Transfusion

Number: 0639

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses auto-transfusers and red blood cell genotyping.

1. Medical Necessity

   Aetna considers the following autotransfusion and cell saver devices medically necessary for procedures that may deplete blood volume:

   1. Emergency or intra-operative autotransfusion, where blood is collected from the wound or a body cavity, processed, and then returned to the individual;
   2. Hemodilution or cell washing autotransfusion, where blood is collected and simultaneously replaced with sufficient volume of crystalloid or colloid solution;
   3. Post-operative autotransfusion (usually done within 2 hours with a chest tube collection device), where the blood from the chest (or other sterile operative sites) is re-infused following heart surgery and traumatic hemithorax.

   Aetna considers autotransfusion and cell saver devices experimental, investigational, or unproven for all other indications because their effectiveness for indications other than the ones listed above has not been established.

   Aetna considers red cell genotyping (including C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, S, s, U) medically necessary in any of the following situations:

   1. For individuals with sickle cell disease, thalassemia syndromes, hemoglobinopathies, and/or other medical conditions requiring recurring transfusions; or
   2. For individuals with post-transfusion hemolysis, when no antibodies are detectable and no other possible cause is known (e.g., sickle cell crisis, mechanical hemolysis due to heart valve failure); or
   3. For individuals with autoimmune hemolytic anemia; or
   4. For multiply transfused individuals and/or individuals who are direct antiglobulin test positive; or
   5. For pregnant women who, prior to their first transfusion, had non-transfusion-dependent thalassemia; or
   6. To help manage hemolytic disease of the fetus and newborn; or
   7. To resolve conflicting serological antibody results.

   Notes: Auto-transfusion and cell saver devices are not considered medically necessary for members undergoing procedures that are expected to require less than 2 units of blood. 

   Examples of procedures that may involve major blood loss and may require autologous blood transfusions or the use of auto-transfusers include, but are not limited to:

   1. Cardiopulmonary bypass surgery and other high-risk cardiac surgeries (e.g., abdominal aortic surgery)
   2. Ectopic pregnancy
   3. Emergency hemorrhage
   4. Hysterectomy
   5. Organ transplantation
   6. Orthopedic surgery (e.g., hip arthroplasty)
   7. Post-operative hemorrhage
   8. Vascular femoral grafts.

2. Experimental, Investigational, or Unproven

   Aetna considers the use of hypoxic red blood cells experimental, investigational, or unproven for improvement of energy metabolism and post-transfusion recoveries because the effectiveness of this approach has not been established.

Background

An autotransfuser is a mechanical device that is used in the process of collecting and re-infusing blood lost from hemorrhage.  Different forms of autotransfusers include intra-operative, emergency, or post-operative salvage devices and hemodilution devices used to re-infuse a patient's own blood.

Many people have safety concerns about receiving transfusions of donated blood.  "Cell salvage" with autotransfusion is a technique designed to reduce the need for such transfusions.  The technique involves collecting blood from surgical sites, to be transfused back into the person during or after surgery if necessary.  The blood is either "washed" before transfusion or transfused directly after being filtered (unwashed).  Risks from cell salvage include infection and blood clotting problems.

Autologous blood transfusion or the use of autotransfusers are contraindicated in blood exposed to bacteria (an infected wound or blood with fecal contamination) or in blood with malignant cells.

A meta-analysis of studies of cell savers in cardiac and orthopedic surgery (Huet et al, 1999) found that both devices that wash and do not wash salvaged blood decrease the proportion of patients who receive a peri-operative allogeneic transfusion.  These investigators found, however, that the post-operative use of devices that do not wash salvaged blood in cardiac surgery was only marginally effective.  The authors noted that cell salvage did not appear to increase adverse events, although side-effects were inconsistently reported and the number of patients studied was relatively small.

A Cochrane evidence review (Carless et al, 2003) found evidence suggesting that cell salvage reduces the need for transfusions of donated blood.  However, the investigators concluded that better quality research is needed to assess the cost-effectiveness of cell salvage across a range of surgical settings compared to other blood-sparing techniques.

Reitman et al (2004) evaluated the necessity and cost-effectiveness of the use of Cell Saver for adult lumbar spine fusions.  These investigators concluded that while patients in the Cell Saver group did require fewer post-operative transfusions, the difference was not as much as expected.  In elective fusions for degenerative conditions of the lumbar spine, blood requirements can usually be satisfied with pre-donation of autologous blood.  With contemporary practices of pre-donation, the use of the Cell Saver appears to be neither necessary nor cost-effective during most elective lumbar fusions.

Gause et al (2008) examined the effectiveness of using intra-operative Cell Saver in decreasing the need for blood transfusion.  Data were collected from 188 patients undergoing consecutive instrumented lumbar laminectomy and fusion.  A total of 141 of these patients had Cell Saver used during their procedures, whereas 47 did not.  In addition, previously published data from similarly treated patients were used for analysis.  Operative blood loss, autologous and allogeneic blood transfusions, discharge hematocrit, and patient factors were analyzed.  A significant increase in the number of blood transfusions was found in the Cell Saver group, which also had a significantly increased blood loss compared with the non-Cell Saver group.  Using analysis of co-variance, these investigators determined the effect of blood loss on the need for transfusion.  The results showed that correcting for blood loss eliminated the significance in the transfusion difference, but Cell Saver still was not able to decrease the transfusion need.  Comparing their current results with their previously published results also demonstrated no benefit of Cell Saver use.  The authors concluded that the use of Cell Saver in instrumented lumbar fusion cases was not able to decrease the need for blood transfusion.  Furthermore, Cell Saver use was associated with a significantly higher blood loss.

In a retrospective review, Scannell et al (2009) examined if Cell Saver use in patients with acetabular fractures reduces the volume or rate of allogeneic blood transfused intra-operatively and post-operatively and if this translated to a decrease in blood-related charges to the patient.  A total of 186 patients with operatively treated acetabular fractures were included in this study.  All patients underwent open reduction internal fixation of their acetabular fracture.  The decision to use Cell Saver was at the surgeon's discretion.  The volume and rate of intra-operative and post-operative allogeneic blood transfused and blood-related charges were evaluated.  Cell Saver was used in 60 cases (32 %), and the average volume of blood auto-transfused was 345 ml.  No differences were observed in the rates (58.3 % versus 48 %, p = 0.1883) or the mean volumes (770 versus 518 ml, p = 0.0537) of intra-operative and post-operative allogeneic blood transfusions between the Cell Saver and the non-Cell Saver groups.  Total blood-related charges in the Cell Saver group were significantly higher than that in the non-Cell Saver group ($1,958 versus $694, p < 0.0001).  Sub-analyses based on fracture pattern, injury severity score, body mass index, days to surgery, and estimated blood loss were performed.  In each sub-analyses, no differences were observed in intra-operative and post-operative transfusion rates and volumes, and total blood-related charges were higher in the Cell Saver groups.  The authors concluded that in the routine use of Cell Saver in acetabular surgery, there was no reduction in the volume or rate of allogeneic blood transfused intra-operatively or post-operatively.  However, blood-related charges were significantly increased.

In a systematic review and meta-analysis of published randomized controlled trials, Wang et al (2009) examined the overall safety and effectiveness of cell salvage in cardiac surgery.  Medline, Cochrane Library, Embase, and abstract databases were searched up to November 2008.  All randomized trials comparing Cell Saver use and no Cell Saver use in cardiac surgery and reporting at least 1 pre-defined clinical outcome were included.  The random effects model was used to calculate the odds ratios (OR, 95 % confidence intervals [CI]) and the weighted mean differences (WMD, 95 % CI) for dichotomous and continuous variables, respectively.  A total of 31 randomized trials involving 2,282 patients were included in the meta-analysis.  During cardiac surgery, the use of an intra-operative Cell Saver reduced the rate of exposure to any allogeneic blood product (OR 0.63, 95 % CI: 0.43 to 0.94, p = 0.02) and red blood cells (OR 0.60, 95 % CI: 0.39 to 0.92, p = 0.02) and decreased the mean volume of total allogeneic blood products transfused per patient (WMD -256 ml, 95 % CI: -416 to -95 ml, p = 0.002).  There was no difference in hospital mortality (OR 0.65, 95 % CI: 0.25 to 1.68, p = 0.37), post-operative stroke or transient ischemia attack (OR 0.59, 95 % CI: 0.20 to 1.76, p = 0.34), atrial fibrillation (OR 0.92, 95 % CI: 0.69 to 1.23, p = 0.56), renal dysfunction (OR 0.86, 95 % CI: 0.41 to 1.80, p = 0.70), infection (OR 1.25, 95 % CI: 0.75 to 2.10, p = 0.39), patients requiring fresh frozen plasma (OR 1.16, 95 % CI: 0.82 to 1.66, p = 0.40), and patients requiring platelet transfusions (OR 0.90, 95 % CI: 0.63 to 1.28, p = 0.55) between Cell Saver and non-Cell Saver groups.  The authors concluded that current evidence suggests that the use of a cell saver reduces exposure to allogeneic blood products or red blood cell transfusion for patients undergoing cardiac surgery.  Sub-analyses suggest that a Cell Saver may be beneficial only when it is used for shed blood and/or residual blood or during the entire operative period.  Processing cardiotomy suction blood with a Cell Saver only during cardiopulmonary bypass has no significant effect on blood conservation and increases fresh frozen plasma transfusion.

