1084 SECTION IX Pediatric Critical Care Hematology and Oncology Risks of Anemia Severe anemia is associated with a higher risk of mortality Carson et al combined the data of two studies involving bloo[.]
1084 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology Risks of Anemia Severe anemia is associated with a higher risk of mortality Carson et al combined the data of two studies involving bloodless surgery in adults and reported that the unadjusted mortality rate was 0.9% when the nadir Hb level was g/dL or greater, 9% if it was between and g/dL, 29.8% if it was between and g/dL, and 41% if it was less than g/dL.21–23 Clearly, the risk of mortality increases when the Hb falls below g/dL It is less obvious when to transfuse if the nadir Hb level is between and g/dL It is important to recognize that the relationship between anemia and outcomes does not mean that transfusion to treat anemia will necessarily improve outcomes There are less data on the relationship between anemia and adverse outcomes in children Lackritz et al.24 followed 2433 anemic African children, 20% of whom received a whole-blood transfusion Transfusion seemed beneficial if the Hb was below 4.7 g/dL and if the patient presented with respiratory distress Given these data, local guidelines were implemented, recommending that whole blood should be transfused to hospitalized children if their Hb was less than g/dL Lackritz25 subsequently enrolled 303 children with a Hb less than g/dL Mostly because blood products were not available, 116 (38%) did not receive a transfusion Each child with severe anemia was matched with the next child hospitalized with a Hb greater than g/dL Death rates were 19.5% in 303 patients with a Hb greater than g/dL who were not transfused, 21.4% in 187 patients with a Hb less than g/dL who were transfused, and 41.4% in 116 patients with a Hb less than g/dL who were not transfused English et al.26 completed a prospective cohort study of 1269 children with malaria hospitalized in Kenya Whole-blood transfusion seemed to decrease mortality if anemia was severe (Hb ,4 g/dL), or if a Hb less than g/dL was associated with dyspnea These studies suggest that the risk of mortality increases significantly among children ill enough to require hospitalization if their Hb is less than g/dL, particularly if respiratory symptoms are present Transfusion of Red Blood Cells: Indications (When) Optimal RBC transfusion practice in PICU patients remains unclear The number of RBC transfusions increased in children younger than 18 years between 1994 and 2014.27 It is estimated that 24.8 million RBC units were distributed by blood banks in the United States in 2015 and pediatric transfusions comprised 5.2% of all RBC transfusions.28 In the PICU, 17% to 76% of patients received RBC transfusions.1,29 Decisions for all of these transfusions were made in the context of limited evidence to guide clinical practice Despite this, some recommendations regarding RBC transfusion in PICU patients can be found in the medical literature A multidisciplinary panel of 42 international experts, the Pediatric Critical Care Transfusion and Anemia Expertise Initiative (TAXI), developed evidence-based and expert consensus-based recommendations on RBC transfusion for critically ill children, using the RAND/UCLA (University of California, Los Angeles) methodology.30 The experts focused on the following specific populations of PICU patients: life-threatening and non-lifethreatening bleeding, respiratory failure, nonhemorrhagic shock, acute brain injury, acquired/congenital heart disease, sickle cell/ oncology/transplant, extracorporeal membrane oxygenation (ECMO)/ ventricular assist device (VAD)/renal replacement therapy, and other patients Members of the TAXI consensus conference agreed on 97 recommendations and a decision tree.11,31–41 The following recommendations refer to five nodes that were added to the decision tree in Fig 91.2 • Hemorrhagic shock or life-threatening bleeding (node #1): For life-threatening hemorrhage, RBC transfusions are clearly indicated, with plasma and platelets (ratio: 1/1/1 or 2/1/1) (see also Chapter 118).42,43 Hemorrhagic Shock or Severe Bleeding (Node 1) The first node of the decision tree is about hemorrhagic shock and life-threatening bleeding In such instances, RBC transfusions are clearly indicated, with plasma and platelets (ratio: 1/1/1 or 2/1/1).42,43 The decision to prescribe RBC transfusions should be based on physiologic state, estimated amount of blood loss (Canadian Blood Services recommends a transfusion if there is an acute blood loss 15% blood volume44) and risk of ongoing lifethreatening hemorrhage, more than on Hb concentration, coagulation tests, and platelet counts A systematic approach to treat hemorrhagic