are the risks of transfusing PRBCs? Each of these questions is addressed individually below. To transfuse or not to transfuse 2

3 1.) What is the hematocrit? Normal, age-specific values for the hematocrit and MCV are listed in Table 1. While these values are a good starting point, it is important to acknowledge that hematocrit requirements also vary significantly by a child s underlying disease and hemodynamic status. Note that oxygen delivery (V D O2) is determined by both cardiac output and oxygen content as per the equation below: V D O2 = CO x [1.38(Hgb)(O2 saturation) +.003(PaO2)] This equation reflects the importance of the hemoglobin (or hematocrit) concentration for oxygen deliver. It also illustrates how cyanotic patients and/or patients with low cardiac output may benefit from a higher hematocrit. Table 1 Normal HCT and MCV values for age AGE HCT: MEAN (RANGE) MCV (LOWEST) Cord Blood 55 (45-65) week 50 (42-66) 3 month 36 (31-41) 6mo-6yr 37 (33-42) yr 38 (34-40) Adult female 42 (37-47) 80 Adult male 47 (42-52) 80 Adapted from Behrman: Nelson Textbook of Pediatrics, 17th ed., Copyright 2004 Elsevier 2.) What are the vital signs? The heart rate, blood pressure, respiratory rate, and oxygen saturation are critical pieces of the puzzle. Heart Rate: if oxygen delivery is poor the body compensates by increasing cardiac output, which in children occurs by an increase in the HR. Respiratory Rate: Anemic patients may be tachypneic in an attempt to increase alveolar oxygenation and/or in an attempt to compensate for a metabolic acidosis resulting from the anemia (see below). Blood pressure: anemia can contribute to hypotension by affecting ventricular function. Furthermore, hypotensive patients likely have impaired oxygen delivery and may therefore benefit from a higher hematocrit as well. Oxygen saturation is an important part of the oxygen delivery equation, as described above. If a FiO 2 > 60% is required to maintain oxygenation, it can contribute to acute lung injury (See Chapter 13 ARDS). An alternative strategy is to maintain a higher hematocrit and wean the FiO 2 to accept lower oxygen saturations. This allows for adequate end organ oxygen delivery without causing oxygen toxicity to the lungs. To transfuse or not to transfuse 3

4 3.) Are there other signs of impaired oxygen delivery? Physical exam: the following are important indicators of poor end-organ perfusion: o Mental status o Urine output o Color and warmth of extremities At the cellular level, poor O 2 delivery can be reflected in the following: o Increased lactate production occurs with poor oxygen delivery as cells transition from aerobic to anaerobic metabolism. Thus an ABG may reveal metabolic acidosis and the serum lactate level may be elevated. o Decreased mixed venous saturation (see Chapter 16 Shock) is another sign that oxygen delivery is inadequate as end organs extract more oxygen due to poor delivery. 4.) Is there ongoing blood loss? Quickly distinguish patients in hemorrhagic shock from those with slower blood loss. A patient s intra-vascular volume status can be approximated based on the patient s age and weight (See Table 2). The noted blood loss can then be used to approximate the degree of shock to anticipate. For Patients in hemorrhagic shock (Table 3), consider the following: o Note that hemorrhagic shock occurs for any blood volume loss of >15%. The body s compensatory mechanisms are effective for up to 40% blood loss above which the patient develops decompensated shock. o Also note that hemorrhagic shock in itself along with aggressive blood product replacement can lead to SIRS (systemic inflammatory response syndrome) causing ARDS and other complications o The physical exam must be monitored closely for the degree of shock and blood product replacement should occur accordingly. o Note a decrease in hematocrit may take an hour or longer to occur and therefore should not be the indicator of transfusion requirement. o Blood products should be available at the bedside for patients with life-threatening bleeding. o Establish the source of and aggressively control the site of bleeding. Consult the appropriate surgical / interventional service for the required treatment. o Other questions to consider during blood product replacement include: Whole blood vs. PRBCs alone The temperature of the product being replaced To transfuse or not to transfuse 4

5 Table 2 Estimated Blood volume Age Estimated Blood volume Pre-term infant ~ ml / kg Term infant 12 month ~ 80 ml / kg > 12 months ~ 70 ml / kg 70 kg adult ~ 5 L Table 3 Hemorrhagic Shock: Signs / Symptoms % Blood volume lost Signs <15% (Compensated) Minimal tachycardia 15% - 30% (Mild) Tachycardia, mild tachypnea, slight decrease in blood pressure, agitation 30% - 40% (Moderate) Hypotension, decreased urine output, delayed capillary refill, mental status changes > 40% (Severe) Profound hypotension, severe tachypnea, obtundation 5.) What are the risks of transfusing PRBCs? Blood products, especially PRBCs, have many well-documented adverse effects. Data from adults (Goodnough et al, NEJM, 1999) demonstrate that the transfusion of one unit of PRBCs carries the following risks: Infectious risk: o Hepatitis B (1/220,000) o Hepatitis C (approx. 1/1 million) o HIV (approx 1/ 2 million), bacteria (1/500,000 for PRBCs, 1/ 2,000 for platelets) o Other viral concerns: CMV (see below), parvovirus o Viruses newly emerging (i.e. West Nile Virus) or not yet identified Other Risks: o Acute hemolytic transfusion reactions (approximately 1/500,000) o Delayed hemolytic transfusion reactions (1/1,000) o Transfusion-related acute lung injury TRALI (1/8,000) Additional considerations for children include o IV infiltration: PRBCs are highly osmolar and can easily cause infiltration leading to significant soft tissue damage o Volume overload o Hyperkalemia o Increased viscosity can cause sludging of the blood and lead to thrombosis and stroke. This phenomenon is of great concern in patients who have had delicate vascular anastomosis (i.e. liver and renal transplants, portocaval shunts, micro-vascular surgery etc.) To transfuse or not to transfuse 5

