Continuous Manual Exchange Transfusion for Patients with Sickle Cell Disease: An Efficient Method to Avoid Iron Overload

Summary

We have outlined a method of continuous manual exchange transfusion for the treatment of sickle cell disease in patients. This safe protocol was designed to effectively limit iron overload in patients in need of chronic transfusions and can be used extensively without any special equipment.

Abstract

Children with sickle cell anemia (SCA) may be at risk of cerebral vasculopathy and strokes, which can be prevented by chronic transfusion programs. Repeated transfusions of packed red blood cells (PRBCs) is currently the simplest and most used technique for chronic transfusion programs. However, iron overload is one of the major side effects of this therapy. More developed methods exist, notably the apheresis of RBC (erythrapheresis), which is currently the safest and most efficient method. However, it is costly, complicated, and cannot be implemented everywhere, nor is it suitable for all patients. Manual exchange transfusions combine one or more manual phlebotomies with a PRBC transfusion.

At the Reference Center of Sickle Cell Disease, we set up a continuous method of manual exchange transfusion that is feasible for all hospital settings, demands no specific equipment, and is widely applicable. In terms of HbS decrease, stroke prevention, and iron overload prevention, this method showed comparable efficiency to erythrapheresis. In cases where erythrapheresis is not available, this method can be a good alternative for patients and care centers.

Introduction

A single point mutation in the β-globin gene is responsible for the production of abnormal hemoglobin (hemoglobin S, HbS). This causes sickle cell anemia (SCA), one of the most common diseases worldwide¹. SCA patients' acute symptoms and some chronic complications can be treated by the transfusion of packed red blood cells (PRBCs). Indeed, the transfusion of normal RBCs corrects the anemia while diluting the sickle RBCs. As a result, it can increase the oxygen transport capacity while decreasing hemolysis and vaso-occlusive events. To avoid chronic complications or to treat patients with acute complications, transfusion combined with the depletion of sickle RBCs, either by phlebotomy or by erythrapheresis, is an effective way to limit the dangerous increase in hemoglobin and blood viscosity while reducing the number of circulating SS RBCs².

One of the main causes of psychomotor handicaps and neurocognitive deficiencies in children with SCA³ is cerebral vasculopathy, a devastating complication of this disease. In SCA children with abnormally high velocities on transcranial Doppler, chronic transfusions are effective in preventing the occurrence of the first stroke⁴. To reduce the risk of recurrence in patients that have already suffered from an ischemic stroke, transfusion therapy is the most adequate method⁵. In the case of chronic therapy, RBC exchange transfusion is better than simple RBC transfusion, as it removes sickle cells and adds normal cells while reducing blood viscosity and limiting iron overload. Nonetheless, simple RBC transfusion is still widely used as a treatment for cerebral macro-vasculopathy. While it rapidly leads to iron overload⁴, this choice is often made because it is technically simple and maximizes the number of patients in transfusion care. Indeed, even if erythrapheresis has been reported to be the most efficient method for the chronic transfusion of SCA patients, it cannot be implemented everywhere; it is not suitable for all patients, especially young children; and it necessitates specific and expensive equipment.

For more than 20 years now, we have been treating SCA children demonstrating cerebral vasculopathy and who were temporarily ineligible for erythrapheresis with a continuous manual exchange transfusion (MET) method. In 2016, our team published a follow-up of patients that had undergone continuous manual transfusion for several years, showing that our method is associated with a satisfactory HbS decrease, efficient stroke prevention, and a limitation of iron overload comparable to that of erythrapheresis⁶. A session of MET can be carried out in any hospital environment without specific apparatuses and by using the same volume needed for erythrapheresis. A notable advantage of this technique is that it could help prevent, or at least diminish, side effects (particularly iron overload) linked to repeated transfusions in patients who are not able to undergo erythrapheresis. The aim of this article is to describe, step by step, how to perform a session of continuous MET in order to allow the medical centers that do not have any apheresis machines, or that have patients who are not eligible for erythrapheresis, to use this method for their SCD patients, especially children.

Protocol

The protocol follows the guidelines of the hospital ethics committee. There are 3 steps in the exchange sessions: patient preparation; initial isovolemic phlebotomy (if appropriate); and whole-blood exchange, consisting of several cycles, or continuous whole-blood phlebotomy, which is associated with the infusion of diluted PRBCs. Depending of the Hb level of the patient, a fourth step of intermediary isovolemic phlebotomy can be added midway through the exchange stage. At the start of the session, all of the necessary material (packed RBCs and 5% serum albumin) must be ready. Also, each step must be prepared in advance. Other than a precision scale and double venous access, no specific equipment is required. However, it is imperative to have constant medical supervision over the whole procedure, and even more so if the exchange volume is high.