Savvidou et al (2009) examined the use of cell saver blood autotransfusion in spinal surgery and evaluated the effectiveness and cost-effectiveness of cell saver blood autotransfusion during lumbar spine fusion in adults.  A total of 50 consecutive candidates for postero-lateral fusion with internal fixation were prospectively randomized into either receiving peri-operatively cell saving autotransfusion (group A: 25 patients) or not (group B: 25 patients).  The use of cell saving technique did not exclude the use of allogenic blood transfusion.  Surgical indications were spinal stenosis, spondylolisthesis, adolescent idiopathic scoliosis, degenerative scoliosis and fractures.  Medical and financial data were recorded.  A cost-analysis was performed.  Patients in group A received 880 +/- 216 ml from cell saver and 175 +/- 202 ml allogenic blood.  The patients in group B received 908 +/- 244 ml allogenic blood.  Blood volumes data collected were expressed in mean +/- SD values.  The cost of blood transfusion in group A was 995 +/- 447 Euro per patient and 1,220 +/- 269 in group B (p < 0.05).  The authors concluded that in elective lumbar fusion blood requirements can be satisfied with the use of autotransfusion.  The use of cell saver appears to be useful and cost-effective during most elective lumbar fusions.

Bowen et al (2010) examined the effectiveness of intra-operative cell salvage systems in pediatric idiopathic scoliosis patients undergoing posterior spinal fusion with segmental spinal instrumentation.  A total of 54 consecutive patients were studied: 21 non-cell saver and 33 cell saver patients.  Data included age, body mass index, Cobb angle, peri-operative hemoglobin levels, mean arterial pressure, surgical time, levels fused, peri-operative estimated blood loss, and peri-operative transfusions.  A Chi square and t- tests were performed for intra-operative and peri-operative allogeneic transfusion between groups.  A regression analysis was performed between selected co-variates and allogeneic transfusion.  Relative risk analysis examined significant co-variates regarding allogeneic transfusion rate.  Allogeneic transfusion rates were lower in the cell saver group (6 % versus 55 % intra-operative and 18 % versus 55 % peri-operative, p < 0.05).  Mean allogeneic transfusion volumes (ml/kg) were also lower (0.4 versus 9.1 intra-operative and 1.9 versus 11.1 peri-operative, p < 0.05).  Multi-variate analysis confirmed these differences were independent of peri-operative blood loss, and also demonstrated that surgical time and blood loss were significantly related to allogeneic transfusion volume.  The allogeneic transfusion relative risk was 2.04 in patients with surgery greater than 6 hours and 5.87 in patients not receiving cell saver blood.  All patients with surgeries greater than 6 hours and estimated blood loss greater than 30 % of total blood volume received cell saver system blood.  The authors concluded that cell saver use decreased allogeneic transfusion, particularly in surgeries greater than 6 hours with estimated blood loss greater than 30 % of total blood volume.  This study confirmed the utility of routine cell saver use during posterior spinal fusion with segmental spinal instrumentation for idiopathic scoliosis.

Anderson and Panizza (2010) noted that endoscopic trans-nasal approaches to the skull base and intra-cranial disease are an emerging subspecialty.  The limits of this approach are often dictated by exposure and blood loss.  Cell salvage techniques are widely used in other surgical fields.  However, in otolaryngology, questions remain regarding its safety because work is performed in a contaminated field.  These researchers presented the evidence for peri-operative cell saver blood transfusion in potentially contaminated fields and the need for further investigation of its use in endonasal surgery.  Medline and evidence-based medicine reviews databases were searched for relevant articles.  All English articles discussing autologous blood transfusion in endonasal surgery were reviewed.  Despite a wide search pattern, no articles that discuss this topic were found in the English literature.  Therefore, these investigators went on to present data on the general use of cell saver blood in contaminated fields.  The authors concluded that cell saver blood is widely accepted in surgery.  It offers many advantages in elective operations in which blood loss is expected to be significant.  Cell saver blood has been transfused from contaminated fields in other forms of surgery without an associated increase in morbidity.  There is good evidence that antibiotic prophylaxis is mandatory in this setting.  There is no direct evidence that cell salvage blood is safe in endonasal surgery.

Reyes and colleagues (2011) examined if the use of cell saver (CS) systems reduce the need of blood products in low-risk patients undergoing cardiac surgery.  Between February and June 2009, all low-risk patients (EuroSCORE less than 10 %) undergoing coronary or valve procedure were selected (n = 63).  Exclusion criteria were: combined procedure, aorta procedure, redo surgery, emergency procedures, creatinine levels greater than 2 mg/ml, anemic patients and patients with a body surface area (BSA) less than 1.6 m2.  Patients were randomized to undergo cardiac surgery with a CS system (group CS; n = 34) or without (control group [CO]; n = 29).  All patients received tranexamic acid during the procedure.  Need of blood products and clinical outcomes were analyzed in both groups.  Mean age was 64.7+/- 12.3 years old with 33 % of female patients.  Baseline clinical characteristics and pre-operative blood count cell were similar in both groups.  Mean CS blood re-infused was 461 +/- 174 ml (maximum: 985; minimum: 259).  A total of 59 red blood packages were transfused in 25 patients (mean of 1.02 +/- 1.3; range of 0 to 5).  The proportion of patients being transfused was similar in both groups (CS: 40 % versus CO: 46.4 %; p = 0.79).  Eleven plasma packages were transfused (CS: 8 versus CO: 3; p = 0.77) and 3 platelet pools were used in group CS and none in group CO (p = 0.08).  Multi-variate analysis showed that pre-operative hemoglobin levels greater than 13.3 g/dL (relative risk [RR]: 0.29; CI: 0.09 to 0.99) and BSA greater than 1.74 (RR: 0.19; CI: 0.54 to 0.68) were protective against blood transfusion.  The authors concluded that in low-risk patients CS system did not reduce the need of blood transfusion.  Clinical outcomes were similar regardless of the use of a CS system.  A low pre-operative hemoglobin level and a low BSA were related with the use of blood products.

The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists' updated clinical practice guideline on "Blood Conservation" (Ferraris et al, 2011) noted that during cardiopulmonary bypass, intra-operative autotransfusion, either with blood directly from cardiotomy suction or recycled using centrifugation to concentrate red cells, may be considered as part of a blood conservation program.

Shantikumar et al (2011) noted that abdominal aortic aneurysm (AAA) repairs, both elective and rupture, are associated with significant blood loss often requiring transfusion.  Cell-salvage autotransfusion has been developed to reduce the need for allogeneic blood.  These investigators reviewed the literature to delineate the role of cell salvage in reducing allogeneic blood use in open AAA repairs.  A systematic search of the English-language literature was performed using the PubMed, Embase and Cochrane databases up to August 2010.  A total of 23 studies were identified.  While some data are conflicting, cell salvage appears to reduce overall use and exposure to allogeneic blood, and reduces length of intensive care unit and hospital stay after elective AAA repairs.  There may be additional benefit by combining cell salvage with other blood-conservation techniques.  Use of cell salvage in ruptured AAA repairs consistently reduced blood-product requirements.  The authors concluded that cell salvage appears to reduce blood-product use in both elective and rupture AAA repairs.  Moreover, they stated that owing to the heterogeneity in methodology of published data, further study may be needed before cell salvage becomes standard practice in open AAA repairs.

Tavare and Parvizi (2011) examined if the use of intraoperative cell-salvage (ICS) leads to negative outcomes in patients undergoing elective abdominal aortic surgery.  Altogether 305 papers were found using the reported search, of which 10 were judged to represent the best evidence to answer the clinical question.  The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated.  None of the 10 papers included in the analysis demonstrated that ICS use led to significantly higher incidence of cardiac or septic post-operative complications.  Similarly, length of intensive treatment unit (ITU) or hospital stay and mortality in elective abdominal aortic surgery were not adversely affected.  Indeed 2 trials actually show a significantly shorter hospital stay after ICS use, one a shorter ITU stay and another suggests lower rates of chest sepsis.  Based on these papers, the authors concluded that the use of ICS does not cause increased morbidity or mortality when compared to standard practice of transfusion of allogenic blood, and may actually improve some clinical outcomes.  As abdominal aortic surgery inevitably causes significant intra-operative blood loss, in the range of 661 to 3,755 ml as described in the papers detailed in this review, ICS is a useful and safe strategy to minimize use of allogenic blood.

