Perioperative Pediatric Erythrocyte Transfusions: Incorporating Hemoglobin Thresholds and Physiologic Parameters in Decision-making

Perioperative erythrocyte transfusion management in the scenario of massive hemorrhage or critical bleeding involves a dynamic strategy focusing on the individualized child’s resuscitation requirements. Massive hemorrhage is defined as blood loss and/or transfusion of more than 40 ml/kg without or without hemodynamic instability. However, evidence to guide erythrocyte transfusion management in the context of massive hemorrhage for pediatric patients is sparse.

For the actively bleeding, hemodynamically unstable pediatric patient, expert consensus recommends goal-directed massive hemorrhage guidelines, including transfusion of erythrocytes, plasma, and platelets in a 1:1:1 ratio (or a 2:1:1 ratio) until the bleeding is no longer life threatening. This ratio-driven, balanced resuscitation strategy is extrapolated from adult trauma. While there is no clear consensus regarding the benefits of a balanced resuscitation strategy in pediatric trauma, recent retrospective studies demonstrate decreased 24-h mortality using a balanced ratio transfusion approach.  Prospective data from Spinella et al. and the Massive Transfusion in Children (MATIC) investigators report that a balanced ratio transfusion strategy (plasma: erythrocyte ratio greater than 1:2) may improve early survival in children with life-threatening bleeding. In the actively bleeding, hemodynamically stable pediatric patient, international perioperative goal-directed massive hemorrhage guidelines and critical bleeding protocols derived from expert consensus suggest maintaining hemoglobin level in the range of 7.0 to 8.0 g/dL in children and 9.0 to 10.0 g/dL in neonates. Despite expert consensus panel agreement of 95 to 100%, Valentine et al. acknowledge that many of these international good practice recommendations are based on weak evidence due to lack of randomized controlled trials and due to studies influenced by survivorship bias. Thus, perioperative physicians must consider the challenges of dynamic fluctuations in the physiologic status of the bleeding child while weighing the risks and benefits of blood loss and blood product transfusion. While individualized goal-directed real time transfusion management of the bleeding child is the intent, with the hemodynamic instability of massive hemorrhage, resuscitation takes precedent. As a result, the decision to transfuse is often more empirically driven in the case of ongoing hemodynamically significant blood loss.

Perioperative erythrocyte transfusions in the pediatric noncardiac surgical bleeding patient may be indicated for treatment of severe anemia, hypotension, and/or decreased oxygen-carrying capacity compromising end-organ function. Procedures such as liver transplantation, craniosynostosis repair, neurosurgery, major orthopedic surgery, and thoracic and abdominal surgery are historically associated with significant blood loss requiring erythrocyte transfusions in over 50% of pediatric cases.

While there are many trials in adult patients supporting restrictive (7 or 8 g/dL) hemoglobin thresholds to be noninferior or superior compared with liberal thresholds (9 or 10 g/dL) across a wide variety of clinical scenarios, critical illness, and surgical procedures only a few prospective trials exist in the pediatric population. Unfortunately, these trials are focused on nonsurgical critically ill children and do not specifically consider the perioperative period. These trials, together with a few observational reports in critically ill children with nonhemorrhagic shock, are presented in table 1.

Perhaps there is a lesson to be learned from the following example of a unique population requiring multiple transfusions throughout their hospitalization. Pediatric burn patients undergo frequent skin excision and grafting procedures. A single-center study implemented a restrictive transfusion strategy (hemoglobin level greater than 7.0 g/dL) and compared the outcomes to a historic cohort (hemoglobin level greater than 10.0 g/dL). The restrictive group had lower mortality rates and less erythrocyte transfusions with no difference in sepsis rates (table 1). While this may represent a change in overall burn management, this study suggests that a restrictive transfusion strategy in pediatric burn patients may improve outcomes.

