Red Blood Cell Transfusion in the Pediatric ICU J. Lacroix, M. Tucci, and F. Gauvin

J. Lacroix, M. Tucci, and F. Gauvin

Introductin

The decision process leading to red blood cell (RBC) transfusion should be based as much as possible on available evidence. Risks and benefits of transfusion as well as the risks attributable to anemia must be taken into account. In this chapter, we will discuss what prompts pediatric intensivists to prescribe a RBC transfusion, what should guide this decision, and what is missing to really make a decision based on an evidence-based approach.

Four questions should be raised when considering administration of a RBC trans- fusion:

) Is there hemorrhagic shock?

) What is the hemoglobin level?

) What is the severity of illness of the patient?

) Is there any other factor that might affect the decision to prescribe a RBC transfusion?

Is there Hemorrhagic Shock?

It is inappropriate to base a decision to transfuse RBCs on the hemoglobin concen- tration in patients with hemorrhagic shock. The rationale of this statement is easy to understand. Hemoglobin concentration does not drop immediately after an acute bleeding event: the intravascular blood volume decreases, but the hemoglobin con- centration will begin to drop only after a few hours, when the circulating blood vol- ume is diluted by fluids given for resuscitation, or after some liquid has moved from the interstitium to the intravascular space. The most important intervention is to stop the acute bleeding and to immediately transfuse if the blood loss is life-threat- ening. The amount of packed RBCs to transfuse should be based on the amount of blood lost, and on the clinical response of the patient.

What is the Hemoglobin Concentration?

When there is no hemorrhagic shock, the hemoglobin concentration is the most

important marker to guide practitioners in the prescription of RBC transfusion. This

was confirmed by respondents to questionnaires addressed to intensivists working

with critically ill adults [1] and children [2, 3]. When asked at the bedside what

drove them to give a RBC transfusion, intensivists responded that the hemoglobin

concentration was the first element in their decision process [4]. Therefore, it makes sense to study what hemoglobin threshold should be used in critically ill patients, taking into account the severity of illness of the patient and the presence or absence of diseases like congenital cardiopathy or sickle cell anemia. A few studies have been published on hemoglobin concentration and what should be the right threshold for RBC transfusion, given the severity of illness and the disease of the patient [5].

What is the Severity of Illness?

A safe hemoglobin concentration in stable ICU patients

There is strong evidence that it is safe not to give RBC transfusion to critically ill children with a hemoglobin concentration between 70 and 95 g/l if they are hemody- namically stable (by stable, we mean that the mean arterial pressure is not less than two standard deviations below normal mean for age and that cardiovascular support has not been increased for at least two hours).

In 1999, H´ebert et al [6] published the Transfusion Requirements In Critical Care (TRICC) study, which involved critically ill adults who were randomized to a restric- tive or a liberal strategy (threshold hemoglobin of 70 and 90 g/l, respectively). The results of this clinical trial did not show any benefit with a higher transfusion thresh- old and, in fact, suggested a possibly increased risk with a RBC transfusion threshold of 90 rather than 70 g/l. An adjusted score estimating the severity of multiple organ dysfunction syndrome (MODS) was significantly lower in the restrictive group (p = 0.03). There were also more hospital deaths in the liberal than in the restrictive group (p ‹ 0.05). The incidence rates of intensive care unit (ICU) deaths and nosoco- mial infections were also higher in patients who received more transfusions.

In 2000, there were no available data on the safety of a restrictive or liberal RBC transfusion strategy in critically ill children. We therefore undertook the Transfu- sion Requirement In Pediatric ICU (TRIPICU) study, a multicenter, randomized, controlled non-inferiority clinical trial designed to determine whether a restrictive transfusion strategy is not inferior to a liberal transfusion strategy in usual clinical pediatric ICU practice when only pre-storage leukocyte reduced, packed RBC units are used. The hypothesis was that the risk of adverse outcome that can be caused by anemia in a restrictive strategy group (threshold for RBC transfusion: hemoglobin concentration of 70 g/l) would not be greater than the risk of adverse outcome attributable to more RBC transfusions in a liberal strategy group (threshold: 95 g/l).