Prieto et al (2013) stated that the role of a cell-saver device in the inflammatory response to cardiac surgery has not been well-documented.  These investigators hypothesized that the use of a cell saver may reduce pro-inflammatory cytokine concentrations in patients undergoing cardiac surgery.  A total of 57 patients presenting for first-time non-emergency cardiac surgery were prospectively randomized to control or cell salvage groups.  Blood samples for inflammatory marker assays were collected from the arterial line on induction of anesthesia, at the end of cardiopulmonary bypass, 1 hour after surgery, and 24 hours after surgery.  Plasma pro-inflammatory cytokines were analyzed using a sandwich solid-phase enzyme-linked immunosorbent assay.  The highest cytokine levels were observed 1 hour after surgery.  When comparing serum interleukin levels in both patient groups during the different peri-operative periods, these researchers found a higher interleukin-8 concentration 24 hours after the procedure, and higher concentrations of the p40 subunit of interleukin-12 at 1 hour and 24 hours post-operatively.  The concentrations of interleukin-6 and p40 were greater in blood stored by the cardiotomy suction system than in blood processed by the cell saver (p = 0.01 in both cases).  The interleukin-8 concentration was higher in the blood processed by the cell saver (p = 0.03).  No significant differences were observed in interleukin-1 and interferon gamma levels in blood from both systems.  Clinical outcomes were similar in both groups.  The authors concluded that these findings suggested that cell salvage in low-risk patients undergoing their first elective cardiac procedure does not decrease the inflammatory response after surgery.

Mizuno et al (2011) noted that intra-operative, salvaged, autologous blood transfusions carried out with autotransfusion devices are commonly used for cardiovascular surgery, and also enable the treatment of massive hemorrhage in orthopedic and gynecologic surgeries to prevent potential complications of homologous blood transfusions, such as transmission of infection, immune reactions, and blood type incompatibility.  Transfusion of salvaged blood in oncologic surgery may cause hematogenous metastasis and dissemination of malignant tumor cells.  However, some investigators have reported that blood irradiation or filtration using leukocyte reduction filters can prevent contamination by malignant tumor cells.  The authors concluded that intra-operative autotransfusion with the combination of blood irradiation and leukocyte reduction filters could be therefore a promising technique for the treatment of profuse hemorrhage in oncologic surgery.

In a meta-analysis, Waters et al (2012) examined the risk of intraoperative blood salvage (IBS) during cancer surgery.  A literature search was performed including the search phrases "blood salvage", "intraoperative blood salvage", "cell salvage", "cell saver", "cell saving", "autotransfusion" and "autologous transfusion".  Data extracted from suitable papers included the authors' names, publication year, cancer type, exclusion criteria, sample size, length of follow-up, and the mean patient age.  The primary end-point of this meta-analysis was a comparison of the OR for cancer recurrence or the development of metastases.  A total of 11 studies were included in the analysis.  The pooled summary of the OR was 0.65 (95 % CI: 0.43 to 0.98; p = 0.0391) using a random-effects model.  Measures of heterogeneity, Q-statistics (p = 0.1615) and I(2) (30.90 %), did not indicate a high degree of between-study variability.  The authors concluded that while significant variability existed between studies, the findings of this meta-analysis suggested that outcomes after the use of IBS are not inferior to traditional intraoperative allogeneic transfusion.  Moreover, they stated that an adequately powered prospective, randomized trial of IBS use is needed to ascertain its true risk during cancer surgery.

Gakhar et al (2013) noted that there is no scientific literature regarding the role of cell salvage and autologous transfusion in metastatic spinal cancer.  In a pilot study, these investigators examined the role of cell salvage during metastatic spine surgery.  A total of 16 spinal metastases patients who received red cell salvage using a leucocyte depletion filter (LDF) were enrolled in this study.  Of these, 10 patients who received salvaged blood transfusion were included in the final analysis.  Data collection involved looking at the case notes, operating room records and the prospectively updated metastatic spinal cancer database maintained in the spinal department.  Cell salvage data was recovered from the central cell salvage database maintained in the anesthetic department.  Amount of salvaged blood ranged from 120 to 600 ml (average of 318 ml).  The average drop in hemoglobin was 1.65 units (range of 0.4 to 2.7 units).  Three patients (30 %) required post-operative allogeneic blood transfusion.  The average follow-up was 9.5 months.  One patient developed new lung metastasis at 7 months.  No patient developed new liver metastases.  Pre-operatively, 6 patients had diffused skeletal metastases.  Of this subgroup, 3 developed new skeletal metastases.  No cases showed any wound-related problems in the post-operative period.  The authors concluded that transfusion of intraoperatively salvaged blood did not result in disseminated metastatic cancer.  They suggested that red cell salvage might have a role during metastatic spine surgery.  The findings of this small, pilot study (n = 10) need to be validated by well-designed studies.

So-Osman et al (2014a) noted that patient blood management combines the use of several transfusion alternatives.  Integrated use of erythropoietin, cell saver, and/or post-operative drain reinfusion devices on allogeneic red blood cell (RBC) use was evaluated using a restrictive transfusion threshold.  In a factorial design, adult elective hip- and knee-surgery patients with hemoglobin (Hb) levels 10 to 13 g/dL (n = 683) were randomized for erythropoietin or not, and subsequently for autologous re-infusion by cell saver or post-operative drain re-infusion devices or for no blood salvage device.  Primary outcomes were mean allogeneic intra- and post-operative RBC use and proportion of transfused patients (transfusion rate).  Secondary outcome was cost-effectiveness.  With erythropoietin (n = 339), mean RBC use was 0.50 units (U)/patient and transfusion rate 16 % while without (n = 344), these were 0.71 U/patient and 26 %, respectively.  Consequently, erythropoietin resulted in a non-significant 29 % mean RBC reduction (OR, 0.71; 95 % CI: 0.42 to 1.13) and 50 % reduction of transfused patients (OR, 0.5; 95 % CI: 0.35 to 0.75).  Erythropoietin increased costs by €785 per patient (95 % CI: 262 to 1,309), that is, €7,300 per avoided transfusion (95 % CI: 1,900 to 24,000).  With autologous reinfusion, mean RBC use was 0.65 U/patient and transfusion rate was 19 % with erythropoietin (n = 214) and 0.76 U/patient and 29 % without (n = 206).  Compared with controls, autologous blood re-infusion did not result in RBC reduction and increased costs by €537 per patient (95 % CI: 45 to 1,030).  The authors concluded that in hip- and knee-replacement patients (Hb level, 10 to 13 g/dL), even with a restrictive transfusion trigger, erythropoietin significantly avoids transfusion, however, at unacceptably high costs.  Moreover, they stated that autologous blood salvage devices were not effective.

So-Osman et al (2014b) stated that patient blood management is introduced as a new concept that involves the combined use of transfusion alternatives.  In elective adult total hip- or knee-replacement surgery patients, the authors conducted a large randomized study on the integrated use of erythropoietin, cell saver, and/or post-operative drain re-infusion devices (DRAIN) to evaluate allogeneic e use of RBC, while applying a restrictive transfusion threshold.  Patients with a pre-operative Hb level greater than 13 g/dL were ineligible for erythropoietin and evaluated for the effect of autologous blood re-infusion.  Patients were randomized between autologous re-infusion by cell saver, DRAIN or no blood salvage device.  Primary outcomes were mean intra- and post-operative RBC use and proportion of transfused patients (transfusion rate).  Secondary outcome was cost-effectiveness.  In 1,759 evaluated total hip- and knee-replacement surgery patients, the mean RBC use was 0.19 (SD, 0.9) erythrocyte units/patient in the autologous group (n = 1,061) and 0.22 (0.9) erythrocyte units/patient in the control group (n = 698) (p = 0.64).  The transfusion rate was 7.7 % in the autologous group compared with 8.3 % in the control group (p = 0.19).  No difference in RBC use was found between cell saver and DRAIN groups.  Costs were increased by €298 per patient (95 % CI: 76 to 520).  The authors concluded that in patients with pre-operative Hb levels greater than 13 g/dL, autologous intra- and post-operative blood salvage devices were not effective as transfusion alternatives: use of these devices did not reduce RBC use and increased costs.