Restrictive erythrocyte transfusion strategies for management of the critically ill child recommended by expert group consensus guidelines are as follows (table 2): (1) consideration of erythrocyte transfusion in the hemodynamically stable critically ill pediatric patient based on clinical judgement for a hemoglobin level of 5.0 to 7.0 g/dL, (2) transfusion is not necessary for pediatric patients with hemoglobin level greater than 7.0 g/dL, and (3) transfusion is advised against for a hemoglobin greater than 9.0 g/dL. These recommendations pertain to the children with the following conditions: critical illness, postsurgery or postprocedural, respiratory failure, sepsis, non–life-threatening bleeding, or renal replacement therapy. These recommendations exclude children with the following conditions: acute brain injury, oncologic disease, stem cell transplantation, hemolytic anemia, sickle cell anemia, severe acute respiratory distress syndrome, mechanical support, or cardiac disease. Such high-risk patients may require higher transfusion targets (hemoglobin levels between 7.0 and 10.0 g/dL), guided by physiologic parameters and clinical judgement. According to Valentine et al.  in these patients, “transfusion should be based on evidence of inadequate cardiorespiratory support or decreased systemic and/or regional oxygen delivery.” Based on the expert consensus recommendations of Lacroix et al.  and Valentine et al. the posttransfusion goal should be to relieve the indication for transfusion and not necessarily achieve a normal hemoglobin level for age, with a reasonable general posttransfusion hemoglobin target between 7.0 and 9.5 g/dL. Finally, it must be stated that these guidelines in hemodynamically stable noncardiac surgery are based on low-quality pediatric evidence (grade 1C or 2C) or expert consensus, except for the nonsurgical critically ill child (grade 1B evidence), and must be followed up by high-quality trials to determine safe transfusion strategies for specific pediatric surgical populations. While these recommendations do not specifically cover the intraoperative period, they can be used as a good practice guide for anesthesiologists caring for a stable child undergoing noncardiac surgery.

Finally, perioperative management of the hemodynamically stable bleeding child for noncardiac surgery should consider the change from baseline hemoglobin level, the calculated allowable estimated blood loss based on weight, the physiologic status of the child as determined by indicators of end organ perfusion, and comorbidities. High-quality outcomes research regarding restrictive transfusion strategies in pediatric perioperative patients is lacking, and while the focus on optimal hemoglobin transfusion parameters should be considered, it is equally important to consider the physiologic parameters that may influence short- and long-term patient outcomes (fig. 1). This concept of harnessing physiologic parameters to guide transfusion decisions will be explored in more detail in the latter part of this clinical focus review.

Pediatric patients undergoing cardiac surgery have additional factors increasing the likelihood of receiving allogeneic blood transfusions including complex surgeries, chronic cyanosis, hypothermia, and the effects of cardiopulmonary bypass (CPB). An analysis of the Society for Thoracic Surgery (Chicago, Illinois) database showed that all registry centers administered erythrocytes to 100% of patients less than 12 months of age undergoing cardiac surgery with CPB.  While transfusion rates decreased in older patients, variability across institutions increased (toddlers, 78.6% [54.6 to 91.7%]; children, 50.0% [25.5 to 63.7%]; adolescents, 25.8% [12.5 to 40%]). Despite multiple studies associating bleeding and erythrocyte transfusions with worse postoperative outcomes the factors influencing transfusion thresholds in this population (age, cardiac physiology, cyanosis or intracardiac mixing, surgical complexity, and CPB effects) have made determining an optimal hemoglobin transfusion threshold elusive. With the increased focus on the risk–benefit profile of erythrocyte transfusions, it is worth revisiting the literature regarding the hemoglobin transfusion threshold trials in pediatric cardiac surgical patients (table 1).

