Anemia and Risk of Hospitalization in Pediatric Chronic Kidney Disease

Anemia is a common complication of chronic kidney disease (CKD), and is largely due to a decrease in erythropoietin production. In both pediatric and adult cases of CKD, anemia is associated with an increased risk of hospitalization and mortality. Several large observational studies in adults have shown that irrespective of dialysis status, CKD patients have lower mortality and morbidity when higher hemoglobin (Hb) levels are achieved. However, the results of randomized, controlled interventional trials in these populations suggest that targeting higher Hb levels may be associated with an increased risk of adverse outcomes. Little is known about the relationship between achieved Hb levels and outcomes in pediatric patients with CKD. Thus, a recent study by Staples et al assessed the prevalence of anemia in children with predialysis CKD, and described the association between anemia and morbidity (hospitalization).

The retrospective cohort study included 2,779 patients (aged 2-20 years) with CKD that were enrolled in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). Patients were categorized by disease severity into one of five stages (I-V) of CKD based on glomerular filtration rate; anemia was defined by a hematocrit <33%. The study’s primary outcome was hospitalization during the 1-year follow-up period after enrollment.

Overall, the prevalence of anemia increased from 18.5% in CKD stage II to 68% in CKD stage V, and more anemic patients were hospitalized than nonanemic patients. After adjusting for a variety of factors such as erythropoietin use, race, height, and albumin, statistical analysis revealed that anemic patients were 55% more likely to be hospitalized than were nonanemic patients. Finally, patients with a hematocrit above 36% did not have an increased rate of hospitalization, nor did patients who underwent a complete correction of anemia.

The results of this study underline important issues regarding the potential care of pediatric CKD patients who are not on dialysis. However, the NAPRTCS database is a voluntary registry, and thus a significant number of pediatric CKD patients may not be enrolled. Furthermore, many patients were excluded from the study because of missing data or failure to follow-up. These limitations allow focus on only a specific cohort of patients that may not be generalizable to the overall pediatric CKD population. Such studies are clearly hypothesis generating and suggest that future controlled, interventional trials should focus on the effects that correction of anemia has on hospitalization rates, quality of life, and other outcomes in this patient population.

Staples AO, Wong CS, Smith JM, Gipson DS, Filler G, Warady BA, Martz K, Greenbaum LA. Anemia and Risk of Hospitalization in Pediatric Chronic Kidney Disease. Clin J Am Soc Nephrol. 2008 Dec 3.

NAAC Expert Commentary:
Anemia is highly prevalent in adult patients with CKD, but the prevalence and consequences are less well documented in pediatric patients. This is particularly important since nephrologists have effective tools to treat this condition, including erythropoiesis-stimulating agents and oral and parenteral iron. The current study adds significant new information to help us better understand the association of anemia and outcomes in younger patients. It is clear that those children with lower Hb levels have increased morbidity, as measured by hospitalizations. While of considerable interest, this study should be considered hypothesis generating, rather than definitive. As the authors point out, future studies need to be prospective, controlled, and interventional. Additional key outcomes need to be evaluated, such as mortality, and other factors that are unique to this population such as growth and development. The authors should be congratulated for conducting and reporting a rigorous analysis of a growing administrative database, and the renal community should urge support for more rigorous studies in pediatric CKD patients in the future.

Blood Transfusion and Anemia Management in Traumatic Brain Injury

Although liberal blood transfusion has become a standard means of treating anemia in brain-injured intensive care patients, recent data has shown that transfusion could be associated with increased mortality and composite complications including multi-organ failure. The findings in this article are of particular interest in the management of traumatic brain injury (TBI), since they focus on anemia and transfusions. A previously published study showed that transfusion was associated with increased brain oxygenation, while other studies demonstrated the opposite effect of transfusion, i.e. reduced oxygenation. As for anemia, some studies showed that a lower Hb level was associated with improved outcomes and other studies showed negative effects of anemia on TBI patients. In view of these mixed results, a recent retrospective study examined the effect of anemia in TBI patients, hypothesizing that blood transfusion would lead to favorable outcomes.

Over the 7-year study period, Hb levels and transfusions were recorded for 1,150 patients with TBI. Of these patients, 46% were anemic (defined as Hb level <9 g/dL) at some point during their first week of admission. This group experienced significantly more complications than that of nonanemic patients. Of the anemic group, 76% received blood transfusions during their first week. Transfusion in this group was associated with more complications and a higher mortality rate than patients who were not transfused. The impact of anemia in the transfused patients was silent but when the transfusion factor was excluded in a logistic regression models, anemia emerged as a significant risk factor for both mortality and complications. In addition, higher risks for mortality and complications were observed with increasing amounts of blood transfused.

Both anemia and transfusion were shown to be independent risk factors for adverse events and mortality. The authors recommend that both anemia and transfusion should be assessed together in TBI patients since in some subgroup the risk of anemia may overshadow that of transfusion. In terms of administration, transfusion may best be reserved for TBI patients on an individualized basis, in which the choice to use transfusions is based on physiologic indications, rather than a achieving a specific Hb threshold. Based on their findings the authors recommended that liberal transfusion policies in TBI patients be abandoned and more studies should be performed to address outcomes in this population.

Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, Margulies DR. Role of anemia in traumatic brain injury. J Am Coll Surg. 2008 Sep;207(3):398-406.

NAAC Expert Commentary:
Trauma patients represent a complex array of physiologic derangements and multiple confounders making them a difficult population to study. High prevalence of early mortality in the severely injured represent the select population that may benefit from specific interventions. Despite this, those who survive may still have severe injuries and continue to bleed, resulting in significant anemia. TBI patients represent more of a challenge since for any trauma patient, brain injury places them at a high risk, if not the highest. In an attempt to achieve the best possible outcomes, high Hb levels were (and still are) targeted as treatment with little or conflicting evidence.