Miao and associates (2014) noted that posterior spinal instrumentation and fusion surgery in school-aged children and adolescents is associated with the potential for massive intra-operative blood loss, which requires significant allogeneic blood transfusion.  Until now, the intra-operative use of the cell saver has been extensively adopted; however, its efficacy and cost-effectiveness have not been well established.  These researchers determined the efficacy and cost-effectiveness of intra-operative cell saver use.  This study was a single-center, retrospective study of 247 school-aged and adolescent patients who underwent posterior spinal instrumentation and fusion surgery between August 2007 and June 2013.  A cell saver was used intra-operatively in 67 patients and was not used in 180 patients.  Matched case-control pairs were selected using a propensity score to balance potential confounders in baseline characteristics.  Allogeneic RBC and plasma transfusions as well as blood transfusion costs were analyzed.  The propensity score matching produced 60 matched pairs.  Compared to the control group, the cell saver group had significantly fewer intra-operative allogeneic RBC transfusions (p = 0.012).  However, when the combined post-operative and total peri-operative periods were evaluated for the use of allogeneic RBC transfusion, no significant differences were observed between the 2 groups (p = 0.813 and p = 0.101, respectively).  With regard to the total cost of peri-operative transfusion of all blood products (RBC and plasma), costs for the control group were slightly lower than those of the cell saver group, but this variance did not reach statistical significance (p = 0.095).  The authors concluded that the use of the cell saver in posterior spinal instrumentation and fusion surgery in school-aged children and adolescents was able to decrease the amount of intra-operative allogeneic RBC transfusion; but failed to decrease total peri-operative allogeneic RBC transfusion.  Moreover, the use of the cell saver was not cost-effective.

Dusik et al (2014) stated that arthroplasty entails considerable exposure to allogenic blood transfusion.  Cell salvage with washing is a contemporary strategy that is not universally used despite considerable potential benefits.  These investigators searched Embase and Medline to determine if blood salvage with washing during primary and/or revision hip and knee arthroplasty resulted in lower rates of transfusion and post-operative complications.  They included 10 studies in the analysis, which they rated according to Downs and Black criteria.  With primary knee arthroplasty, there was a reduction in transfusion rate from 22 % to 76 % and a 48 % reduction in transfusion volume (n = 887).  With primary hip arthroplasty, there was a reduction from 69 % to 73 % in transfusion rate and a 31 % reduction in transfusion volume (n = 239).  There was a significant decrease in length of hospital stay (9.6 versus 13.6 days).  Studies of revision arthroplasty reported a 31 % to 59 % reduction in transfusion volume (n = 241).  The authors concluded that the available evidence demonstrated reduced exposure to allogenic blood with the use of salvage systems.  Studies have been under-powered to detect differences in infection rates and other post-operative complications.  Moreover, they stated that future cost analysis is warranted.

Liang and colleagues (2015) determined the safety and effectiveness of intra-operative cell salvage system in decreasing the need for allogeneic transfusions in a cohort of scoliosis patients undergoing primary posterior spinal fusion (PSF) with segmental spinal instrumentation.  A total of 110 consecutive scoliosis patients undergoing PSF were randomized into 2 groups according to whether a cell saver machine for intra-operative blood salvage was used or not.  Data included age, body mass index, peri-operative Hb levels, surgical time, levels fused, peri-operative estimated blood loss, peri-operative transfusions and incidence of transfusion-related complications.  A Chi-square test and t-tests were performed for intra-operative and peri-operative allogeneic transfusion between groups.  A regression analysis was performed between selected covariates to investigate the predictive factors of peri-operative transfusion.  Peri-operative allogenic blood transfusion rate was lower in the cell saver group (14.5 versus 32.7 %, p = 0.025).  Mean intra-operative RBC transfusion requirement was also lower (0.21 U/patient versus 0.58 U/patient, p = 0.032).  A multi-variate analysis demonstrated that number of fused segments (OR: 1.472; p = 0.005), pre-operative Hb level (OR: 0.901; p = 0.001), and the use of cell saver system (OR: 0.133; p = 0.003) had a trend toward significance in predicting likelihood of transfusion.  The authors concluded that cell saver use significantly reduced the need for allogeneic blood in spine deformity surgery, particularly in patients with low pre-operative Hb or longer operation time.  They stated that this study confirmed the utility of routine cell saver use during PSF with segmental spinal instrumentation for scoliosis patients.

Post-Operative Autotransfusion in Total Joint Arthroplasty (e.g., Hip and Knee)

Ji and colleagues (2017) stated that total joint arthroplasty is associated with significant blood loss and often requires blood transfusion.  However, allogeneic blood transfusion may lead to severe problems, such as immunoreaction and infection; PAT, an alternative to allogeneic blood transfusion, is controversial.  These investigators conducted a meta-analysis to evaluate the ability of PAT to reduce the need for allogeneic blood transfusion following TKA and THA.  Systematic literature searches for RCTs were performed using PubMed, Embase, and the Cochrane Library until February 2016; RRs and WMD with 95 % CIs were calculated using fixed-effect or random-effect models; these investigators also evaluated publication bias and heterogeneity.  A total of 17 trials with 2,314 patients were included in the meta-analysis.  The pooled RRs of allogeneic blood transfusion rate between autotransfusion and the regular drainage/no drainage groups for TKA and THA were 0.446 (95 % CI: 0.287 to 0.693; p < 0.001) and 0.757 (95 % CI: 0.599 to 0.958; p = 0.020), respectively.  In the subgroup analysis performed in TKA patients according to control interventions, the pooled RRs were 0.377 (95 % CI: 0.224 to 0.634; p < 0.001) (compared with regular drainage) and 0.804 (95 % CI: 0.453 to 1.426, p = 0.456) (compared with no drainage).  In the subgroup analysis performed for THA, the pooled RRs were 0.536 (95 % CI: 0.379 to 0.757, p < 0.001) (compared with regular drainage) and 1.020 (95 % CI: 0.740 to 1.405, p = 0.904) (compared with no drainage).  The authors concluded that compared to regular drainage, autotransfusion reduced the need for allogeneic blood transfusion following TKA and THA.  This reduction was not present when comparing autotransfusion to no drainage.  Moreover, they stated that the reliability of the meta-analytic results concerning TKA was limited by significant heterogeneity in methods among the included studies.

The author stated that this meta-analysis had several drawbacks.  First, the reliability of pooled results concerning TKA was limited by significant heterogeneity in methodological approaches.  Second, the number of studies including data related to secondary outcomes was small.  Thus, further meta-analyses including more studies and more information on safety outcomes are needed in the future.  Third, the results were based on many unadjusted factors.  A more precise analysis should be conducted that allows for the time of randomization, drain insertion time, timing of drain opening and closing, and financial factors.  Finally, the protocol for the systematic review was not prospectively registered.  Thus, the transparency of this approach could not be ascertained.

Intra-Operative Cell Salvage in Urological Surgery

In a retrospective, cohort study, Kinnear and colleagues (2018) examined the effect of (ICS in open radical prostatectomy.  All patients undergoing open radical prostatectomy for malignancy at the authors’ institution between October 4, 2013 and October 4, 2017 were enrolled.  Patients were grouped and compared based on whether they received ICS.  Primary outcomes were allogeneic transfusion rates (ATRs), and disease recurrence; secondary outcomes were complications and transfusion-related cost.  A total of 59 men were enrolled; 30 used no blood conservation technique, while 29 employed ICS.  There were no significant differences between groups in age, pre- or post-operative Hb, Charlson co-morbidity index, operation duration or length of stay (LOS).  Tumor characteristics were also similar between groups, including pre-operative prostate specific antigen (PSA), post-operative Gleason score, T-stage, nodal status and rates of margin positivity.  Compared with controls, the ICS group had longer follow-up (945 versus 989 days; p = 0.0016).  The control and ICS groups were not significantly different in rates of tumor recurrence (6 versus 3 patients; p = 0.30) or complications (10 versus 5 patients; p = 0.16).  While the proportion of patients receiving allogenic transfusion was similar (9 versus 6 patients; p = 0.41), fewer red blood products transfused (40 versus 12 units) meant transfusion related costs were lower in ICS patients (AUD $47,666 versus $37,429).  The authors concluded that ICS reduced transfusion related costs, without affecting ATRs, tumor recurrence or complication rates.  The researchers stated that these findings extended the literature supporting ICS in oncological surgery; however, prospective randomized studies are needed to confirm the existing level III evidence.

The authors stated that this study was limited by its retrospective nature, small size (n = 29 in the ICS group), non-randomized nature and short follow-up.  While there were no significant differences in group demographics, selection bias may nevertheless have impacted these findings.