1. Patient Installation

1. Carry out laboratory tests prior to starting the exchange transfusion session. Perform them on the same day, less than 24 h before the session. Do not perform the tests before a physician checks the results of the following tests.
   NOTE: The tests include a complete blood count, reticulocyte count, HbS rate measurement, indirect antiglobulin test (IAT), calcemia and electrolytes measurement, and liver function and coagulation tests, routinely performed by the hospital's hematology and biochemistry units.
2. Have the physician perform a thorough and complete physical examination of the patient, and pay specific attention to hemodynamic parameters such as heart rate, blood pressure, respiratory rate, and oxygen saturation. Obtain a recent body weight. Maintain an oxygen saturation >98% throughout the exchange session. To do so, administer patients with 1 L of oxygen via a nasal cannula while in supine position with the feet slightly raised.

2. Blood Product Preparation

1. Calculate and obtain the initial phlebotomy volume (see Table 1). For example, if the initial Hb rate of the patient for the session is 10 g/dL, bleed 12 mL/kg of blood in 60 min. For a patient of 30 kg, bleed 360 mL of blood (these are appropriate volumes).
   NOTE: An Hb rate of around 8 g/dL prior to the exchange transfusion must be reached because the initial phlebotomy volume is calculated based on the patient's Hb level (Table 1).
   No prior phlebotomy is required if the Hb level is below 8.5 g/dL. The initial phlebotomy must not exceed 5 mL/kg of body weight in the case of patients who have suffered from a recent stroke (within the last 3 months).

Initial Hb level (g/dL)	10	9.5	9	8.5
Volume to be bled (mL/kg)	12	10	8	5
Minimal duration of phlebotomy (min)	60	60	45	20

Table 1. Calculation of the Volume of the Initial Phlebotomy During Manual Exchange Transfusion.
The initial phlebotomy volume is calculated based on the patient's initial Hb level, with the goal of reaching an Hb rate around 8 g/dL prior to the exchange transfusion. The duration of the initial bleeding depends on the volume of the phlebotomy. No prior phlebotomy is required if the Hb level is below 8.5 g/dL. The initial phlebotomy must not exceed 5 mL/kg of body weight in the case of patients who have suffered from a recent stroke.

2. Calculate the exchange volume; the total exchange volume is 35 - 45 mL/kg of body weight (e.g., if the patient is a child of 30 kg, the volume of the exchange transfusion will be around 1,200 mL).
   NOTE: This volume is both the volume of blood that will bleed during the exchange step and the volume of diluted PRBCs that will be transfused to the patient during the exchange step. The final volume depends on the volume of the exchange transfusion, calculated with the body weight of the patient.
3. Obtain the appropriate volume of 5% serum albumin solution (from the pharmacy) so that it is ready for use at the beginning of the session. Calculate the required volume: 50 - 100 mL to infuse prior to initiating the phlebotomy, plus the same volume during the initial phlebotomy to compensate for bleeding, plus 1/3 of the exchange volume to dilute the PRBCs.
4. Obtain the appropriate volume of phenotypically matched PRBCs (i.e., 2/3 of the calculated exchange volume from the blood bank).
5. Reduce the hematocrit of the PRBCs from 60% to 40% by diluting the PRBCs with 5% serum albumin.
   NOTE: The dilution must be performed at the blood bank in a new blood bag. If this is not possible, use a 3-way tap to simultaneously transfuse the PRBCs and the 5% serum albumin and respect the flow proportions of 2/3 for the PRBCs and 1/3 for the albumin solution.

3. Patient Preparation

1. Prepare two peripheral venous lines on two different limbs, one for the phlebotomy and one for the infusion of the albumin solution and PBRCs; the venous line for phlebotomy necessitates sufficient blood flow, and the one for infusion requires standard blood flow. Use a single venous access for infusion and phlebotomy with a 3-way tap if venous access is seriously limited.
2. Administer 1 g of calcium per os to the patient before and after the exchange session; this prevents the occurrence of hypocalcemia due to the presence of a calcium chelating anticoagulant in the transfusion bags.