Due to the high rate of bleeding and transfusion in cardiac surgery, the majority of pediatric perioperative transfusion trials supporting restrictive transfusion practices are in cardiac surgical patients. Many pediatric cardiac centers target hemoglobin level on-CPB of greater than 8 g/dL based on two randomized trials (and post hoc analyses) in infants undergoing biventricular repair with low-flow hypothermic CPB, which demonstrated improved outcomes and neurocognitive development.  However, a single pediatric center caring for Jehovah’s Witness patients has provided some insight into the feasibility and safety of lower on-CPB hemoglobin triggers. Utilizing blood conservation techniques developed for their pediatric Jehovah’s Witness patients, Naguib et al. demonstrated that a target on-CPB goal of a hemoglobin level of greater than 7.0 g/dL allowed for bloodless surgery in 36% of children weighing between 6 and 18 kg and in 81% of those weighing more than 18 kg. While no major adverse events were reported, neurocognitive and developmental testing was not performed, making it difficult to determine the long-term impact of this practice. A recent randomized trial in adult cardiac patients found that moderate hemodilution to a hematocrit of 21 to 25% on CPB was associated with increased risk of postoperative neurocognitive dysfunction and stroke compared to mild hemodilution (hematocrit greater than 25%), despite no differences in cerebral oximetry, hemodynamics, and pre- and post-CPB hematocrits.  While adult cardiac centers may tolerate on-CPB hemoglobin levels as low as 7.0 g/dL, with monitoring for evidence of tissue hypoxia through serial lactate levels, cerebral oximetry, and mixed venous oxygen saturation it is hard to extrapolate this data to pediatric patients due to differences in cyanotic and acyanotic heart disease, cerebral autoregulation, and preexisting cardiovascular and neurologic disease burden. Expert consensus recommends an on-CPB hemoglobin target of 8 g/dL or higher for acyanotic pediatric patients undergoing biventricular repair; however, there is currently not enough outcome data to make recommendations regarding on-CBP targets in cyanotic patients.

Relatively large CPB priming volumes result in hemodilution of erythrocytes, platelets, and coagulation factors, thus increasing the need for blood product transfusions. As clinicians consider ways to reduce transfusions, one method that has been shown to decrease CPB-related hemodilution and thus erythrocyte transfusions is to miniaturize CPB circuits. Allowing for a 50% reduction in the CPB prime volumes, these miniaturized circuits have permitted several institutions to perform complex neonatal surgeries without the need for erythrocyte or platelet transfusion in 30 to 50% of neonates.  In summary, despite the absence of prospective trials, minimizing CPB prime volumes can reduce the need for blood product transfusions in pediatric patients undergoing cardiac surgery. 

Three randomized trials have demonstrated that implementing a postoperative restrictive transfusion strategy resulted in fewer transfusions and lower hemoglobin levels but no difference in lactate levels or arteriovenous oxygen nor adverse clinical outcomes in children undergoing biventricular or palliative procedures  (table 1). These trials demonstrated that hemodynamically stable children who underwent biventricular repair tolerate hemoglobin levels greater than 7.0 g/dL without impaired clinical outcome, while children who underwent palliative procedures tolerate hemoglobin levels greater than 9.0 g/dL.  These trials focused on postoperative intensive care unit (ICU) transfusion practices, not intraoperative transfusion thresholds. Therefore, although individualized goal-directed transfusion is the aim, prospective studies focusing on intraoperative transfusion thresholds for complex cardiac surgical patients are lacking. A recent retrospective study demonstrated that each 5% increase in ICU arrival hematocrit greater than 38% for acyanotic and 42% for cyanotic children was associated with a significant increase in the odds of perioperative mortality and major complications.  While this retrospective study can only demonstrate an association of worse outcomes with higher intraoperative hemoglobin level, it highlights the need for prospective studies with well defined perioperative transfusion guidelines reserving transfusions for patients with clinical evidence of poor oxygen delivery and avoiding overtransfusion in clinically stable patients.

Although a number of prospective studies demonstrate no benefit of higher hemoglobin thresholds and a larger number of retrospective studies associate erythrocyte transfusions with worse outcomes  clinicians remain skeptical in adopting restrictive transfusion strategies for pediatric cardiac surgical patients due to a lack of robust outcome data and the unique physiology requiring physicians to optimize oxygen delivery in patients with chronic hypoxemia and dynamic intracardiac shunts. A goal-directed erythrocyte transfusion strategy targeting specific physiologic parameters may be a more appropriate approach to transfusion than a specific hemoglobin target. However, without high-quality outcome data on physiologic transfusion thresholds, expert consensus recommends a restrictive approach to transfusion in cardiac children. Current expert consensus recommends a postoperative hemoglobin transfusion threshold in stable, acyanotic cardiac patients with hemoglobin levels greater than 7.0 or 8.0 g/dL in the presence of signs of symptomatic anemia (grade IB evidence). For stable, cyanotic cardiac children without signs of symptomatic anemia, the recommended postoperative transfusion threshold is a hemoglobin level greater than 9.0 g/dL (grade 1C). 

