• Acute Normovolemic Hemodilution


    Acute Normovolemic Hemodilution (ANH) is a term used to describe a perioperative blood conservation technique (Figure 1) used predominantly by anesthesiologists. Various alternate terms include acute normovolaemic haemodilution, acute isovolemic hemodilution, acute normovolemic anemia, intraoperative autolgous donation, hemospasia, even "controlled exsanguination."



    Figure 1 - Acute Normovolemic Hemodilution Diagram



    ANH enjoys considerable popularity in Europe, but has waned recently in the United States and Canada. It is probably one of the most misunderstood perioperative blood conservation techniques. When utilized correctly, ANH is an extremely helpful modality. However, when used incorrectly, it has limited efficacy. ANH has a long and esteemed history dating back to 1972. Many studies have been performed in many countries, showing that ANH is associated with reduced surgical hemorrhage and reduced allogeneic blood transfusion.



    Basic Principles


    The technique essentially employs two maneuvers:


    • Whole blood is collected from a patient via gravity into blood bags containing anticoagulant on the day of surgery before anticipated surgical blood loss. Some practitioners term this "whole blood sequestration." (WBS)

    • As blood is collected, asanguinous fluid must be infused to maintain normovolemia or euvolemia. This is accomplished with either crystalloid (normal saline,
      lactated Ringer's solution
      ) or
      colloid
      (albumin,
      hetastarch
      ) The term "acute normovolemic hemodilution" describes this compensatory physiologic maneuver. Acute, since it is conducted relatively rapidly; normovolemia, since the volume of the patient's blood is maintained normal; and hemodilution, which occurs as a result of the asanguinous fluid infusion.



    The development of hemodilution has a variety of implications for both the patient and the practitioner. Hemodilution is associated with reduced blood viscosity, reduced afterload and increased cardiac output. However, since the
    hemoglobin
    (Hb) concentration of the patient's blood is reduced secondary to
    hemodilution, any blood lost via the surgical field in the form of hemorrhage, contains relatively less Hb.
    For example, a patient with a Hb concentration of 14g/dL, loses 1,000 mLs of blood during a surgical procedure. The amount of Hb lost equals 140 g. Consider that same patient undergoing ANH to a Hb concentration of 10g/dL now losing 1,000 mLs of blood. The Hb content of that blood now contains only 100g of Hb, thats 40g less.


    Other advantages of ANH include provision of a fresh supply of coagulation factors and
    platelets. Once reinfused, these procoagulant components are thought to augment a patient's inherent coagulation function.
    In turn, surgical hemorrhage might be reduced perioperatively. Blood sequestered in the OR should be reinfused on completion of the surgery. If this blood not infused, then there are several regulatory standards that mandate how this blood is stored. ANH is often confused with other blood conservation modalities.
    Preoperative autologous blood donation
    (PABD) is completely different to ANH in that a patients donates anywhere from 1-3 units of blood on a weekly basis prior to the actual date of the surgery. The popularity of PABD has waned over the last few years, because much of this blood is indeed wasted.



    Blood component sequestration refers to a specific technique in which blood is collected intraoperatively, but then subjected to various procedures, including apheresis, centrifugation and blood component separation. From a defined volume of whole blood, platelet concentrate, plasma and packed red blood cells are separated and then used as needed during the surgical procedure. Touted as the preparation of a "personalised blood bank" for patients, blood component sequestration has also not been readily embraced by the medical profession, since outcome studies have been somewhat unconvincing. The main difference between ANH or "whole blood sequestration" and blood component sequestration is cost. The latter requires sophisticated apheresis or autotranfusion equipment.


    Another modality often confused with ANH is a technique of autolgous blood collection that occurs during cardiac surgery. Performed by perfusionists, as cardiopulmonary bypass commences, heparinized blood is collected from the venous limb of the extracorporeal circuit "en masse" into a large blood collection bag.