shock and to activate massive transfusion protocols is recommended.45 • Severe anemia in PICU patients without severe bleeding (node 2): The TAXI recommendation is that a RBC transfusion should be prescribed in PICU patients with Hb concentration less than g/dL,11 and that practitioners prescribe RBC transfusion using their experience and clinical data, such as severity of illness and evidence of decreased O2 consumption if the Hb concentration is between and g/dL.40 It is recommended to move to node in critically ill children with Hb level of g/dL or greater PICU Patients With Severe Anemia Without Severe Bleeding (Node 2) RBC transfusion is more questionable if there is no severe bleeding Pediatric intensivists have stated in two surveys that their decision to prescribe an RBC transfusion would be based on reasons such as low Do2 or Vo2, cardiovascular insufficiency, respiratory failure or use of certain specific technologies such as ECMO, hemodialysis, hemofiltration, plasmapheresis, or exchange transfusion Nonetheless, the most frequent reason to transfuse RBCs was reported to be a low Hb concentration,1,9 which is the core of node in the decision tree The Hb level that should prompt a pediatric intensivist to prescribe RBC transfusion remains a matter of debate, but there is some evidence in the medical literature that can guide practitioners Hemoglobin Less Than or Between and g/dL (Node 2) There are data showing that the risk of mortality increases rapidly if the Hb concentration of hospitalized adults21 or children26 drops below g/dL There are strong data suggesting that wholeblood transfusion (with an equivalent of RBC unit within it) might prevent death in severely ill children with an Hb level less than g/dL.25,26 The TAXI recommendation is that an RBC transfusion should be prescribed in PICU patients with Hb concentration less than g/dL.11 RBC transfusion in PICU patients is strongly associated with a low Hb level (multivariate odds ratio (OR) if Hb less than g/dL: OR, 61.3; 95% CI, 27.75–134.7).29 However, what should drive RBC transfusion in critically ill children with Hb between and CHAPTER 91 Transfusion Medicine 1085 Transfuse RBC: plasma: platelets in ratio of 2:1:1 or 1:1:1 until bleeding is no longer life threatening d Hemorrhagic shock1 Critically ill child or child at risk for critical illness Hb 9 g/dL c Congenital or acquired myocardial dysfunction Use clinical judgment5, There is no evidence that transfusion above 10 g/dL is beneficial d Pulmonary hypertension • Fig 91.2 Pediatric critical care Transfusion and Anemia Expertise Initiative (TAXI) red blood cell (RBC) transfusion clinical decision tree Three different recommendations can be found at the end of each branch of the tree (1) An RBC transfusion is probably useless (pink boxes); (2) an RBC transfusion can be useful or is mandatory (yellow or green boxes); (3) the right decision is unclear (white boxes) The pink circles show the numbers of five nodes ECMO, Extracorporeal membrane oxygenation; Hb, hemoglobin; PARDS, pediatric acute respiratory distress syndrome; VAD, ventricular assist device (From Valentine SL, Bateman ST, Bembea MM, et al Consensus recommendations for red blood cell transfusion practice in critically ill children from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative [TAXI] Pediatr Crit Care Med 2018;19[9]:884–898.) 1086 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology g/dL is unclear There are no hard data on the association of Hb between and g/dL and adverse outcomes, and there are no data on the usefulness of RBC transfusion in this population TAXI recommended that practitioners use their clinical judgment and prescribe RBC transfusion using their experience and clinical data, such as severity of illness and evidence of decreased O2 consumption.40 • Hemodynamically unstable patients (node 3): The recommendation of TAXI is to use clinical judgment in hemodynamically unstable patients36,40 and to move to node in hemodynamically stable critically ill children (hemodynamically stable mean arterial pressure not ,2 standard deviations below normal mean for age and cardiovascular support—pressors/ inotropes and fluids—not increased for at least hours) Hemodynamically Unstable Patients Without Serious Bleeding (Node 3) In PICU patients without a life-threatening bleeding and with an Hb level of g/dL or greater, members of TAXI suggested to check what is the hemodynamic status (node in the decision tree) In the Transfusion Requirement in PICU (TRIPICU) trial, a child was considered hemodynamically stable if the mean arterial pressure was not less than standard deviations below normal mean for age and if the cardiovascular support (vasopressors/inotropes and fluids) had not been increased