In a systematic review and meta-analysis, Kinnear and colleagues (2019) evaluated the safety and efficacy of ICS in urology.  These investigators carried out a search of Medline, Embase and Cochrane Library to August 2017 using methods pre-published on PROSPERO.  Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines.  Eligible titles were comparative studies published in English that used ICS in urology.  Primary outcomes were ATRs and tumor recurrence; secondary outcomes were complications and cost.  A total of 14 observational studies were identified (4,536 patients); ICS was compared with no the blood conservation technique (7 studies), pre-operative autologous donation (PAD; 5 studies) or both (2 studies).  Cohorts underwent open prostatectomy (11 studies), open cystectomy (2 studies) or open partial nephrectomy (1 study).  Meta-analysis was possible only for ATRs within prostatectomy studies.  In this setting, ICS reduced ATR compared with no the blood conservation technique (OR 0.34, 95 % CI: 0.15 to 0.76) but not PAD (OR 0.76, 95 % CI: 0.39 to 1.31).  In the non-prostatectomy setting, ATRs amongst patients who underwent ICS were significantly higher or similar in 1 and 2 studies, respectively.  Tumor recurrence was found to be significantly less common (2 studies), similar (8 studies) or not measured (4 studies).  All 6 studies reporting complications found no difference in their ICS cohorts.  Regarding cost, 1 study from 1995 found ICS more expensive than PAD, while 2 more recent studies found ICS to be cheaper than no blood conservation technique.  As a result of inter-study heterogeneity, meta-analyses were not possible for recurrence, complications or cost.  The authors concluded that low-level evidence exists that, compared with other blood conservation techniques, ICS reduced ATR and cost while not affecting complications.  It did not appear to increase tumor recurrence post-prostatectomy, although follow-up durations were short.  These researchers stated that small study sizes and short follow-ups meant conclusions could not be drawn with regard to recurrence after nephrectomy or cystectomy; randomized trials with long-term follow-up evaluating ICS in urology are needed.

Red Cell Genotyping

Osman et al (2017) noted that blood group antigen systems are not limited to the ABO blood groups.  There is increasing interest in the detection of extended blood group systems on the red cell surface.  The conventional method used to determine extended blood group antigens or red cell phenotype is by serological testing, which is based on the detection of visible hemagglutination or the presence of hemolysis.  However, this technique has many limitations due to recent exposure to donor red cell, certain drugs or medications or other diseases that may alter the red cell membrane.  These researchers examined the red cell blood group genotype by SNP real-time PCR and compared the results with the conventional serological methods in multiply transfused patients.  A total of 63 patients participated in this study whose peripheral blood was collected and blood group phenotype was determined by serological tube method while the genotype was conducted using TaqMan single nucleotide polymorphism (SNP) RT-PCR assays for RHEe, RHCc, Kidd and Duffy blood group systems.  Discrepancies were found between the phenotype and genotype results for all blood groups tested.  The authors concluded that accurate RBC antigen profiling is important for patients requiring multiple transfusions.  The SNP RT-PCR platform is a reliable alternative to the conventional method.

The position paper/guideline om “Red blood cell specifications for patients with hemoglobinopathies” by the International Collaboration for Transfusion Medicine (ICTM) (Trompeter et al, 2020) recommended the following:

• Patients with sickle cell disease (SCD) who do not have alloantibodies and who are anticipated to have a transfusion (simple or exchange transfusion) should probably be transfused with CcEe- and K-matched red blood cells (RBCs) to reduce the risk of alloimmunization (low quality of evidence, weak recommendation).  RBCs matched for CcEe and K can be provided by phenotyping or genotyping RBCs.  Genotyping appears to be more accurate.  Providing matched RBCs is recommended although patients may not have developed alloantibodies in the past, as there is a potential for alloantibody development with future transfusion.
• Patients with thalassemia syndromes who do not have alloantibodies and who require RBC transfusion should probably be transfused with CEK matched RBCs to reduce the risk of alloimmunization (low quality of evidence, weak recommendation).  RBCs matched for CcEe and K can be provided by phenotyping or genotyping RBCs.  Genotyping appears to be more accurate.

NasrEldin et al (2021) stated that the Mediterranean hemopathic syndromes (MHS) are the most prevalent hemoglobinopathies in the Mediterranean basin.  Transfusion therapy is the key treatment for these disorders, especially for severe forms of the disease.  To-date, pre-transfusion serological typing of RBC antigens is the standard tool for reducing complications of transfusion in these patients.  These researchers compared genotyping with phenotyping of non-ABO RBC antigens in patients with MHS, and examined the effect of transfusion therapy on their results.  A total of 198 MHS patients were recruited, screened, and proven negative for allo-antibodies.  They were grouped into 2 groups: 20 newly diagnosed patients with no transfusion history (group 1); and 178 previously diagnosed patients undergoing transfusion therapy (group 2).  Subjects were interviewed and clinically examined; full blood count (FBC) and high performance liquid chromatography (HPLC) were carried out group 1 patients only.  Genotyping and phenotyping of non-ABO RBC antigens were performed for group 1, and 25 patients out of group 2 were propensity score-matched (PSM) with group 1.  Both groups were gender- and age-matched; 55 % and 74 % of groups 1 and 2 had major disease, respectively.  Insignificant differences were observed between genotyping and phenotyping of non-ABO RBC antigens in group 1, while significant discrepancies and mixed field results were noted in group 2 patients.  Discrepancies were obvious with JKa, JKb, and little c antigens.  The authors concluded that molecular typing is a powerful tool for pre-transfusion testing in chronically transfused MHS patients.  This testing lowered incidence of transfusion reactions.  JKa, JKb and little c antigens are the most clinically significant non-ABO RBC antigens.

Li et al (2022) noted that the ABO blood group system is the most important blood group system in clinical transfusion.  Serological technology is a routine method for the identification of ABO blood groups, however, which have some limitations in the identification of complicated ABO samples with weakened antigens or antibodies, abnormal plasma proteins, poly-agglutination, or cold agglutinin, etc.  With the development of molecular biology technology, ABO blood group gene was cloned, and ABO blood group genotyping technology based on DNA was established.  The genotyping technologies with different throughputs such as PCR-SSP, Droplet-AS-PCR, PCR-RFLP, PCR-SBT, SNaPshot, MALDI-TOF MS and NGS have emerged.  Genotyping has overcome the limitations of serology, and has become an indispensable method to solve difficult blood type, providing strong support for the correct identification of ABO blood group, as well as providing guarantee for precision blood transfusion.

Wong et al (2022) stated that SCD patients are often treated with RBC transfusion.  Pre-transfusion tests usually entail limited serological antibody testing.  RBC allo-immunization to RBC antigens is a frequently encountered complication observed in chronically transfused patients.  Genetic factors such as the human leukocyte antigen (HLA) are known to influence and regulate immune responses.  HLAs are highly polymorphic and play an important role in regulating immune responses, including RBC allo-immunization.  In a systematic review and meta-analysis, these investigators examined the association between HLA Class II allelic polymorphisms with the possible risk of developing RBC allo-antibodies.  A total of 4 databases were searched for relevant studies between 2000 and 2021 following the PRISMA guidelines; and 4 studies fulfilled the eligibility and quality criterion, and 3 alleles, HLA-DRB1*04, HLA-DRB1*15 and HLA-DQB1*03, that were found to be potentially associated with an increased risk in alloantibody formation were included.  The primary outcome measure was allo-immunization by RBC antigen exposure in multiply transfused SCD patients.  The total estimate of allo-immunization of the SCD patients was 2.33 (95 % CI: 1.58 to 3.44), revealing susceptibility to RBC allo-antibody formation.  Heterogeneity between the studies was insignificant, suggesting the differences associated with random sampling errors.  The results demonstrated that SCD patients carry an increased risk of producing RBC allo-antibodies.  The authors concluded that a strategy to prevent RBC allo-immunization is genotyping for genetically susceptible SCD patients receiving multiple transfusions.  Early identification of genetic variants that can potentially increase the risk of RBC allo-immunization could aid in the screening process and selection of phenotypically matched RBC units.

Furthermore, an UpToDate review on “Red blood cell (RBC) transfusion in individuals with serologic complexity” (Ward and Bakhtary, 2024) states that “RBC genotyping involves testing for the genetic variants that encode specific blood group antigens.  RBC genotyping is not used routinely, but its role is evolving, especially to prevent alloimmunization in certain populations.  Its use is institution dependent.  Genotyping can be especially useful for individuals with one or more of the following:

• High likelihood of alloimmunization (e.g., multiply transfused individuals)
• Blood types that are not well represented in the donor pool
• Confusing serologic results, such as due to a combination of alloantibodies and autoantibodies with autoimmune hemolytic anemia”.