    Patient Selection


    In selecting patients for ANH, one should take into consideration the patient's overall condition, presence or absence of anemia, presence of comorbid conditions, the type of surgery, and the surgeon's skills. "Surgeon skills" in part include how effective is a surgeon's ability to keep blood loss to a minimum. Not every patient is eligible for ANH. Not every surgical procedure requires ANH. Patients undergoing surgical procedures associated with minimal blood loss clearly will not benefit from ANH. Surgeons differ in their skill levels; Halstedian principles refer to a surgical technique in which meticulous hemostasis is maintained. Some surgeons are able to adhere to these principles quite readily. Informed consent should be obtained from any patient prior to peforming ANH. The informed consent process requires that the ANH technique, benefits and any dangers be fully disclosed to the patient.


    Indications


    Contrary to current thinking, any surgical procedure in which there is a potential for significant surgical blood loss is suited to ANH. This includes:


    1. Cardiac surgery - on of off-pump procedures, minimally invasive techniques

    2. General surgery - major bowel or cancer resections

    3. Neurosurgery - major back procedures

    4. Orthopedic surgery - major back, joint replacement procedures

    5. Thoracic surgery - lobectomy, pneumonectomy

    6. Urologic surgery - prostatectomy, cystectomy, nephrectomy

    7. Vascular surgery - major reconstructive vascular surgery


    Contraindications


    There are a few absolute contraindications to ANH, in which ANH cannot be used under any circumstances. These include:


    • presence of severe sepsis

    • respiratory failure

    • myocardial pump failure

    • hemorrhagic shock secondary to trauma

    • severe anemia


    Less severe degrees of anemia become a relative contraindication to ANH. Patients with mild forms of anemia might be eligible for ANH; however, the volume of blood that may be collected will be less, since baseline Hb or hematocrit are reduced. Other relative contraindications include:


    • Severe respiratory disease

    • End-stage renal disease

    • Coronary artery disease with or without a history of myocardial infarction (MI)

    • Congestive heart failure

    • History of a cerebrovascular accident (stroke)


    In all of the above, the patient's medical status should be evaluated in relation to the type of surgery planned. For example, a patient with documented coronary artery disease may have experienced a mild prior MI, had a percutaneous coronary metallic stent placed, and from a medical standpoint, presents similar risks to a person without coronary artery disease. Anemia of any severity or etiology is best treated and corrected prior to surgery, if ANH is contemplated.


    How To Do It


    In order to perform ANH, blood collection bags that contain anticoagulant are needed. Citrate is one of the most popular anticoagulants used for ANH, typically premixed with various formulations of phosphate and dextrose, termed "CPD." Commercially manufactured blood bags of various sizes with a known volume of CPD are used for ANH. Once a patient is deemed suitable for ANH, additional factors must be considered.


    Timing


    Most practitioners perform ANH after the induction of anesthesia, prior to the commencement of surgery. Performing ANH prior to the induction of anesthesia, with the patient awake, is performed in some centers. Cited advantages include having an abundance of time and the ability to assess the hemodynamic consequences in the absence of any anesthetic effects. Performing ANH after the surgery has commenced may be problematic, if the early phases of surgery are associated with brisk surgical hemorrhage. In this scenario, it would be difficult to simultaneously sequester any whole blood.


    Blood Collection


    An adequate site for blood collection must be planned for and an adequately sized conduit or catheter must be placed. Peripheral venous lines are popular, but are fraught with problems including venous valves, tubing resistance, sludging and the need for an intravenous catheter of at least 18 gauge size. Arterial lines may be used - here, arterial pressure serves as a pressure head that pumps the blood into the collection bag. The disadvantage of arterial lines is that during blood collection, the ability to monitor arterial blood pressure is lost. Central lines remain the most reliable and effective means of blood collection. They may be placed anywhere, although internal jugular and subclavian lines are the most popular. Many of the aforementioned problems associated with peripheral IV lines are not present with central lines. However, irrespective of the location of the venous conduit, blood sequestration is a passive process, in which venous pressure and gravity also influence the speed of blood collection.


    Step 1 - Calculation of the volume of blood to be collected.


    The following information should be collated;


    1. The patient's weight. Weight in kg is needed in order to calculate the estimated blood volume (EBV). This reflects the total circulating blood volume in the vascular tree. This has been the subject of considerable debate but in general is approximately 70 mLs/kg for females and 75 mLs/kg in males. Therefore, a 90 kg male patient might be expected to have an EBV of 90 X 75 mLs = 6750 mLs.