in the last hours before an RBC was considered.4 Members of TAXI considered a patient to be hemodynamically unstable if the patient does not meet this definition There are few hard data in hemodynamically unstable patients However, a large randomized controlled trial and a meta-analysis of all available evidence reported that RBC transfusions not improve the outcome of critically ill septic adults even if they are experiencing an uncontrolled shock state.46,47 The recommendation of TAXI is to use clinical judgment in hemodynamically unstable patients.36,40 • Hemodynamically stable noncardiac patients (node 4): Specific recommendations for goal-directed transfusion therapy remain undetermined at the present time.11,40 TAXI members concluded that an RBC transfusion should not be given in hemodynamically stable noncardiac PICU patients with an Hb level of g/dL or greater if they belong to any of the following subpopulations: septic patients,48 noncardiac postsurgery,49 severely burned children,50 trauma patients,51 respiratory failure (excluding severe pediatric acute respiratory distress syndrome [ARDS]),34 nonhemorrhagic shock,36 non-lifethreatening hemorrhage,35 and ECMO, VAD, or RRT.31 TAXI recommended to move to node in cardiac patients Hemodynamically Stable Noncardiac Patients (Node 4) What should prompt intensivists to prescribe an RBC transfusion in hemodynamically stable noncardiac PICU patients with an Hb level of g/dL or greater? Some high-quality studies have addressed this question Two randomized controlled trials evaluated RBC transfusion strategies in children The first study was performed in 106 African children with malaria crisis (hematocrit 12%–17%) Whole-blood transfusion did not improve mortality rate (1 in 53 vs in 53) in patients without respiratory or cardiovascular compromise.52 In the TRIPICU study, a randomized controlled trial involving 637 stable critically ill children with an Hb level of 9.5 g/dL or less, 320 patients were allocated to an RBC transfusion threshold of g/dL of Hb (restrictive group) and 317 to a threshold of 9.5 g/dL (liberal group) A statistically significant noninferiority was found: 38 and 39 patients, respectively, developed new or progressive MODS, and there were 14 deaths within 28 days postrandomization in both strategy groups The conclusion was that a restrictive strategy is as safe as a liberal strategy in stable critically ill children Moreover, 174 patients (54%) in the restrictive group received no RBC transfusion compared with (2%) in the liberal group (P , 0001), and patients in the restrictive group received 54% fewer RBC transfusions These data and the primum non nocere principle support adopting a restrictive transfusion strategy for stabilized critically ill children.11 Is there anything else than the Hb level that should guide RBC transfusion strategy in hemodynamically stable PICU patients with an Hb level of g/dL or greater? Guidelines from many organizations emphasize that the decision to administer RBCs should not be based solely on Hb levels but should involve sound clinical judgment and good common sense.11,40,53–55 Should we use physiologic markers to guide RBC transfusion in PICU patients? Goal-directed transfusion therapy using such markers is frequently advocated.11 While it is theoretically rational to base the decision to transfuse RBCs on physiologic need, it is still a matter of debate as to what parameters best determine that need It has been suggested that an RBC transfusion is indicated for patients with symptomatic anemia, but most critically ill children are unable to report these symptoms Some have suggested that systemic markers of oxygenation deficit, such as systemic Vo2, Vo2/Do2 dependence, blood lactate level, Scvo2, mixed venous O2 saturation or O2ER, might be useful.56–59 Others have proposed that parameters reflecting regional oxygenation deficit—such as brain tissue O2 pressure,60 gastric tonometry,10 tissue O2 saturation measured by near-infrared spectroscopy,14 or digital O2ER measured by noninvasive devices—may be more reliable Actually, it is presently not known which markers are best suited to guide RBC transfusion therapy and what cutoff values should be used to determine the need for RBC transfusion The concept of goal-directed transfusion therapy is laudable but is presently vaguely defined and not supported by hard data Specific recommendations for goal-directed transfusion therapy remain undetermined at the present time.11,40 In practice, a low Hb concentration remains the most frequent and primary justification for pediatric intensivists to prescribe an RBC transfusion.1 Therefore, it makes sense that the Hb concentration be the first parameter assessed when an RBC transfusion is considered Given the