We enrolled 637 stable critically ill children who had a hemoglobin concentration

below 95 g/l within 7 days after admission to the ICU. We randomly assigned 320

patients to a restrictive group and 317 patients to a liberal group. Hemoglobin con-

centrations were maintained 21 „ 2 g/l lower in the restrictive compared to the lib-

eral group (p ‹ 0.0001). The restrictive group received 54 % fewer RBC transfusions,

and 174 patients (54 %) received no RBC transfusion compared with 7 patients (2 %)

in the liberal group (p ‹ 0.0001). The number of patients who developed new or pro-

gressive MODS (primary outcome) was 38 (11.9 %) in the restrictive versus 39

(12.3 %) in the liberal group (absolute risk reduction: 0.4 %; 95 % confidence inter-

val: – 4.6 % to 5.4 %). There were 14 deaths (4.4 %) in each group within 28 days of

randomization. No differences were found in other outcomes. The conclusion of the

TRIPICU study was that a RBC transfusion threshold of 70 g/l in stable critically ill

children significantly decreased RBC transfusion requirements without increasing

adverse events when pre-storage leukocyte-reduced RBCs were used.

Some similarities and some differences between the TRICC [6] and the TRIPICU stud- ies [7] are striking. For example, the proportion of patients with two or more organ sys- tem failures was similar at baseline in the two studies: 31 % (257/838) in the TRICC study [6] and 37 % (233/637) in the TRIPICU study. Yet, there was a difference in the number of in-hospital deaths in the TRICC study (93 vs. 118, p = 0.05), but not in the TRIPICU study (14 vs. 14). Many explanations for this apparent discrepancy can be considered.

First, a regression to the mean or an alpha error are possible, but the results of the TRIPICU study are consistent and statistically significant. Second, the case-mix and the populations are different: the TRICC study involved critically ill adults, while the TRIPICU study included critically ill children. Adults may be more vulner- able to the adverse consequences of RBC transfusion. For example, it is possible that adults with coronary heart disease do not support anemia as well as other critically ill patients; atherosclerosis is rare in pediatric ICU patients. Another plausible expla- nation for difference in the adverse effects of transfusion is that RBC units were not pre-storage leukocyte-reduced in the TRICC trial [6], while they were in the TRI- PICU study [7]. Blood components with fewer than 5 × 10

white blood cells (WBCs) can be labeled as leukocyte reduced. More cytokines can be detected in older RBC units with a higher number of leukocytes [8 – 11]. There is some clinical evidence that leukocyte-reduction is effective in decreasing the incidence rate of inflamma- tory-related complications of RBC transfusion. The data from one randomized clini- cal trial suggests that leukocyte-reduction improves the postoperative outcome of some patients [12]. Implementation of pre-storage leukocyte-reduction as a stan- dard procedure was associated with reduction in bronchopulmonary dysplasia, reti- nopathy of prematurity, and necrotizing enterocolitis in premature infants [13], and of post-transfusion fever in older patients [14]. The TRIPICU study does not prove that pre-storage leukocyte-reduction decreases the risk of developing MODS in criti- cally ill patients because it was not designed to address this question, but it suggests that pre-storage leukocyte-reduction may be of some benefit in critically ill patients.

Lowest hemoglobin concentration in stable ICU patients

We can conclude from the evidence described above that it is safe not to give a RBC transfusion to stable critically ill patients if their hemoglobin concentration is higher than 70 g/l. Yet, one can ask, what is the lowest hemoglobin concentration that can be well supported by such patients (Fig. 1).

Fig. 1. In stable critically ill chil- dren, it is probably safe not to give a red blood cell (RBC) transfusion if the hemoglobin (Hb) concentration is higher than 70 g/l. Higher Hb concentrations are possibly required in children with cardiac disease.

The randomized clinical trial com- pleted by Rivers et al [24] sug- gested that it might be useful to keep the hematocrit over 30 % (Hb over 100 g/l) during the first six hours of resuscitation of unstable patients in severe sepsis or shock.

B: benefits; R: risks;

There is some evidence that severe anemia can be detrimental to critically ill patients. Oxygen delivery (DO

depends heavily on hemoglobin concentration, and there is a risk that severe anemia causes cellular dysfunction [15]. Anemia was associ- ated with a poorer outcome in the CRIT trial, a descriptive prospective study that included 4892 consecutive critically ill adults collected from 213 American ICUs [16]. A retrospective cohort descriptive study involving 1958 Jehovah’s Witness Patients showed that the odds ratio for mortality increased in adults with ischemic heart disease if their pre-operative hemoglobin contentration dropped below 100 g/l [17]. Another prospective descriptive study involving 300 Jehovah’s Witness patients showed that the odds ratio for mortality increased in healthy adults without ischemic heart disease if their post-operative hemoglobin concentration dropped below 40 g/l [18]. Three pro- spective studies run in Kenya involving respectively 2433 [19], 1223 [20], and 1269 [21]

hospitalized children showed that the risk of death was significantly higher if their hemoglobin concentration was lower than 50 g/l and if they did not receive a RBC transfusion; these children were not critically ill, but most of them had some respira- tory symptoms. In another clinical trial, 100 hospitalized, preterm infants were ran- domized either to a restrictive or a liberal group (three different threshold levels were considered in each group, the threshold being higher when patients were sicker); the risk of developing intraparenchymal brain hemorrhage or periventricular leukomala- cia and episodes of apnea was higher in the restrictive group [22].