    2. The baseline, initial or starting Hb concentration or hematocrit.

    3. The target Hb for hematocrit for ANH. This is typically a value that reflects a level of Hb or hematocrit that is safe and tolerated by the patient without adverse effects.

    4. Average Hb or hematocrit = the baseline and target Hb or hematocrits are summed and divided by a factor of 2.

    5. The standard ANH equation (actually derived from the differential expression);

      • Volume of Blood that may be sequestered using ANH = Baseline Hb or hematocrit - target Hb or hematocrit/ Average Hb or hematocrit X EBV


    For example, take a male patient weighing 90 kg with a starting Hb of 14 g/dl. We elect that a Hb of 10 g/dl is a safe, end-point for ANH.


    The volume of blood that may be sequestered = 14-10/12 X 6750 = 2,250 mLs.


    Step 2 - Attachment of blood collection equipment to patient


    Standard blood collection bags contain CPD anticoagulant typically have tubing and a needle attached. The needle may be detached and various connectors welded or interposed in the tubing, so that they may connect to a port in the intravenous line.
    The actual port for connection may be a stopcock, or a dedicated port on a central line - a location as proximal to the patient is optimal, so as to minimize tubing dead space. Using sterile technique, the modified blood collection bag tubing is connected to the selected port. (Figures 2, 3)


    Step 3 - Commencement of whole blood sequestration


    • See "Closed-Circuit" variation of this technique below.


    The stopcock or port is opened and blood should be seen flowing into the blood collection bag tubing from the patient. The blood collection bag is placed on the ground or on an agitator. (Figures 4, 5) As blood flows into the collection bag, it is important that admixture of blood and CPD occurs actively. When an agitator is used, this occurs automatically. However, in the absence of an agitator, the blood must be manually kneaded every minute. Vigilance must be maintained to ensure that blood in the collection tubing does not slow or sludge. In this setting, blood would clump and then coagulate in the tubing leading to flow obstruction. Some agitators have integrated scales so that when a certain end-point is reached, an alarm sounds. Typically, 450 mLs of whole blood are collected. For purely manual techniques, experience is needed to adjudge that the blood collection bag is not underfilled or overfilled. Once one bag is filled, another bag is connected.


    Step 4 - Asanguinous fluid administration


    Concurrent with the blood collection process, asanginous fluid must be administered, in order to manintain normovolemia. ANH assumes that for each mL of blood collected, one mL of fluid is administered. Unfortunately, this is sometimes difficult to achieve in a clinical setting. Crystalloid is particularly unique, in that following infusion, a sizeable proportion of that volume moves out of the circulation into the perivascular spaces; as much as 2 mLs out of every 3 mLs infused. Thus, 3 mLs of crystalloid must be infused to balance the 1 mL of blood collected. So, for example, if 1L of blood is sequestered, 3Ls of lactated Ringer's must be infused. Again, from a clinical standpoint, it is difficult to achieve these mathematical constructs. So, some clinicians use colloid instead of crystalloid, which is not associated with extravascular fluid movement. Here, one mL is infused for each one mL of blood collected. A mixture of colloid and crystalloid is sometimes used, in a 1.5:1 mL ratio. In order to administer fluid quite rapidly, another intravenous access site is needed - this may be another peripheral intravenous port. If a central line port is selected, care must be taken to ensure that blood collection and fluid infusion do not mix - fluid infusion should therefore be downstream from the blood collection site.


    Step 5 - Storage of whole blood


    Once a whole blood bag is full, it must be disconnected, the tubing sealed, the bag labeled and kept in a safe location in the OR. (Figure 6) The blood bags must remain under the purview of the anesthesiologist at all times, ensuring that administrative error does not occur. This blood is typically stored at room temperature (20 degrees C) for up to 6 hours. After 6 hours, this blood product should be refrigerated at zero degrees C, in accord with American Association of Blood Banks (AABB) guidelines. The bags should be intermittently agitated to ensure that sludging or clumping of red blood cells or platelets does not occur.