While there is a paucity of data on perioperative neonatal blood transfusions, neonates (age 0 to 30 days old) are one of the most frequently transfused groups, with up to 42 to 90% of premature and low-birth-weight neonates receiving at least one blood transfusion during their hospitalization.  Although most of the perioperative transfusion literature in neonates comes from the pediatric cardiac literature, a recent single-center study reported that 6% (25 of 420) of neonates undergoing index general surgery cases received perioperative transfusions. Risk factors for perioperative transfusion included surgery type, history of prematurity, prior transfusion, or structural heart disease. High-quality outcomes data regarding transfusion triggers for neonates in the perioperative period are evolving. Herein is highlighted recent literature and expert consensus guidelines on transfusion thresholds in neonates, premature, and extremely low-birth-weight infants in an attempt provide guidance for perioperative transfusion decisions.

Neonates can be divided into two categories based on gestational age: term or preterm (preterm defined as gestational age less than 37 weeks); and/or based on weight: low birth weight (between 2,500 and 1,000 g) or extremely low birth weight (less than 1,000 g). There is no universally accepted definition of the “normal” hemoglobin level for neonates, as they have unique physiologic and developmental differences mandating a wide range of recommended hemoglobin thresholds (tables 1 and 2). Furthermore, the definition of liberal versus restrictive transfusion threshold varies widely across different weights, ages, and critical illnesses ranging from liberal (hemoglobin level of 7.5 to 12.0 g/dL) to restrictive (hemoglobin level of 6.5 to 10.0 g/dL) as detailed in tables 1 and 2. Due to the limited ability to tolerate physiologic stress, historical recommendations have favored more liberal transfusion strategies. Erythrocyte transfusions are independently associated with intraventricular hemorrhage  necrotizing enterocolitis,, bronchopulmonary dysplasia, retinopathy of prematurity,  and death.  In fact, due to the lack of transfusion-related outcome data at the time, neonates were not included in the guidelines of Valentine et al.

Although the trial of Lacroix et al.  suggests that restrictive transfusion strategies appear to be safe in the neonatal population, there has been a lack of consensus on the optimal hemoglobin levels for term and preterm neonates until recently. Previously, in the Premature Infants in Need of Transfusion Outcomes (PINTOS) trial, Kirpalani et al. reported no difference in death, cerebral palsy, cognitive delay, or severe hearing/visual impairment between restrictive and liberal transfusion strategies at 18 to 21 months in extremely low-birth-weight neonates. However, a post hoc analysis of this study suggested that higher hemoglobin levels may be associated with better cognitive outcomes.  Consequently, multicenter randomized clinical trials by Kirpalani et al.  in the Transfusion of Prematures (TOP) study and Franz et al.  in the Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants (ETTNO) study were conducted comparing restrictive versus liberal transfusion thresholds in extremely low-birth-weight preterm infants on the risk of death or neurocognitive outcomes at 2 yr. Transfusion thresholds were determined by postconceptual age and state of health. Both trials found that a restrictive transfusion strategy did not increase the risk of death, cerebral palsy, cognitive deficit, necrotizing entercolitis, bronchopulmonary dysplasia, or retinopathy of prematurity.  While previous guidelines recommended higher hemoglobin thresholds for extremely low-birth-weight neonates, both studies demonstrated no difference in mortality or neurodevelopmental impairment at hospital discharge or at 22- to 26-month follow-up utilizing a restrictive transfusion strategy. As such, these studies recommend employing a restrictive transfusion strategy using a hemoglobin transfusion threshold ranging from 7.0 to 11.0 g/dL, based on postconceptual age, age-specific hemoglobin reference ranges, level of respiratory support, ongoing or anticipated red cell loss due to critical illness, and nutritional status (table 2).