Modified Ultrafiltration for Cardiopulmonary Bypass in Pediatric and Neonatal Cardiac Surgery

In a systematic review, Xing et al (2010) examined the safety and effectiveness of modified ultra-filtration (MUF) during pediatric cardiac surgery.  These investigators identified clinical studies via electronic searches of the Cochrane Library (Issue 2, 2009), PubMed (1991 to April 2009), Embase (1991 to April 2009), China National Knowledge Infrastructure (CNKI, 1994 to April 2009), VIP (1991 to April 2009) and China Biomedicine Database (CBM, 1991 to April 2009), with the languages limited in English and Chinese.  In strict accordance with the inclusion and exclusion criteria of the studies, 2 authors independently examined the quality of the included studies.  Meta-analysis of the studies was carried out using RevMan5.0 software, and the studies that could not be combined was analyzed descriptively.  A total of 9 studies entailing 587 patients were included.  The results showed that compared with the group without UF, the MUF group was superior in duration of post-operative mechanical ventilation (mean difference [MD] = -3.66, 95 % confidence interval [CI]: -6.02 to -1.29, p = 0.002) and showed no significant differences from the conventional UF group (MD = -3.21, 95 % CI: -6.90 to 0.49, p = 0.09).  Compared with balanced UF group, the mechanical ventilation time, intensive care unit (ICU) monitoring time, and the results of chest drainage in children were similar.  Compared with the group receiving conventional or balanced UF alone, the combined group of MUF had similar ventilation time (MD = -2.34, 95 % CI: -6.74 to 2.07, p = 0.30] and ICU time (MD = -0.12, 95 % CI: -0.31 to 0.06, p = 0.19).  The included studies reported no UF-related complications.  The authors concluded that MUF improved the clinical outcomes of patients undergoing cardiopulmonary bypass (CPB) during pediatric cardiac surgery; however, the available evidence has not been sufficient to support the notion that the MUF achieved better clinical results than conventional or balanced UF.

In a prospective, single-center randomized controlled trial (RCT), Zhou et al (2013) examined the effectiveness of a combined UF strategy on the surgical treatment of pediatric patients with congenital heart diseases.  A total of 65 pediatric patients who underwent open heart surgery with CPB to treat congenital heart disease were enrolled.  Subjects were randomized into 2 groups: conventional UF + MUF (CM group) and prime + zero-balanced + MUF (PZM group).  In the CM group (n = 33), conventional UF was carried out after removal of the aortic clamp, and MUF was carried out after the completion of CPB.  In the PZM group (n = 32), UF was carried out for the circuit prime solution, zero-balance UF was carried out after removal of the aortic clamp, and MUF was carried out after the completion of CPB.  The blood gas parameters and tumor necrosis factor alpha (TNF-α) content in the priming solution and peri-operative blood samples were analyzed.  In addition, post-operative parameters, including mechanical ventilation time, respiratory indices, ICU time, and hospital time, were recorded; 1 hospital death occurred in each group.  No severe complications occurred in either group.  The lactic acid, glucose, and TNF-α contents in the priming solution and peri-operative blood samples were significantly lower in the PZM group compared with the CM group.  The respiratory indices were statistically significantly better in the PZM group compared with the CM group in the early post-operative period.  No significant differences were observed between the 2 groups regarding the post-operative ventilation time, inotropic support, homologous blood transfusion, drainage, ICU time, or post-operative hospital time.  The authors concluded that the combined use of UF of prime solution, zero-balance UF, and MUF strategy was associated with a modest improvement in pulmonary function compared with the combination of conventional and MUF strategies in the early post-operative period; however, the principal clinical outcomes were similar.

In a meta-analysis, Hu et al (2021) examined the effects of the addition of MUF and conventional UF (CUF) to CUF alone on post-operative hemoglobin (Hb), surgical, and UF data, as well as post-operative clinical outcomes in pediatric patients undergoing cardiac surgery.  These investigators carried out a systematic search to identify RCTs that compared MUF and CUF combination with CUF alone in pediatric cardiac surgery undergoing CPB in PubMed, Embase, Cochrane Library, and Web of Science without any language or date limitation in February 2020.  For each included study, the primary outcomes including post-CPB and post-operative hematocrit (Hct), surgical and UF data, post-operative clinical outcomes including volume of chest tube drainage within 48 hours after surgery and peri-operative blood requirement, ventilation support duration, and length of stay (LOS) in the ICU and hospital were collected and analyzed.  The analysis was conducted using STATA version 12.0.  A total of 8 studies totaling 405 patients were included in this meta-analysis.  The results indicated that MUF + CUF increased the post-CPB Hct (standard MD [SMD] = 1.85, 95 % CI: 0.91 to 2.79).  Meanwhile, UF volume was higher in CUF+MUF infants than CUF-alone infants (SMD = 1.46, 95 % CI: 0.51 to 2.41, p = 0.003).  The clinical outcomes, including post-operative hemodynamic changes, prime volume, blood requirement, chest tube drainage volume, mechanical ventilation duration, and LOS I the ICU, were unclear because of the unstable sensitivity analyses.  The authors reported beneficial effects of using MUF and CUF for pediatric cardiac surgery, including increase post-CPB Hct and UF volume when compared with CUF alone.  Meanwhile, MUF and CUF did not significantly influence the post-operative hospital LOS duration, CPB, and aortic occlusion duration.

Walczak et al (2021) stated that new CPB device techniques emerge and were reported in the scientific literature.  The extent to which they are actually adopted into clinical practice is unclear.  Since 1989, these investigators have periodically surveyed pediatric cardiac centers to determine practice patterns.  In December 2016, a 186-question perfusion survey was distributed to pediatric cardiac surgery centers globally using a Web-based survey tool.  Responses were received from 93 North American (NA) centers (the U.S. and Canada) and 67 non-NA (NNA) centers, representing 19,645 cumulative annual procedures in NA and 27,776 in NNA centers on patients less than 18 years of age.  Wide variation in practice was evident across geographic regions.  However, the most common pediatric circuit consisted of a hard-shell (open) venous reservoir, an arterial roller pump, and a hollow-fiber membrane oxygenator with a separate or integrated arterial filter.  Compared with previous surveys, there was increased use of all types of safety devices.  The use of an electronic perfusion record was reported by 50 % of NA centers and 31 % of NNA centers.  There was wide regional variation in cardioplegia delivery systems and cardioplegia solutions.  A total of 79 % of the centers reported the use of some form of MUF.  The authors concluded that the survey showed that there remained variation in perfusion practice for pediatric patients.

Walczak et al (2022) noted that the use of CPB in neonatal, infant, and pediatric patients continuously evolves as new devices and innovative techniques were introduced.  Since 1989, periodic pediatric perfusion surveys have been carried out to determine practice patterns involving demographics, equipment, and perfusion techniques.  The objective of this study was to provide an updated perspective on international pediatric and congenital perfusion practice since the last survey conducted in 2016.  In July 2021, a 100-question perfusion survey was distributed to 284 pediatric cardiac surgery centers using a secure Web browser-based data application.  Each center was given a unique survey hyperlink to ensure 1 response per institution and to monitor the response rate.  Centers were given 1 month to complete the survey and electronic reminders were sent weekly to non-respondents.  After the survey was closed, information from completed surveys was exported to a software program for analysis.  Responses were received from 153 of 284 pediatric centers for a response rate of 54 %.  A total of 60 respondents (39 %) were from NA centers, and 93 respondents (61 %) were from NNA centers.  The vast majority of centers use a roller head arterial pump (93 %), hollow fiber oxygenators with open reservoirs (86 %), and integrated arterial line filters (73 %).  The use of MUF was reported by 76 % of centers; and 92 % of centers reported the use of selective antegrade cerebral perfusion for aortic arch repairs.  The N + 1 staffing model was most prevalent (52 %), followed by 2 perfusionists per case (33 %).  The authors concluded that periodic surveys continue to be a useful modality in assessing regional variation in pediatric perfusion practice.  This survey marked the 1st time the majority of responses came from NNA institutions. 

Bierer et al (2022) stated that the use of CPB could be associated with significant hemodilution, coagulopathy, and a systemic inflammatory response syndrome (SIRS) for infants and children undergoing cardiac surgery.  Intra-operative UF has been employed for many years to ameliorate these harmful effects.  The authors described an advanced intra-operative UF technique, subzero balance simple MUF (SBUF-SMUF), a combination of continuous and non-continuous form of UF.  These investigators stated that the continuous SBUF component is used during the entire CPB time and precisely targets a slight negative volume balance during the CPB time as an optimal peri-operative perfusion strategy.  This approach avoids inaccurate “eye-balling” of fluid balance.  The adjustable control of SBUF volume infusion rate and UF effluent rate by Braun Infusomat Space pumps allows for individualized weight standardization; thus, could be safely applied to a range of neonatal and pediatric patients.  After separation from CPB, this UF circuit configuration allowed for efficient and effective transition from SBUF to SMUF.  Physical alterations to the CPB manifold are completely avoided.  The authors concluded that SBUF-SMUF could be safely and efficiently implemented to optimize the inflammatory, coagulation and volume parameters for infants and children undergoing open-heart surgery with CPB.