RBC transfusions are frequently given to critically ill children if their hemoglobin concentration is low. A retrospective study undertaken in 240 critically ill children with a hemoglobin concentration e 90 g/l and conducted in five American pediatric ICUs showed that most pediatric intensivists would transfuse if the hemoglobin con- centration drops below 64 g/l [23]. In fact, all patients with a concentration e 53 g/l and 38 out of 41 with a concentration e 64 g/l received at least one RBC transfusion while only 33 of the 105 patients with a Hb concentration & 80 g/l were transfused.

Thus, severe anemia increases the risk of poorer outcome, at least in severely ill patients. The available evidence suggest that a RBC transfusion should be given if the hemoglobin concentration drops below 50 g/l. It is probably appropriate to do so if the hemoglobin concentration is between 50 and 70 g/l, but the evidence to sup- port this is not so strong. On the other hand, stable critically ill children do not require a RBC transfusion if their hemoglobin concentration is above 70 g/l.

Threshold hemoglobin concentration for RBC transfusion in sicker ICU patients

The randomized clinical trial by Rivers et al [24] in the emergency room of a univer-

sity-affiliated american hospital showed that a rapid ( ‹ 6 hours) protocol-driven

aggressive therapy with a specific goal decreased the mortality of adults with severe

sepsis and septic shock. The primary goal was to attain a central venous oxygen sat-

uration (ScvO

) greater than 70 %. The rationale was that providing enough DO

should prevent the appearance of more cellular insults in critically ill patients and

decrease the severity of organ dysfunction that could occur thereafter. In this ran-

domized clinical trial, standard treatment was compared to a protocolized approach

and all the following actions that could improve DO

and/or decrease oxygen uptake

(VO

) were considered: early endotracheal intubation and mechanical ventilation,

aggressive infusion of crystalloids and colloids (up to 80 ml/kg within six hours),

RBC transfusion to maintain the hematocrit over 30 %, inotrope administration

(dobutamine), and vasoconstrictive therapy (epinephrine, norepinephrine, dopa-

mine). The results were spectacular, with a mortality rate of 46.5 % in the standard

treatment group (133 patients) compared to 30.5 % in the ‘early goal-directed ther- apy’ group (130 patients, p = 0.009). The importance of maintaining the hematocrit above 30 % in this success story is unknown, but it might be substantial. Actually, Rivers [25] believes that critically ill patients should receive more aggressive treat- ment at the beginning, while less agressive therapy may be required once the patient becomes stable. There are no other data supporting such an approach, but it makes sense to treat anemia more aggressively in sicker patients until they improve. There- fore, it may be appropriate to keep the hemoglobin concentration over 100 g/l (hematocrit of 30 %) during the first hours of treatment of severely ill patients, while later on, a hemoglobin concentration of 70 g/l may be high enough to fulfill the oxy- gen requirements of stable patients.

Children with cardiac diseases

Myocardial protection may be the most important goal to attain in children with con- genital heart disease. Patients with impaired ventricular function cannot increase their cardiac output as efficiently as other patients. Moreover, even at rest, oxygen extraction by myocardial cells is elevated, which implies a lessened coping capacity when anemia occurs. Thus, increasing the hemoglobin concentration may be the only way to increase DO

and adequately support cardiac function in these patients.

The heart is clearly very sensitive to the hemoglobin concentration: Weiskopf et al [26] showed that the heart rate increases steadily in healthy adults at rest when hemoglobin concentration is decreased from 140 to 50 g/l. In healthy animals under- going acute hemodilution, evidence of heart dysfunction appears only once the hemoglobin concentration drops below 33 to 40 g/l [27]. However, animals with 50 % to 80 % coronary artery stenosis can show evidence of ischemic insult to the heart with a hemoglobin concentration as high as 70 to 100 g/l [28]. There is some evi- dence that prevention of organ dysfunction, including ‘myocardial protection’, with a higher hemoglobin concentration may be a good goal in adults with coronary dis- ease. A retrospective study involving 1475 adults showed that the risk of developping renal injury after coronary bypass surgery was higher if the hematocrit dropped below 24 % [29]. In adult patients with cardiovascular disease who refused blood products for religious reasons, Carson et al [17] showed that the risk of mortality after elective surgery increased significantly when the hemoglobin level dropped below 100 g/l whereas in healthy patients who accepted transfusion, the risk of mor- tality increased only with a hemoglobin concentration below 40 g/l [18].