    Step 6 - Reinfusion of whole blood


    Timing of whole blood reinfusion is an important aspect in the blood management and conservation approach. Blood should be reinfused as surgical conditions dictate. During rapid uncontrolled surgical hemorrhage whole blood might be needed to restore blood volume. If surgical hemorrhage is slow and protracted, whole blood would be needed to restore Hb levels to normal and correct a surgical anemia. During cardiac surgery, whole blood reinfusion might occur after protamine administration, so that the procoagulant effect of the whole blood would be maximized. Any blood that remains at the end of the surgical procedure should be reinfused in the OR. In exceptional circumstances, whole blood that is not infused requires refrigeration. If hypervolemia is likely to occur from blood reinfusion, the use of a diuretic may be indicated.


    When whole blood is collected with ANH, each subsequent unit becomes progressively more dilute. When blood is reinfused, it is recommended that the last collected unit be infused first. This paradigm probably does not have much relevance in patients weighing more than 80kg.



    Closed Circuit System


    When perforning ANH for patients with religious-based objections to allogeneic blood, such as Jehovah's Witnesses, ANH can be performed with special modifications. The whole blood collection circuit and fluid administration system have to remain continuous with the patient's intravascular compartment.


    • Blood collection bags have to be pre-connected to intravenous ports, via a series of stopcocks.

    • Once one blood bag is full, the tubing connected to that bag has to be retroflushed with asanguinous fluid to ensure that this blood does not clot and obstruct the tubing.

    • Once the blood collection end-point has been achieved, it should be allowed to trickle slowly back into the patient, so that it resembles venous flow.


    The continuous circuit principle has some additional benefits, not readily appreciated by many practitioners. Since the circuit is closed, sterility control is enhanced. One disadvantage to this closed-circuit system is that currently, it is cumbersome and difficult to use. The ensemble of bags, tubing, stopcocks and connectors can be unwieldy to some anesthesiolgists.


    If all the whole blood cannot be administered in the OR, reinfusion can continue into the postoperative period. When patients emerge from anesthesia, they and their families need to be prepared that this whole blood is autologous, and the end-phase of the ANH technique is in progress.


    It should also be noted that a closed circuit system may not be absolutely required in all situations. During ANH some Jehovah's Witnesses might allow the blood to be withdrawn and held close by for reinfusion toward the end of the procedure. This is considered a matter of personal choice or conscience.


    Monitoring


    The following basic hemodynamic parameters should be monitored during the conduct of ANH:


    1. Heart rate

    2. Systemic blood pressure.

    3. Pulse oximetry.

    4. Capnography.


    For more advanced cases, in which large volumes of whole blood sequestration are planned, or if the patient has certain comorbid conditions, additional parameters include:


    1. Central venous pressure.

    2. Pulmonary arterial pressure.

    3. Cardiac output. (Figure 7)

    4. Transesophageal echocardiography (TEE). (Figure 8)


    The ECG will provide heart rate and ST segment information. Systemic blood presure is best monitored with an arterial line that records beat-to-beat pressure. Capnography is recorded with an anesthetic gas monitor. Central venous pressure may be measured with a central line, while pulmonary artery pressure and cardiac output are recorded with a pulmonary artery catheter. Transesophageal echocardiography provides real-time assessment of ventricular and valvular performance.


    Problems and Pitfalls


    The challenge for the busy anesthesiologist is trying to safely perform ANH, while monitoring the patient and performing other critical tasks such as recording the conduct of anesthesia. Distraction from the blood collection process is a distinct reality. Blood collection may slow secondary to obstruction in the collection tubing; the collection bag may overfill; blood may clump or coagulate in the blood bag seondary to inadequate admixture.


    Hemodynamic changes may occur during blood collection. Blood pressure may decrease, while heart rate and cardiac output may increase. Patients with coronary artery disease may not tolerate ANH and manifest coronary ischemia, requiring immediate cessation of the blood collection process.


    The autologous blood must remain under the purview and control of the anesthesiologist, so that administrative errors do not occur. This blood should not be confused with allogeneic blood, and sent back to the blood bank. During cardiac surgery with CPB, the extracorporeal circuit requires priming with asanguinous fluid (~1.5 L). This second phase hemodilution often limits the target Hb for ANH. Reducing the pump prime volume enables the collection of greater volume of whole blood, and is particularly useful when performing ANH.