Palanzo et al (2023) stated that MUF is used at the termination of CPB in pediatric and neonatal patients undergoing congenital heart surgery to reduce the accumulation of total body water; thereby, increasing the concentration of RBCs and the other formed elements in the circulation.  MUF has been reported to remove circulating pro-inflammatory mediators that result in SIRS post-operatively.  A total of 400 patients undergoing cardiac surgery requiring CPB and weighing less than or equal to 12 kg were retrospectively examined for the effectiveness of MUF.  After the termination of CPB, blood was withdrawn via the aortic cannula and passed through a hemo-concentrator attached to the blood cardioplegia set and returned to the patient via the venous cannula.  The entire CPB circuit volume in addition to the patient's circulating blood volume were concentrated until the Hct value displayed on the CDI 500 Blood Parameter Monitor within the MUF circuit reached 45 % or there was no more volume to safely remove.  At the same time, a full unit of fresh frozen plasma (FFP) could be infused as water was being removed; thus, maintaining euvolemia.  MUF was carried out in all 400 patients with no MUF-related complications.  Following the conclusion of MUF, anecdotal observations included improved surgical hemostasis, improved hemodynamic parameters, decreased transfusion requirements, and decreased ventilator times.  The authors concluded that complete MUF allowed the clinician to safely raise the post-CPB Hct to at least 40 % while potentially removing mediators that could result in SIRS.  Furthermore, a full unit of FFP could be administered while maintaining euvolemia.

An UpToDate review on “Blood management and anticoagulation for cardiopulmonary bypass” (Ghadimi and Welsby, 2024) lists UF as one of the strategies to minimize excessive hemodilution before and during CPB.

Furthermore, the American Association of Thoracic Surgery’s primer on “Cardiopulmonary bypass” (AATS, 2024) stated that “Despite miniaturization of CPB circuits, the priming volume can be many times the blood volume of the patient.  This leads to an increase in total body water and subsequent peripheral, pulmonary, visceral, and cerebral edema.  Aggressive diuresis, ultrafiltration on CPB, and modified ultrafiltration (MUF) have been used to manage the increase in total body water.  In addition to removal of excess water, ultrafiltration potentially decreases the circulating levels of inflammatory mediators.  Continuous ultrafiltration can be achieved through the pump while on CPB.  MUF is performed after weaning from CPB but prior to removal of the cannulas.  A right atrial cannula (typically the previously removed vent) is placed.  Blood is removed from the venous cannula, circulated through the ultrafiltration filter (where it is hemo-concentrated), and returned to the patient through the right atrial cannula”. 

Hypoxic Red Blood Cells

According to Hemanext Inc (Lexington, MA), red blood cells (RBCs), leukocytes reduced, oxygen/carbon dioxide reduced are also known as hypoxic RBCs (HRBCs).  The Hemanext ONE RBC Processing and Storage System that produces HRBCs, was developed to limit the detrimental effects of oxidative damage on RBCs during storage, and designed to bring new levels of innovation, clinical value and consistency to transfusion medicine.  This novel product leverages cutting-edge technology to protect the quality, functionality, and viability of RBCs by processing and storing them in a low-oxygen (hypoxic) state.  Supposedly, HRBCs have the potential to benefit all patients, especially those requiring transfusion for chronic conditions, such as thalassemia, sickle cell disease (SCD), and myelodysplastic syndromes (MDS), as well as those in need of urgent peri-operative transfusions.

DʼAlessandro et al (2020) noted that blood transfusion is a life-saving intervention for millions of recipients globally every year.  Storing blood makes this possible but also promotes a series of alterations to the metabolism of the stored RBCs.  It is unclear if the metabolic storage lesion is correlated with clinically relevant outcomes and whether strategies aimed at improving the metabolic quality of stored units, such as hypoxic storage, would improve performance in the transfused recipient.  A total of 12 healthy donor volunteers were recruited in a 2-arm cross-sectional study, in which each subject donated 2 units to be stored under standard (normoxic) or hypoxic conditions (Hemanext technology).  End-of-storage measurements of hemolysis and autologous post-transfusion recovery (PTR) were correlated to metabolomics measurements at days 0, 21, and 42.  Hypoxic RBCs)showed superior PTR and comparable hemolysis to donor-paired standard units.  Hypoxic storage improved energy and redox metabolism (glycolysis and 2,3-diphosphoglycerate), improved glutathione and methionine homeostasis, decreased purine oxidation and membrane lipid remodeling (free fatty acid levels, unsaturation and hydroxylation, acyl-carnitines).  Intra- and extra-cellular metabolites in these pathways (including some dietary purines) showed significant correlations with PTR and hemolysis, although the degree of correlation was influenced by sulfur dioxide (SO2) levels.  The authors concluded that hypoxic storage improved energy and redox metabolism of stored RBCs, which resulted in improved post-transfusion recoveries in healthy autologous recipients -- an FDA gold standard of stored blood quality.  Furthermore, these researchers identified candidate metabolic predictors of PTR for RBCs stored under standard and hypoxic conditions.  Moreover, these investigators stated that future studies aimed at validating the candidate markers of stored blood quality will have to take into account processing strategies in the study design; and larger studies are needed to validate and expand on the present observations by taking into account the role of donor biology on transfusion outcomes and markers thereof.

The authors stated that this study had several drawbacks.  First, correlative analyses were carried out on metabolic measurements on a total of 24 units (paired normoxic and hypoxic units from the same 12 donors).  Second, due to the increased numbers of observations, despite post-hoc correction for multiple observations conducted (false discovery rate), some of the reported findings may just result from spurious correlation and will need to be confirmed prospectively in independent cohorts.  Third, the small sample size of the cohort recruited for this study (n = 12 healthy donors) may also be insufficient to examine the impact of the heterogeneity of donor biology, including donor sex, ethnicity, and age, with respect to hemolysis and PTR parameters.  Undoubtedly, RBCs have to survive storage without hemolyzing and circulate long enough upon transfusion to ensure the delivery an effective “dose” of transfused blood; however, such conditions are necessary but not sufficient to ensure that transfused RBCs are actually functional.  Further investigations are needed to examine if the metabolic markers of PTR reported here would also be predictive of direct measurements of the RBC “physiome”, namely, measurements of the RBC physiological profile that are affected by RBC metabolism (e.g., oxygen affinities, deformability, control of cell volume, control of vasoactive effectors, redox “buffering” capacity).  In previous studies on rodent models of shock, limited improvements in PTR (approximately 3 %) did not mirror a markedly superior performance of hypoxic RBCs in resuscitating hemorrhaged rats.  Units donated by the same donors (as is the case in this trial) tend not to show consistent reproducible levels of spontaneous hemolysis across multiple donations.  Furthermore, spontaneous hemolysis does not recapitulate the RBC propensity to hemolyze following additional, more physiologically relevant insults, such as oxidant, osmotic, or mechanical stress.  Fourth, PTR in healthy subjects is insufficient to provide information regarding the actual RBC recovery in non-healthy, heterologous patients.  Several studies have highlighted that PTR of allogenically transfused RBC in patients with acute inflammatory disorders was significantly reduced, while in patients with immature innate immune systems, the PTR was increased or was insensitive to age-mediated storage.

Rabcuka et al (2022) stated that RBCs incur biochemical and morphological changes, collectively termed the storage lesion.  Functionally, the storage lesion manifests as slower oxygen unloading from RBCs, which may compromise the effectiveness of transfusions where the clinical imperative is to rapidly boost oxygen delivery to tissues.  Recent analysis of large real-world data linked longer storage with increased recipient mortality.  Biochemical rejuvenation with a formulation of adenosine, inosine, and pyruvate can restore gas-handling properties; however, its implementation is impractical for most clinical settings.  These researchers examined if storage under hypoxia, previously shown to slow biochemical degradation, also preserves gas-handling properties of RBCs.  A micro-fluidic chamber, designed to rapidly switch between oxygenated and anoxic superfusates, was used for single-cell oxygen saturation imaging on samples stored for up to 49 days.  Aliquots were also analyzed flow cytometrically for side-scatter (a proposed proxy of O2 unloading kinetics), metabolomics, lipidomics, and redox proteomics.  For bench-marking, units were biochemically rejuvenated at 4 weeks of standard storage.  Hypoxic storage hastened O2 unloading in units stored to 35 days, an effect that correlated with side-scatter but was not linked to post-translational modifications of Hb.  Although hypoxic storage and rejuvenation produced distinct biochemical changes, a subset of metabolites including pyruvate, sedoheptulose 1-phosphate, and 2/3 phospho-d-glycerate, was a common signature that correlated with changes in O2 unloading; and correlations between gas handling and lipidomic changes were modest.  The authors concluded that hypoxic storage of RBCs preserved key metabolic pathways and O2 exchange properties; thus, improving the functional quality of blood products and potentially influencing transfusion outcomes.  Moreover, these researchers stated that these findings provided a frame-work for evaluating the functional quality of stored RBCs for future clinical trials examining the transfusion effectiveness of alternative storage regimes.