available evidence, critically ill children must receive an RBC transfusion if their Hb level is below g/dL In stable patients—including septic patients,48 patients having undergone noncardiac surgery,49 severely burned children,50 and trauma patients51—it is suggested to consider RBC transfusion if the Hb concentration is less than g/dL, but a transfusion is not recommended if the Hb concentration is above this threshold However, determinants other than the Hb concentration must be considered, including age, severity of illness, or evidence of organ dysfunction or O2 dependency, such as elevated blood lactate level or low Scvo2 For example, it would seem appropriate to consider a higher threshold and a more aggressive RBC transfusion strategy in unstable patients for whom the optimal and safe lower limit of the transfusion threshold has not been established Moreover, any recommendations made must also factor in specific considerations for disorders such as sickle cell disease61 and cardiac conditions (node 5) CHAPTER 91 Transfusion Medicine In summary, the TAXI recommendation in noncardiac PICU patients is “In critically ill children or those at risk for critical illness, who are hemodynamically stable and who have an Hb concentration 7 g/dL, we recommend not administering a RBC transfusion.”40 Can we apply this recommendation to all noncardiac PICU patients, whatever their basic disease? TAXI members concluded that an RBC transfusion should not be given in hemodynamically stable noncardiac PICU patients with an Hb level of g/dL or greater if they belong to any of the following subpopulations: noncardiac postsurgery,11 respiratory failure (excluding severe pediatric ARDS),34 nonhemorrhagic shock,36 non-life-threatening hemorrhage,35 ECMO, VAD, or RRT.31 Should PICU patients with respiratory dysfunction receive more RBC transfusions? In the TRIPICU study, 234 and 246 patients with respiratory dysfunction were enrolled in the restrictive and liberal group (threshold Hb for RBC transfusion: 7.0 and 9.5 g/dL, respectively).4 The number of cases of new/progressive MODS was similar, 33 and 35, respectively Duration of mechanical ventilation was also comparable in these 480 patients (6.4 6.0 vs 6.3 5.3 days; absolute risk difference: –0.16; 95% CI, –1.2 to 0.9; P 75), including 73 with an acute lung injury (ALI; 7.2 6.5 vs 7.1 6.2 days; absolute risk difference: –0.12; 95% CI, –3.1 to 2.9; P 94) and 48 with ARDS (10.5 9.2 vs 8.5 7.2 days; absolute risk difference: –2.0; 95% CI, –6.8 to 2.8, P 40) Thus, targeting higher Hb thresholds does not improve outcome in stable critically ill children with respiratory problems if their Hb level is greater than g/dL There is little evidence supporting the belief that a higher Hb level is required in severely ill septic patients The outcome of 137 septic children (34 in septic shock, 31 with severe sepsis) allocated in the TRIPICU study to a restrictive or liberal transfusion strategy was similar, with 13 of 69 versus 13 of 68, respectively, developing new/progressive MODS (absolute risk difference: 0.3%; 95% CI, –12% to 14%).48 Holst randomized 1005 adults with septic shock to receive an RBC transfusion only if their Hb level fell below or g/dL.46 Some of these patients were hemodynamically unstable The 90-day mortality was similar (43.0% vs 45.0%; relative risk: 0.94; 95% CI, 0.78–1.09; P 44) Thus, a threshold Hb of g/dL can probably be safely applied in critically ill children with sepsis, severe sepsis, and septic shock The optimal Hb level to trigger RBC transfusion in braininjured patients and oncologic patients has not been defined yet.62–65 Members of TAXI recommended to consider giving an RBC transfusion in critically ill children with acute brain injury if the Hb level is 10 g/dL or less39 and in patients with oncologic diagnoses or with stem cell transplant if their Hb level is g/dL or less.38 TAXI suggests using clinical judgment in PICU patients with alloimmune or autoimmune anemia, with severe pediatric ARDS.34 RBC exposure is very large in children under ECMO or VAD.66–68 This practice is not without risks.69,70 TAXI suggests using clinical judgment in children under ECMO or VAD.31 • Cardiac patients (node 5): TAXI33 suggests a postoperative Hb level of g/dL in pediatric cardiac patients when there is good postoperative cardiac function in the absence of persisting cyanotic heart disease and a postoperative Hb level of g/dL in PICU patients with persisting cyanotic heart disease TAXI suggests using clinical judgment in PICU patients with acquired myocardial dysfunction or pulmonary hypertension The experts added, “there is no evidence that transfusion above 10 g/dL is beneficial.”33,40 1087 Cardiac Patients (Node 5) Critically ill children with cardiac