6 Risks vs. benefits of transfusions: A landmark randomized controlled trial in adult ICU patients (Hebert et al., NEJM, 1999) compared a restrictive strategy of RBC transfusion (goal hemoglobin 7-9 g/dl) with a liberal transfusion strategy (goal hemoglobin g/dl). Not surprisingly, patients in the liberal transfusion group received significantly more PRBCs. However, patients in the restrictive group had significantly lower mortality rates during hospitalization (while overall mortality rates were not significantly different). A similar, more recent RCT (Lacroix et al, NEJM 2007) was performed in pediatric ICU patients comparing a goal hgb of 7g/dL and 9.5 g/dl, and demonstrated no differences in mortality or multiple organ dysfunction syndrome between groups. The how-to of transfusing PRBCs: Type & Cross: patients ABO and Rh status is determined o The patient s blood is initially screened to detect if there are any antibodies to common blood cell antigens. If this screen is positive, the specific antibodies then need to be identified. This process can take hours or even days, particularly in patients who have received numerous transfusions. Red Blood Cell preparation: o RBCs are given most commonly as packed RBCs. They are prepared by centrifugation of one unit of whole blood with removal of most of the plasma and are resuspended in an additive solution for storage in the refrigerator. o Whole Blood transfusions can also be considered in massive transfusion requirements, but availability is institution depend. Also, the storage time for whole blood is limited. Units of blood (generally ml) are often split into aliquots for small children to limit exposure to different donors. The hematocrit of these aliquots is generally around 70%. There are some blood units where the hematocrit is higher ( dry packs have a hematocrit of around 90%), but these are too viscous to be placed into small aliquots. How much blood should be transfused? The transfusion dose should be determined based on the specific clinical scenario, e.g. desired Hct, hemorrhagic shock, acidosis, minimizing donor exposure, etc. Specific considerations include: Adults: one unit of PRBCs will raise the hematocrit by 3%. Children: 10 ml/kg PRBCs should raise the hematocrit by 4-6%. To minimize further transfusions and exposure to multiple donors, consider transfusing 15 ml/kg unless concerns for thrombosis exist. Diuretics should be administered during or following the transfusion when concerns of volume overload exist. To transfuse or not to transfuse 6

7 Blood should be administered over 2-4 hours but can be given IV push in emergencies. Infectious, immune and potassium considerations: Immunocompromised patients: o Patients less than four months should receive CMV negative blood due to the poor immune function of this age group. o Patients that are immunosuppressed (transplant patients, hem/onc patients, DiGeorge, etc.) should also receive CMV negative blood. Methods of processing RBCs: o Irradiation inactivates and leukoreduction filters the WBC s that persist in PRBC units. These WBC s can lead to a transfusion reaction, can cause alloimmunization to HLA antigens, and can serve as reservoirs for viruses such as CMV. o Washing the RBCs refers to a process where saline is washed through the unit to reduce the potassium level. Patients with hyperkalemia or compromised renal function should receive washed RBCs. Note it takes up to 90 extra minutes to wash a unit of PRBCs. Freshest available blood should administered in these patients, as PRBCs hemolyze over time and increase extracellular potassium levels. Platelets Platelets are critical for hemostasis. A normal platelet count is 150, ,000 for all age ranges. Thrombocytopenia is often seen in critically ill children and can be due to: o Bone marrow suppression o Sepsis o DIC o Ongoing consumption due to bleeding, splenic sequestration o Medications. An absolute threshold for platelet transfusion is <5,000 in most circumstances due to the risk of a spontaneous intra-cranial hemorrhage. When the platelet count is > 5,000, the decision to transfuse should hinge on the following: o Signs of active bleeding decreasing hematocrit o Patient at increased risk of a CNS bleed of particular concern in neonates o Etiology of the low platelets a platelet transfusion will be less effective if the thrombocytopenia is immune-mediated, e.g. ITP o Are there pro-thrombotic concerns? A platelet-threshold should be identified for ICU patients with thrombocytopenia. The range varies based on the specific clinical scenario, e.g. from 10,000 (i.e. for To transfuse or not to transfuse 7