In a recent review of evidence-based guidelines for neonatal transfusions, Zerra et al.  point out that the trials of Kirpalani et al. and Franz et al.  function to compare liberal versus restrictive transfusion strategies based on laboratory thresholds alone (hemoglobin or hematocrit). Zerra et al.  highlight the need to identify more all-inclusive markers of physiologically relevant outcomes such as tissue oxygen delivery and long-term effects of transfusions on neurodevelopment, immunity, and inflammation, especially in neonates with varying levels of illness, age, and gestational age. While these data are difficult to extrapolate to the intraoperative period, especially for neonates with ongoing bleeding, the current literature suggests that term and preterm, low-birth-weight and extremely low-birth-weight neonates appear to tolerate restrictive transfusion strategies without increased risk of neurocognitive deficits (tables 1 and 2) in a hemodynamically stable patient without evidence of end-organ tissue hypoxia.

The etiology of a low hemoglobin level in pediatric patients may stem from chronic anemia (nutritional deficiencies, disease state, and side effects of treatment) or acute blood loss from ongoing bleeding. Although the etiology of anemia is often not delineated, multiple studies have demonstrated that preoperative anemia is associated with increased blood transfusions  and overall mortality.  While an in-depth discussion of anemia as a risk factor for perioperative morbidity and mortality is beyond the scope of this review, these studies found that anemic children tend to be younger, required emergency surgery, and had a higher incidence of major comorbidities. Unfortunately, it is unclear whether the adverse outcomes from perioperative anemia are related to the etiology of anemia, the subsequent transfusions to treat the anemia, or both. Recent studies from Africa suggest that children with chronic anemia but without evidence of respiratory distress, hemodynamic instability, or altered consciousness may safely tolerate a hemoglobin level between 4.0 and 6.0 g/dL (table 1).  These data suggest that a child’s ability to tolerate certain hemoglobin levels may differ depending on the cause and chronicity of the anemia, thus highlighting the importance of patient factors on anemia tolerance and the need for individualized goal-directed guidelines for transfusions.

In fact, patient blood management experts have called for goal-directed individualized guidelines for hemoglobin management including or withholding erythrocyte transfusion rather than focusing on a single hemoglobin threshold number. A 2021 Cochrane Review on transfusion thresholds for guiding erythrocyte transfusions identified that the major limitation of most transfusion strategy trials is that these trials “compare only two separate thresholds for hemoglobin concentration, which may not identify the actual optimal threshold for transfusion in a particular patient. Hemoglobin concentration may not be the most informative marker of the need for transfusion in individual patients with different degrees of physiologic adaptation to anemia.” This statement is reminiscent of an oft-repeated statement in pediatric medicine: One size does not fit all. Despite the increasing support for restrictive transfusion strategies in pediatric patients, international expert consensus guidelines on erythrocyte transfusions agree decisions to transfuse should not be dictated by hemoglobin concentration alone but should also consider the child’s underlying physiologic condition and anemia-related signs and symptoms (table 2). Unfortunately, currently lacking is a decision-making algorithm that identifies specific individuals for whom permissive anemia is unsafe or, conversely, individuals that meet transfusion triggers for whom transfusion is actually unnecessary. However, emerging literature suggests that combining patient hemodynamics and serial measurements of biochemical markers indicative of sufficient perfusion (e.g., lactate, base deficit, pH) with novel technologies, such as cerebral and somatic dynamic near infrared spectroscopy, may allow us to better quantify and monitor oxygen consumption and delivery and the decision to transfuse or to withhold transfusion.