disease receive more RBC transfusions than other PICU patients.29,71 There is no evidence indicating that this strategy improves outcomes On the contrary, anecdotal experience with bloodless cardiac surgery for congenital heart disease in children whose families refuse transfusion suggests that a lower Hb level may be well tolerated.72,73 eTable 91.1 summarizes the available data on this question Biventricular (Noncyanotic) Cardiac Physiology The results of three randomized controlled trials suggest that using a g/dL threshold is safe in the postoperative care of noncyanotic congenital heart disease in stabilized patients older than 28 days Willems et al.74 analyzed a subgroup of 125 postoperative cardiac patients enrolled in the TRIPICU study after cardiac surgery No significant difference in the incidence of new or progressive MODS (12.7% vs 6.5%; P 36), PICU length of stay (7.0 5.0 vs 7.4 6.4 days) or 28-day mortality (2 vs deaths) was found between the restrictive and liberal groups De GastBakker et al.75 compared outcome in pediatric cardiac surgery patients aged more than weeks allocated to receive an RBC transfusion if their Hb level dropped below 8.0 g/dL (restrictive) or 10.8 g/dL (liberal group) Patients with cyanotic cardiac disease were excluded Randomization occurred before surgery With respect to RBC transfusion, the research protocol was initiated in the operating room and maintained up to PICU discharge In the 107 patients enrolled and retained for analysis, duration of mechanical ventilation, PICU length of stay, and the incidence of adverse events were similar in both groups while hospital length of stay was shorter in the restrictive group (median and interquartile range 7–11 vs and 7–14 days, P 063) Cholette et al.76 enrolled 53 and 52 children with biventricular physiology after their cardiac surgery; 53 were allocated in a restrictive and 52 in a liberal RBC transfusion strategy Despite lowerthreshold Hb concentrations in the restrictive group (7.0 vs 9.5 g/dL), lactate, arteriovenous O2 difference, and clinical outcomes were similar The British Society of Haematology77 and TAXI33 supports the acceptance of a postoperative Hb level of g/dL in children when there is good postoperative cardiac function in the absence of persisting cyanotic heart disease Univentricular (Cyanotic) Physiology Two randomized controlled trials have addressed RBC transfusion in cyanotic heart disease Cholette et al.78 randomized 30 subjects to a restrictive and 30 subjects to a liberal RBC transfusion strategy (threshold Hb: 9.0 and 13.0 g/dL, respectively) No differences between groups in mean lactate were found (1.4 0.5 vs 1.4 0.4 mmol/L) or peak (3.1 1.5 vs 3.2 1.3 mmol/L) As well, no differences were found in C(a2v)o2, C(a2c)o2, or clinical outcome measures Cholette et al.76 also randomized 57 children after bidirectional Glenn or Fontan procedures: 29 patients were allocated to a restrictive and 28 patients to a liberal transfusion strategy (respective threshold Hb: and 12 g/dL) No differences were noted with regard to peak blood lactate level (3.0 1.5 vs 3.1 1.3 mmol/L), ventilator support, duration of vasoactive agent administration, ICU or hospital length of stay, or survival.78 More data are required before a restrictive transfusion strategy can be safely implemented in patients with cyanotic heart disease TAXI33 recommends a postoperative Hb level of g/dL in PICU patients with persisting cyanotic heart disease 1087.e1 eTABLE Postoperative Mortality in Randomized Controlled Trials Comparing Restrictive and Liberal Red Blood Cell 91.1 Transfusion Strategies in Children With Congenital Cardiopathy Study Cardiac Physiology 74 TRANSFUSION STRATEGY (DEATHS/ PATIENTS) Threshold Hemoglobin (g/dL) Restrictive Liberal Mortality Willems (2010) Biventricular 7.0/9.5 2/63 2/62 28-day de Gast-Bakker (2013)75 Biventricular 8.0/10.8 0/53 0/54 In-hospital Biventricular 7.0/9.5 1/53 1/52 In-hospital 3/169 3/166 76 Cholette TOTAL Biventricular 78 Univentricular 9.0/13.0 0/30 1/30 Pediatric intensive care unit Cholette (2017)76 Univentricular 9.0/12.0 5/29 6/28 In-hospital TOTAL Univentricular 5/59 7/58 Cholette (2011) ... between and g/dL and adverse outcomes, and there are no data on the usefulness of RBC transfusion in this population TAXI recommended that practitioners use their clinical judgment and prescribe RBC... Members of TAXI considered a patient to be hemodynamically unstable if the patient does not meet this definition There are few hard data in hemodynamically unstable patients However, a large randomized... noncardiac PICU patients with an Hb level of g/dL or greater? Some high-quality studies have addressed this question Two randomized controlled trials evaluated RBC transfusion strategies in children