4. First Step of MET: Isovolemic Phlebotomy, if Appropriate

1. Start the infusion of 5% albumin on one venous access. After infusing about 20 - 50 mL of albumin solution, begin phlebotomy on the second venous access.
2. To perform the bleeding, install a peripheral intravenous access connected to an empty bleeding bag in the patient's arm. Place the bag below the level of the patient's bed. Observe the venous blood gradually fill the bleeding bag.
   1. If the blood flow is too low, lift up the patient's bed (or lower the bleeding bag) in order to increase the height difference between the arm and the bleeding bag, thus increasing the blood flow. Optionally, in case of very low blood flow, have the nurse draw blood manually with a 50-mL syringe using a 3-way tap placed on the venous line.
      NOTE: The flow of the phlebotomy must be the same as the flow of the infusion so as to strictly maintain the isovolemic balance.
3. Weigh the bleeding bag on a precision scale during the phlebotomy in order to adapt the infusion flow in real time to compensate for the volume bled.
   NOTE: If no scale is available or if there is only a single venous access, bleed 20 mL of blood each time 20 mL of albumin is infused.
4. At the end of the phlebotomy step, check the Hb levels using an Hb point-of-care test according to the manufacturer's instructions and make sure that it is around 8 g/dL.
5. Monitor the patients every 5 min during the initial isovolemic phlebotomy step. Stop the phlebotomy if clinical changes relevant to the patient's age are observed.

5. Second Step of MET: Isovolemic Exchange Transfusion

1. For safety reasons, start the transfusion of diluted PRBCs first. Transfuse the first 20 mL of blood and then start the phlebotomy. The planned total volume of the phlebotomy at this step is the same as the volume of the transfusion (35 - 45 mL/kg of body weight).
   NOTE: The rate of the phlebotomy must be the same as the infusion rate of the diluted PRBCs, following the same method as in the previous step (i.e., weigh on a precision scale or alternate 20 mL cycles).
2. Midway through the exchange step, check the Hb levels, as described in step 4.3. If the level is > 9.5 g/dL, perform an additional round of phlebotomy. If not, continue the exchange transfusion.
3. Monitor the patients every 15 min during the exchange transfusion step; a nurse must keep a close watch on the occurrence of any clinical and/or hemodynamic changes.

6. Additional Phlebotomy

1. Perform an additional bleeding phlebotomy (see step 4.1) if the Hb levels midway through the exchange step are > 9.5 g/dL, as there is a risk of reaching a too-high level of Hb at the end of the session.
   NOTE: The volume of the additional phlebotomy step depends on the Hb level (Table 2).
   Compensate with a 5% albumin infusion, as described above, in order to keep the additional phlebotomy isovolemic, just like in the other steps.

Midway Hb level (g/dL)	10.5	10	9.5
Volume to be bled (mL/kg)	8	6	3
Minimal duration of phlebotomy (min)	30	20	15

Table 2. Calculation of the Volume of the Intermediate Phlebotomy During Manual Exchange Transfusion.
Perform an additional phlebotomy if the Hb level midway through the exchange step is higher than 9.5 g/dL, as there is a risk of reaching a too-high level of Hb at the end of the session. The duration of the initial bleeding still depends on the volume of the phlebotomy.

2. Just like the initial phlebotomy, monitor the patients every 5 min. Stop the phlebotomy immediately if clinical changes occur.
3. After the additional phlebotomy, check the Hb levels using an Hb point-of-care test, and then continue the exchange procedure using the same method.

7. Final Laboratory Test

1. At the end of the exchange transfusion, perform laboratory tests for Hb, HbS, and calcemia. Do not allow the patient to leave before the results of the laboratory tests (or at least the Hb levels) have been checked by a physician.
   NOTE: Overall, while the duration of the procedure varies depending on the volume to bleed and to exchange, it lasts around 4 h, on average.

Results

Here, we will compare the safety, cost, and efficiency of the MET method with erythrapheresis⁶, which is the most effective method to decrease the percentage of HbS in SCD patients. To do so, we recorded 1,353 transfusion exchange sessions in the Reference Center of SCD, including 333 sessions of AET and 1,020 sessions of MET, all in SCD children suffering from cerebral vasculopathy and/or strokes. For patients, we chose MET in children with a body weight under 25 ...

Discussion

The risk associated with this procedure is an unexpected misbalance between the phlebotomy and the transfusion, which can have dangerous consequences. A rapid depletion will lead to hypovolemia and acute anemia, while an excess transfusion without bleeding will lead to a dangerous increase in blood viscosity. In both cases, SCA patients could suffer from vaso-occlusive complications, as well as strokes. For this reason, one nurse must be dedicated to each patient and stay at his bedside during the whole procedure. There ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Precision scale
Cannula (x2)	Macopharma
Transfusion tubing (x2)	Macopharma
Bleeding bag (x4)	Macopharma
3 Way tap
Syringe (x4)
Hemoglobin test	HemoCue	Hb 201+ System