Recently, critics of the above neonatal transfusion trials, point out that erythrocyte transfusion strategies based on hemoglobin thresholds alone may not be an accurate predictor of physiologic relevant outcomes such as tissue oxygen delivery, especially in a neonate with varying levels of illness, age, and gestational age. Several studies, including two recent prospective trials, in extremely low-birth-weight preterm neonates demonstrated that cerebral and somatic oximetry may reflect tissue hypoxia better than the hemoglobin level alone. In addition to increases in cerebral and somatic oxygenation and decreases in fractional oxygen extraction after blood transfusions, two recent studies found that oxygen extraction preferentially increases in the brain over the gut in more anemic and immature infants.  Another recent study compared the effect of erythrocyte transfusions on pulmonary vascular resistance by echocardiography and cerebral and splanchnic oxygen saturations in neonates with or without a patent ductus arteriosus.  The authors report a decrease in pulmonary vascular resistance (change in right ventricular pressure) and cerebral oxygen extraction after erythrocyte transfusion in all patients, but neonates with patent ductus arteriosus had significantly lower splanchnic oxygen saturation and higher fractional oxygen extraction, even after an erythrocyte transfusion. This study highlights the complexity of the relationship between tissue oxygenation/extraction and transfusion decisions in patients with cardiac shunts. While the premature extremely low-birth-weight population has received significant attention due to large research networks, studies examining physiologic parameters for transfusion triggers in other pediatric populations are scarce. A single study in 92 pediatric scoliosis patients found associations between a 15% drop in cerebral oximetry with lower hematocrits and lower blood pressure.  Although the authors demonstrate that lower hematocrits are associated with decreased cerebral oximetry, it is not clear whether a 15% drop in cerebral oximetry is clinically significant. Furthermore, this study does not differentiate the independent association of hypotension or anemia on decreases in cerebral oximetry. Highlighted is the need for future research to identify novel methods to monitor tissue oxygen delivery, as hemoglobin number alone may not be an accurate predictor of physiologic relevant outcomes in perioperative pediatric patients with different illness severities, comorbidities, ages, or surgical procedures.

Furthermore, although erythrocyte transfusion increases hemoglobin levels with a corresponding increase in blood oxygen content, a child’s tolerance of anemia is based more on tissue oxygen delivery, end organ perfusion, oxygen extraction, and compensatory physiology than a single hemoglobin number. In a recent study of adult blunt-trauma patients, Özakin et al.  correlated multiple physiologic and laboratory parameters in patients who required erythrocyte transfusions with those who did not. Harnessing this data, the authors developed a score using lactate, base deficit, and systolic blood pressure to predict a need for blood transfusion. While this study does not specifically compare outcomes based on hemoglobin levels, it does emphasize the complexity of the decision to transfuse, as well as the need for developing more comprehensive tools utilizing multiple physiologic and laboratory parameters to guide transfusions in perioperative pediatric patients.

Therefore, prospective research harnessing restrictive hemoglobin strategies together with end organ monitoring, physiologic markers of tissue hypoxia, and long-term patient outcomes is needed to further guide goal-directed care of the anemic and/or bleeding child. We propose such a model in figure 1, which shows hypothetical physiologic strategies to guide erythrocyte transfusion decisions in pediatric patients perioperatively.

Pediatric erythrocyte transfusion practices have long been extrapolated from adult research and guidelines despite children being physiologically unique from adults. The development and acceptance of evidence-based pediatric restrictive hemoglobin transfusion thresholds has been challenging for numerous reasons. First, anemia tolerance, bleeding risk, and transfusion recommendations are dependent on weight, gestational age, physiologic parameters, surgical and medical complexity, and institutional practice. Second, prospective outcome studies focusing on pediatric erythrocyte transfusion thresholds are few and further complicated due to a smaller, heterogeneous patient population, varied institutional surgical volume, and limited resources directed at these studies.

Despite the lack of robust outcome data, several trials and expert consensus guidelines recommend utilizing a restrictive transfusion strategy in many pediatric populations. International expert consensus statements recommend against a single hemoglobin transfusion trigger, reinforcing that the decision to transfuse should be based on an assessment of the patient’s underlying comorbidities and anemia symptoms.

The authors propose there is no ideal, one size fits all, hemoglobin threshold for the pediatric patient in the perioperative period. Instead, future research should focus on patient-centered outcomes that incorporate patient factors, surgical and medical complexity, and physiologic parameters to develop tools to guide the management of anemic and/or bleeding pediatric patients. Knowledge that the child is physiologically optimized would go a long way in promoting restrictive goal-directed transfusion decisions in the perioperative setting. In conclusion, anesthesiologists caring for pediatric surgical patients should turn our collective focus to the individualized patient and the physiologic status of the neonate, infant, child, or adolescent in deciding the optimal hemoglobin threshold, while avoiding erythrocyte transfusions whenever possible.