Is it appropriate to apply these data to children? Coronary atherosclerosis is rare

in the pediatric population while it is the most frequent cardiovascular problem in

adults. In spite of this, it seems reasonable to hypothesize that anemia can cause

more damage to a sick heart. A randomized clinical trial reported that a lower

hematocrit (21.5 % vs. 27.8 %) during the cardiopulmonary bypass of pediatric car-

diac surgeries was associated with poorer neurodevelopmental outcome [30]. There

is almost no other evidence that higher hemoglobin concentrations protect children

with congenital heart disease. Nonetheless, many experts in pediatric cardiology

believe in maintaining elevated hemoglobin levels in children without cyanotic heart

disease and advocate levels of 120 – 130 g/l in neonates and 100 g/l in infants and

children [15]. Not surprisingly, a bedside survey showed that the hemoglobin con-

centration before RBC transfusion was indeed higher during the postoperative

period of cardiac surgery than for other patients in the pediatric ICU [31]. In spite

of this, experts in the United Kingdom advocate low hemoglobin thresholds of

70 – 80 g/l in stable children with non-cyanotic heart disease [32]. There is indeed almost no ‘hard evidence’ that ‘myocardial protection’ with higher hemoglobin con- centrations can be a good goal to direct therapy in children with cardiac disease.

Thus, given that definitive evidence describing the optimal hemoglobin threshold for transfusion is lacking, it seems reasonable to assume that critically ill children with non-cyanotic cardiac disease should be maintained at a hemoglobin concentra- tion above 70 to 100 g/l.

Equally unproven is the optimal hemoglobin concentration for children with cya- notic heart disease. Many textbooks in pediatric cardiology and pediatric cardiac sur- gery advocate elevated hemoglobin levels and several recommend specific thresholds that range from 100 to 180 g/l [15]. In fact, there are no good clinical studies that ade- quately address the question. A case series that included seven children with cyanotic congenital heart disease reported a decreased right to left shunt when increasing the hemoglobin concentration from 130 to 164 g/l; the authors specifically attributed the benefit seen to the decreased shunt and did not think that the benefit could be attrib- uted to an increased VO

[33]. Interestingly, experience with bloodless surgery for complex cyanotic defects suggests that cardiac surgery can be safely performed with a lower concentration of hemoglobin without evidence of increased risk. Thus, as stated by Beekman and Tuuri in 1985 [33], it is still true in 2007 that “the optimal hemoglobin concentration for children with cyanotic heart disease has yet to be determined”. Pres- ently, it seems appropriate to consider a hemoglobin level above 100 or 120 g/l as rea- sonable for hemodynamically stable children with a cyanotic heart disease.

Other determinants should be considered in critically ill children with cardiac diseases. For example, in a prospective cohort study of 548 children undergoing car- diac surgery, RBC transfusions were more frequent not only when the preoperative hematocrit was considered low, but also in younger patients, if the surgery was com- plex, and with longer duration of hypothermia [34].

In summary, the optimal hemoglobin concentration in critically ill children with cardiac diseases is not well defined. Good clinical studies are required before any strong statements can be promoted about when these patients should receive a RBC transfusion.

Other diseases

There is good evidence supporting the point of view that a high hemoglobin concen- tration (above 90 or 100 g/l) is required in critically ill children with sickle cell dis- ease [35, 36]. This may be true for other diseases, but hard data on this are lacking.

Other Factors that may Modulate Decisions about RBC Transfusion

Determinants other than the hemoglobin concentration can modulate the decision to prescribe a RBC transfusion in pediatric ICU [2, 3], as confirmed by two studies

1

study: An observational cohort study that included 303 children consecutively admitted to an academic pediatric ICU reported that 45 children (15 %) received between 1 and 33 RBC transfusions, for a total of 103 transfusions. The stated rea- sons for administering a RBC transfusion included not only a low hemoglobin con- centration, but also the presence of respiratory failure (84/103), active bleeding (67/

103), hemodynamic instability (50/103), blood lactate level 8 2 mmol/l (10/103) or

sub-optimal DO

(6/103) [4].