8 a patient with no signs of bleeding who has good functioning platelets) to 100,000 (i.e. for a patient on ECMO). For post-operative patients, a discussion with the surgeons regarding the specific surgery and risk of bleeding can help direct care. This threshold should constantly be re-evaluated by asking the questions above. How to order platelets: Platelets are obtained by one of two methods: o Through whole blood donation: a unit of blood is taken from the donor and platelets are harvested from the unit o Apheresis: blood is taken from the donor via one needle and run through a centrifuge. The platelets are taken off and the majority of the RBCs and plasma are then returned to the donor via a 2 nd needle. This method has the advantage of enabling 6-8 times as many platelets to be collected from a single donor. When possible, apheresed platelets should be administered in PICU patients. Usually, ½ - 1 unit of apheresed unit is administered which equals 3 6 units of regular platelets. Platelets can be packed to reduce the volume of the transfusion, but this process increases the preparation time by 1-2 hours. Fresh frozen plasma (FFP) and cryoprecipitate Disorders of the coagulation cascade often necessitate transfusion of FFP and/or cryoprecipitate. A brief schematic of the coagulation cascade is depicted below. aptt PK F XII HMWK F VIII F V F XIII F XI F IX F X Prothrombin Fibrinogen Cross- linked Fibrin F VII PT A coagulation panel includes a o Prothrombin time (PT)/ International Normalized Ratio (INR) o Partial thromboplastin time (PTT) To transfuse or not to transfuse 8

9 o Fibrinogen levels. A DIC panel includes everything in a coagulation panel plus the following: o D-dimers are produced when cross-linked fibrin molecules are degraded and are therefore more specific to DIC. o Fibrin split products are degradation products of fibrin and fibrinogen and are elevated in DIC, but may not be specific to DIC. Elevated FDPs can also be seen in SLE, OCPs, etc. Etiologies of abnormal coagulation parameters include: Liver dysfunction is a common cause since a majority of the coagulation factors are made in the liver. Even before other signs of liver dysfunction are present often, an elevated INR is noted. Sepsis DIC is a consumptive coagulopathy. A bleeding diathesis that is produced after the coagulation factors are consumed. Hypoproteinemia (i.e. protein-losing enteropathy or nephrosis) Congenital or acquired individual factor deficiencies Medications: o Coumadin affects the production vitamin K-dependent coagulation factors II, VII, IX, and X, and therefore predominantly affects the PT/INR. o Heparin acts by activating anti-thrombin 3 (AT3), thereby increasing the rate at which the plasma cofactor inactivates thrombin, activated factor X (factor Xa), and other coagulation enzymes. Heparin predominantly affects the PTT. Treatments for a coagulopathy: FFP contains all of the clotting factors (except low doses of fibrinogen) ml/kg of FFP is administered in an actively bleeding child with abnormal PT / PTT. For patients with continued coagulopathy, e.g. liver failure, the INR is often maintained below to prevent any spontaneous bleeding. Cryoprecipitate contains fibrinogen, factor VIII, factor XIII, vwf, and some fibronectin. For actively bleeding patients with a fibrinogen level below mg/dl, Cryoprecipitate is generally advised. Giving 1 unit of cryoprecipitate per each 5kg body weight should raise the fibrinogen by 75 mg/dl. Fibrinogen levels are decreased in DIC and liver failure (note also that fibrinogen is an acute phase reactant and can be elevated in inflammatory states). Alternative modalities for treating bleeding, coagulopathy 1.) Vitamin K: Vitamin K is important for the synthesis of factors II, VII, IX, & X made in the liver, and should be considered in all patients with elevated INR that warrants correction. To transfuse or not to transfuse 9

10 2.) Activated Factor VIIa (NovoSeven): This was initially designed as an agent to control bleeding in hemophilia patients who have developed antibodies to factor VIII or IX. Due to its ability to generate thrombin formation, however, it has more recently been used to control hemorrhage in the presence of complex coagulopathy brought about by trauma and surgery. While it is a very expensive medication, it should be considered (and may ultimately be cost-effective) in patients requiring large amounts of blood products. The dose is µg/kg, administered as bolus injection through a central venous catheter and a second dose can be administered in 4 hours if bleeding persists. The following agents are seldom used outside of the OR, but warrant mentioning: 3.) Aprotinin: Aprotinin is an antifibrinolytic and protease inhibitor which is often used during and immediately following cardiac surgery, i.e. fibrin clot that has already formed is maintained. It has also been used to control bleeding during ECMO, given as a continuous infusion at a rate of 10,000 units/kg/hr. 4.) Aminocaproic Acid (Amicar): Aminocaproic acid, an analogue of lysine, is an antifibrinolytic agent indicated for the treatment of excessive bleeding resulting from hyperfibrinolysis (patients with bleeding and low fibrinogen). It has been compared with aprotinin in some pediatric studies on surgery for congenital heart disease, and the two were found to have roughly equal efficacy and may be synergistic. 5.) Protamine: Protamine is a heparin antagonist (derived from salmon testicles!!) and should be considered in cases of significant bleeding following the administration of heparin. The dose is 1 mg IV for every 100 units of heparin remaining in the patient; if 30 minutes have elapsed since the injection of heparin one-half the dose may be sufficient. Protamine should be used with caution, however, as it can cause severe hemodynamic effects with flushing and hypotension. To transfuse or not to transfuse 10