This well conducted retrospective study (although suffering form no control group), analyzed the TBI patients by grouping them into anemic versus nonanemic, transfused and nontransfused cohorts. Although there were many confounders, transfusion for the anemic and nonanemic remained an independent factor associated with negative outcomes, including renal failure and mortality. The most common reason for transfusion in this study was hemorrhage and anemia. Management of hemorrhage is still dominated with transfusion support but options for treatment of anemia other than transfusion are available. This study demonstrates that anemia is detrimental (independent risk factor for negative outcome) and that transfusion therapy for anemia compounds the problem. Therefore, reassessment of any transfusion decision is sorely needed and slowly gaining acceptance.

As the authors suggest, more studies are needed to determine if a TBI subpopulation exists, which might still benefit from transfusion, and determine if transfusion would attenuate the negative outcomes associated with anemia. Moreover, other treatment modalities for anemia need to be studied to determine whether negative effects of anemia can be reversed, leading to improvement in morbidity and mortality rates.

Exploring Anemia Management Strategies in the Pediatric ICU

Anemia of critical illness – stemming from blood loss, underlying disease, and treatments causing bone marrow suppression – is common in children admitted to the pediatric intensive care unit (PICU). Although red blood cell (RBC) transfusion is a standard treatment for critically ill children, infections, lung injury, hemodynamic compromise, and immunosuppression are possible side effects of this therapy. Despite the potential seriousness of these risks, no multicenter data exists on anemia and transfusions in the PICU. Therefore, a recent study by Bateman et al focused on PICU interventions, such as blood conservation protocols and erythropoietin therapy, to assess the epidemiology of anemia and RBC transfusion in children with extended PICU stays.

To achieve this, the authors designed a multicenter, prospective observational study taking place in 30 PICUs in the United States and Canada. A total of 977 children <18 years of age, were consecutively enrolled from September 8, 2004 through March 29, 2005. The authors note that although this group of children represents only about 20% of PICU admissions, these patients account for a disproportionate use of PICU resources. The authors, therefore, specifically sought to capture outcomes and complications associated with transfusion therapy in this group. In total, 49% of children received one or more RBC transfusions during their stay, with 6% receiving transfusion after discharge.

To examine the effect of transfusion on outcome, the study compared complications that occurred on day three or later in two groups: those transfused on PICU day 1 or day 2 (N=363) and those with no transfusions during their PICU stay (N=494). Children in the transfused group were characterized by (1) higher rates of anemia on PICU admission, (2) higher severity of illness (PRISM III) score, (3) higher daily average blood loss, (4) greater likelihood of shock, (5) more surgical procedures, and (6) greater frequency of cardiovascular disorders. In addition, the transfused group was younger in comparison to the non-transfused group. Logistic regression analysis was used to compare the odds of complications for those who did or did not undergo transfusion. The group receiving transfusion had an increased risk of death and cardiac arrest (odds ratio 20.0; 95% CI 2.6 - 166.7); a higher rate of nosocomial infections (OR 1.9; 95% CI 1.2 - 3.0); and more cardiac and respiratory dysfunction (OR 2.1; 95% CI 1.5 - 3.0). Also, children receiving transfusion experienced longer overall stays in the PICU (9.3 vs. 7.5 days), and 12 of 15 deaths occurred in children who received four or more transfusions. No further details about the deaths were provided. However, it raises the question as to whether transfusion is a marker for rather than an initiator of poor outcome.

Since transfusions (74%) predominantly occurred within the first 48 hours of the PICU stay, this study provides evidence against the efficacy of erythropoietin administration and emphasizes the need for a greater focus on blood loss prevention. Indeed, the authors emphasize that blood loss from blood draws accounted for the majority of total blood loss occurring during the PICU stay in all age groups. The authors also emphasize that anemia, especially those with hemoglobin levels <5 g/dL, represents an independent risk factor for death in children. They suggest, as have other studies, that a reasonable transfusion threshold be <7 g/dL of hemoglobin in otherwise stable children. Clinical variability and severity such as the presence of shock and cardiovascular disease may require a higher transfusion threshold. Importantly, the high incidence of death among children who received four or more transfusions warrants further studies to establish effective guidelines for transfusion strategies.

Bateman ST, Lacroix J, Boven K, Forbes P, Barton R, Thomas NJ, Jacobs B, Markovitz B, Goldstein B, Hanson JH, Li HA, Randolph AG; Pediatric Acute Lung Injury and Sepsis Investigators Network. Anemia, blood loss, and blood transfusions in North American children in the intensive care unit. Am J Respir Crit Care Med. 2008 Jul 1;178(1):26-33.

NAAC Expert Commentary:
One of the major uncertainties in the field of transfusion medicine emphasized during this decade has been how to optimize the use of transfusion therapy to maximize clinical utility and minimize adverse impact. The study by Bateman et al places further scrutiny on this dilemma. They note that although anemia is common in PICU patients, little is known about its etiology and the use and efficacy of transfusion therapy. The authors add that the majority of blood loss in PICU patients is due to phlebotomy. They also note that several complications, including death, cardiac arrest, and nosocomial infections are more common in the transfused group. However, this study is not designed to prove whether transfusion causes these complications or whether use of transfusion, especially multiple units, is a marker for sicker children. It is clear, based on the information in this paper, and until further studies are forthcoming, that efforts should be made to reduce blood draws to a minimum and to use blood transfusion therapy judiciously.