Fig. 2. Algorithm for RBC transfusion in critically ill children. In stable patients, RBC transfusion is usually mandatory if the hemoglobin (Hb) concentration is lower than 50 g/l (definition of ‘stable’: the mean arte- rial pressure is not less than two standard deviations below normal mean for age and cardiovascular sup- port has not been increased for at least two hours). A RBC transfusion is probably useful if the Hb concen- tration is between 50 and 70 g/l; It makes no difference if the Hb is between 70 and 95 g/l. A transfusion may be detrimental if the Hb concentration is higher than 95 g/l. These thresholds for transfusion are probably different in unstable patients and in patients with cardiac disease. The right threshold Hb concen- tration for RBC transfusion in patients with other conditions, like some hemolytic anemias, is not well determined. B: benefits; R: risks;

2

study: In a prospective cohort study of 985 consecutive pediatric ICU admissions at Sainte-Justine Hospital, the four most significant determinants of a first RBC transfusion included not only the presence of anemia (defined by a hemoglobin level

‹ 95 g/l) during the pediatric ICU stay (13.26; 95 %CI: 8.04 – 21.88; p ‹ 0.001), but also an admission diagnosis of cardiac disease (8.07; 95 %CI: 5.14 – 14.65; p ‹ 0.001), an admission Pediatric risk of Mortality (PRISM) score 8 10 (4.83; 2.33 – 10.04;

p ‹ 0.001) and the presence of MODS during the pediatric ICU stay (2.06; 95 %CI:

1.18 – 3.57; p = 0.01) [31].

These studies show that many host-related and disease-related characteristics, as

well as the hemoglobin concentration, account for the practice pattern variability

observed in pediatric ICUs with respect to RBC transfusion. For pediatric intensi-

vists, it seems generally that more severe illness requires a lesser tolerance of anemia

in order to insure adequate DO

. Yet, it is essential to obtain solid evidence on this

subject because it is unclear what degree of anemia, what severity of illness, what

type of disorders, and what specific goals should dictate therapy with RBC transfu-

sion.

Conclusion

‘Goal-directed therapy’ can improve the outcome of critically ill patients. Rivers et al [24] showed that early goal-directed aimed at keeping ScvO

g/eater than 70 % improves the outcome of patients with severe sepsis or septic shock. Van den Berghe et al [37] showed that tight blood glucose control between 4.44 and 6.1 mmol/l (80 – 110 mg/dl) improves the outcome of critically ill patients.

The concept of goal-directed therapy can be applied to blood transfusion medi- cine. However, what goal to use is still a matter of debate. Many ‘goals’ have been suggested in the literature, such as mixed venous oxygen saturation (SvO

), blood lactate level, DO

and/or VO

; none has been validated [38]. Currently, maintaining the hemoglobin concentration above a given threshold and taking into account the severity of illness and the etiologic disease remain the most reliable determinants of RBC transfusion in critically ill children.

In Figure 2, we propose an algorithm for RBC transfusion in pediatric ICU; three questions should be addressed:

1. The first question concerns the presence or absence of hemorrhagic shock.

2. The second question asks if the patient is stable or not, whether he/she is severely ill, and whether he/she presents some specific disease.

3. The third question concerns the hemoglobin concentration.

A large randomized clinical trial [7] suggests that a hemoglobin concentration between 70 and 95 g/l is safe in most stable critically ill children if pre-storage leuko- cyte reduced packed RBC units are used. Some published data suggest that a trans- fusion is probably required in pediatric ICU patients if their hemoglobin concentra- tion is lower than 70 g/l, and that it is mandatory if their hemoglobin concentration is lower than 50 g/l. Higher thresholds are probably appropriate in more severely ill patients (for example, patients in shock) and in patients with cardiac disease, but more investigations are required before any strong recommendations can be made in such instances.

There is evidence that algorithm-driven prescription of RBC transfusion can decrease the number of transfusions given to critically ill adults [39]. The efficacy, the safety and the usefulness of the flow chart suggested in figure 2 remain to be determined by prospective studies; meanwhile, it makes sense to base the decision to give RBC transfusion to critically ill children on the available evidence, as is done in this figure.

Acknowledgement: The research program of our group on blood product transfu- sion is supported by the Canadian Institutes of Health Research (Grants #84300 and

#130770), the Canadian Blood Bank Services, the Fonds de la Recherche en Sant´e du Qu´ebec (Grants #3348 and #3568), and H´ema-Qu´ebec.

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