Karafin et al (2023) noted that RBCs transfusions are beneficial for patients with SCD; however, ex-vivo studies suggested that inflamed plasma from patients with SCD during crises may damage these RBCs, diminishing their potential effectiveness.  The hypoxic storage of RBCs may improve transfusion effectiveness by minimizing the storage lesion.  These researchers tested the hypotheses that the donor RBCs exposed to the plasma of patients in crisis would have lower deformability and higher hemolysis than those exposed to non-crisis plasma; and hypoxic storage, compared to standard storage, of donor RBCs could preserve deformability and reduce hemolysis.  A total of 18 SCD plasma samples from patients who had severe acute-phase symptoms (A-plasma; n = 9) or were at a steady-state (S = plasma; n = 9) were incubated with 16 RBC samples from 8 units that were stored either under conventional (CRBC) or hypoxic (HRBC) conditions.  Hemolysis and micro-capillary deformability assays of these RBCs were analyzed using linear mixed-effect models after each sample was incubated in patient plasma over-night at 37° C.  Relative deformability was 0.036 higher (p < 0.0001) in HRBC pairs compared to CRBC pairs regardless of plasma type.  Mean donor RBC hemolysis was 0.33 % higher after incubation with A-plasma compared to S-plasma either with HRBC or CRBC (p = 0.04).  HRBCs incubated with steady-state patient plasma showed the highest deformability and lowest hemolysis.  The authors concluded that hypoxic storage significantly influenced RBC deformability.  Patient condition significantly influenced post-incubation hemolysis.  Together, HRBCs in steady-state plasma maximized donor RBC ex-vivo function and survival.

In an editorial that accompanied the afore-mentioned study by Karafin et al (2023), Antonelou (2023) stated that “The most rigid stored RBCs are expected to be cleared from the circulation in a short time following transfusion, leading to reduced therapeutic return20 and probably increased risk for negative outcomes.  What about stored RBCs with moderately affected deformability levels?  Studies in transfused surgery patients suggest that restoration of bulk RBC deformability does not readily occur in vivo; however, the complex pathophysiology of transfusion-requiring states (e.g., active bleeding) warrants caution in interpreting such studies.  This is one (among many) obstacles that can be overcome by ex vivo experimentation in donor–recipient pairs.  In this context, a valuable follow-up to the Karafin study would include measuring the baseline storage (and patient) RBC deformability …. The potential impact of RBC mechanics on the pathophysiology and clinical manifestations of SCD and other diseases, as well as on the performance of transfused RBCs, highlights the need for its systematic assessment …. What can be finally argued by the study of Karafin et al is the usefulness of ex vivo experiments in studying the post-storage performance of donor RBCs under well-defined, controlled conditions.  The post-storage performance emerges as a mixed function of donor, blood product, and recipient variables.  The take-home message is that ex vivo deformability of RBCs stored in SCD plasma was “pre-determined” by the specific storage conditions (i.e., hypoxic versus normoxic), in stark contrast to the ex vivo hemolysis that was a function of recipient plasma factors which apparently differ (in terms of either presence/absence or concentration) between steady-state and VOC crisis in SCD.  With hypoxic storage, the aggravating factors of the crisis-state plasma did not significantly deteriorate the donor RBC deformability compared to the steady-state plasma.  Normal storage conditions lacked the numerous beneficial effects of hypoxic storage; however, RBCs stored at lower oxygen levels were almost equally susceptible to the strong hemolytic effects of VOC plasma compared to the conventional RBCs, at least for the monitoring time and conditions used in those experiments.  A comparative analysis of the two plasma sources could reveal candidate hemolytic factors that can be subsequently examined individually for their potential impact on transfused RBCs …. I hope the paper of Karafin et al will stimulate and encourage further use of those research tools and metrics in the field of the RBC storage lesion”.

Reikvam et al (2023) noted that anemia is a common symptom of hematological malignancies and RBC transfusion is the primary supportive treatment, with many patients becoming transfusion-dependent.  Hemanext Inc. has developed a CE mark certified device to process and store RBCs hypoxically -- citrate-phosphatedextrose (CPD)/phosphate-adenine-glucose-guanosine-saline-mannitol (PAGGSM) RBCs, leukocytes-reduced (LR), O2/CO2 reduced -- with the objective of improving RBC quality for transfusion.  In an interim analysis, these investigators described the first patients to receive hypoxic RBCs, administered as part of a pilot post-marketing study in Norway.  The primary outcome was AEs within 24 hours of transfusion initiation and overall up to 7 days (± 1 day) post-transfusion.  Secondary outcomes included changes in Hb levels post-transfusion.  A total of 5 patients with hematological malignancies were included (80 % men, mean age of 69.8 [SD ± 19.3] years).  Prior to the study, patients had been receiving conventional RBC transfusions every 2 weeks.  Subjects received 2 units of hypoxic RBCs over a 2-hour period without complication.  One mild AE (rhinovirus) was reported 2 days post-treatment and was deemed unrelated to treatment.  The mean ± SD pre-transfusion Hb level was 7.7 ± 0.5 g/dL, evolving to 9.0 ± 0.9 g/dL following administration of hypoxic RBCs; an increase of 17 %.  The authors concluded that this interim analysis demonstrated that transfusion with hypoxic RBCs processed with the CPD/PAGGSM LR, O2/CO2 reduced system was effective and well-tolerated in patients with hematologic malignancies.  These investigators stated that this pilot post-marketing surveillance study was designed to collect preliminary safety data on the transfusion of hypoxic RBCs, produced with the CPD/PAGGSM LR, O2/CO2 reduced system, in 2 patient groups: acute burn and hematological malignancies.  This interim safety analysis has demonstrated that hypoxic RBCs were well-tolerated in patients with hematological malignancies, and 5 additional subjects with hematological malignancies will subsequently be enrolled and transfused.  Safety and tolerability of hypoxic RBCs in 10 patients with burn injury will then be studied and reported in addition to a summary report of the full study cohort.  These researchers stated that further studies examining the effectiveness of hypoxic RBC administration in patients with thalassemia in Italy, MDS in Germany, and SCD in the U.S. are planned.  They stated that the overall clinical program will examine if the use of hypoxic RBCs can reduce transfusion interval versus conventional RBCs in patients requiring acute and chronic transfusions, as well as any improvements in other outcomes, including patient QOL and reduction in ferritin levels over time in patients who require chronic RBC transfusion compared with conventional RBCs.

Hay et al (2023) stated that RBC storage lesion results in decreased circulation and function of transfused RBCs.  Elevated oxidant stress and impaired energy metabolism are a hallmark of the storage lesion in both human and murine RBCs.  Although human studies don't suffer concerns that findings may not translate, they do suffer from genetic and environmental variability among subjects.  Murine models could control for genetics, environment, and much interventional experimentation can be performed in mice that is neither technically feasible nor ethical in humans.  However, murine models are only useful to the extent that they have similar biology to humans.  Hypoxic storage has been shown to mitigate the storage lesion in human RBCs, but has not been studied in mice.  RBCs from a C57BL6/J mouse strain were stored under normoxic (untreated) or hypoxic conditions (SO2 approximately 26 %) for 1 hour, 7 days, and 12 days.  Samples were tested for metabolomics at steady state, tracing experiments with 1,2,3-13C3-glucose, proteomics and end of storage PTR.  Hypoxic storage improved PTR and energy metabolism, including increased steady state and 13-C3-labeled metabolites from glycolysis, high energy purines (adenosine triphosphate) and 2,3-diphospholgycerate.  Hypoxic storage promoted glutaminolysis, increased glutathione pools, and was accompanied by elevation in the levels of free fatty acids and acyl-carnitines.  The authors concluded that the findings of this study isolated hypoxia, as a single independent variable, and demonstrated similar effects as observed in human studies.  These researchers stated that these findings also revealed the translatability of murine models for hypoxic RBC storage and provided a pre-clinical platform for ongoing study.  Furthermore, these investigators noted that this approach allows studies of other factors (e.g., sex, and age) as well as novel storage additives that impact post-transfusion performances of the transfused RBC in humans and mice.  Moreover, these researchers stated that the main drawbacks of this trial included that no direct measures of reactive oxygen or nitrogen species were conducted; and murine models of blood storage may not perfectly recapitulate human RBC storage.

References