    The Oxygen Bridge Concept with Blood Substitutes


    A blood substitute is a pharmacological agent that performs the typical functions of natural blood. Several commercial entities are in the process of commercializing various blood subsitutes for red blood cells and platelets. Red blood cell substitutes are of two main types;


    • HBOC - Hemoglobin-based oxygen carriers

    • PBOC - Perfluorocarbon-based oxygen carriers


    The term 'blood substitute' has generated some controversy, since HBOCs and PBOCs are not really a replacement for natural blood. In turn, the term "oxygen therapeutic agent" has been adopted, to more accurately describe the actual function of these agents.


    One agent, Oxygent (R) or perflubron is a 3rd generation pefluorocarbon, manufactured by a company in California, Alliance Pharmaceuticals. Innovative in their approach, Alliance have patented a technique called "Augmented ANH" (R), which essentially describes a modification of whole blood sequestration in which the anemia associated with ANH is actually treated with the PBOC. The theory behind this maneuver is that the PBOC serves as an "oxygen bridge" during ANH. Other companies have adopted a similary apprach with their proprietary products. Unfortunately, the efficacy of this approach has not been demonstrated, as yet.


    The Current Debate


    ANH is a highly useful modality, but unfortunately, it is surrounded in controversy. The various issues surrounding the controversy are;


    Safety of the Iatrogenic Production of Anemia


    ANH produces an anemic syndrome, inducing anesthesiologists and surgeons to conclude that it may be potentially unsafe in certain patient/disease categories, since tissue hypoxia or ischemia may result.
    The recommended target Hb for ANH ranges from 7 g/dl for the healthy patient to 10 g/dl for patients with associated cardiac, respiratory or neurologic disease. Liebermann was unable to detect systemic evidence of inadequate oxygen delivery in volunteers subjected to Hb values of 5 g/dl and oxygen delivery as low as 7.3 mL O2/ kg/ min.



    Bleeding Diasthesis


    ANH is also thought to contribute to a bleeding diathesis during surgery. Since coagulation factors are sequestered from the patient, subsequent surgical hemorrhage may be compounded by a dilutional thrombocytopenia or hypofibrinogenemia.


    Efficacy of ANH


    ANH efficacy may be defined in terms of an outcome variable or surrogate marker. Some examples include the volume of autologous RBCs that was saved or “spared”, the reduction in the allogeneic blood transfusion rate, the maximal allowable or actual volume of perioperative surgical blood loss, potential or realized economic savings, etc. The volume of autologous RBCs that is “spared” may be calculated mathematically using a model that inputs known parameters. On the other hand, “outcome” studies examining the impact of WBS on a particular variable are performed in a clinical or perioperative setting. Since 1974, approximately 250 clinical reports and studies examining ANH efficacy have been published. The majority conclude that ANH does exert clinically measurable blood conservation effects. However, approximately 12% (n=25) fail to demonstrate ANH efficacy. Why the divergence?


    Bryson recommends that better study design, randomization, and implementation of uniform transfusion criteria would be needed in future studies to produce data that would meet a “test of heterogeneity” and be more convincing.


    Actual ANH volume/technique. Rosengart
    and Helm
    advocate that the ability of ANH to impact blood conservation is linked to “maximal volume”, i.e., the greater the volume of whole blood collected during ANH, the more effective ANH is.


    Mathematical models define the limits of ANH, allowable surgical blood loss and ANH efficacy in terms of “maximum blood savings.” Three models conclude that autologous RBC savings are modest, whereas two conclude that if transfusion trigger and fractional surgical blood loss criteria are met, ANH efficacy is significant.


    ANH currently is performed by anesthesiologists by connecting blood bags containing anticoagulant to an intravenous line and then allowing blood to drain via gravity into the bag left on the OR floor. Sometimes, a shaker or scale is placed on the ground to guide the blood-collection process. This approach is somewhat primitive and tedious, so that some anesthesiologists do not want the extra hassle, or feel that they are distracted from closely monitoring the patient's hemodynamics during a case. If ANH were automated, or had a more user-friendly technology base, its popularity might be enhanced, and meaningful clinical studies performed.


    In summary, consensus opinions, divergent mathematical models, contradictory clinical findings, methodological flaws, variations in technique and lack of technology has contributed to a large debate over whether ANH is really efficacious.


    See also


    References


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