Anemia is common in pediatric and adult patients with heart failure (HF) and has also been associated with the need for ventricular assist device (VAD) implantation.1–3 Furthermore, anemia has been recognized as a continued comorbidity in adult patients after VAD implantation, even in the setting of improving end-organ function.4 In adults, VAD-related anemia has been reported as a risk factor for decreased long-term survival.4
Iron deficiency is the most common etiology of anemia seen in adults with chronic HF.2,5 Iron deficiency may be due to poor nutritional intake or absorption in these patients. The prevalence and characteristics of anemia or iron deficiency in pediatric HF patients receiving mechanical circulatory support (MCS) from a VAD are not known. The impact or success of iron therapy in children with HF has also not been reported.
We examined our cohort of pediatric patients on durable VADs. Our aims were as follows: 1) to assess the frequency of anemia and iron deficiency in pediatric HF patients on durable VADs (including EXCOR—Berlin Heart Gmbh, Berlin, Germany, HVAD—HeartWare, Framingham, MA, or HeartMate II LVAD—Thoratec Corporation, Pleasanton, CA); and 2) to compare the frequency and characteristics of anemia between the cohort of patients on pulsatile VADs (P-VADs: EXCOR—Berlin Heart) and continuous-flow VADs (CF-VADs: HVAD—HeartWare or HeartMate II LVAD—Thoratec). We hypothesized that 1) anemia is common in pediatric VAD patients; 2) iron deficiency is common in VAD patients; 3) anemia is more common in P-VAD patients; and 4) VAD patients with anemia have higher allosensitization over time possibly related to volumes of packed red blood cell (pRBC) transfusions.
We included all patients <21 years of age placed on either a P-VAD or CF-VAD for at least 7 days at Texas Children’s Hospital from February 2006 to February 2015. Institutional Review Board approval was obtained. Demographic and clinical data were collected from the electronic medical records and retrospectively reviewed. Red blood cell (RBC) indices were collected and evaluated at four time points: 1) before device implantation; 2) within the first 24 hours of device implantation; 3) at the end of iron therapy; and 4) in last 24 hours before explant, death, or at most recent follow-up. The assessment before device implantation reflects the hematologic indices in a patient with severe HF needing impending MCS. The 24 hour postimplant hemoglobin time point was chosen to minimize the influence by intraoperative blood loss and initial postoperative fluctuations of hemoglobin and was a value that was consistent up to 72 hours later. This was also used as the baseline “implant” values of the patients on MCS and to assess the variation in hematologic indices over the course of device implantation. Iron deficiency indices were collected and evaluated at three time points: 1) before iron therapy; 2) within 2 weeks after completing exogenous iron administration; and 3) just before VAD explant, death, or at most recent outpatient follow-up. The iron deficiency indices before iron therapy were all also within 4 weeks of VAD implantation. Renal function was assessed by serum urea and creatinine levels, recording values on the day of implant and on the day of explant.
Anemia and severe anemia were defined using hemoglobin criteria per World Health Organization (WHO) guidelines adjusted for gender and age.6 Anemia was categorized as microcytic, normocytic, or macrocytic, using age-appropriate values for RBC volume. Iron deficiency was defined by the presence of at least two of the following four criteria: 1) serum iron less than 50 μg/dl; 2) ferritin less than 20 ng/ml; 3) transferrin more than 300 ng/ml; and 4) transferrin saturation less than 15%.
One milliliter of pRBC transfusion is equivalent to 1 mg of administered elemental iron.7 To account for the confounding influence of pRBC transfusions, the volume of pRBCs transfused during the period of VAD implantation (excluding intraoperative pRBC transfusions) was obtained from the Blood Bank Data Repository. The indications for blood transfusion were practice dependent, based on hematocrit less than 30% and other clinical features such as postoperative blood loss, hemodynamics, and patient symptoms. Data about supplemental iron administration, from multivitamin tablets, iron supplements, or intravenous iron, were also collected. Total elemental iron administered over the course of the VAD support was normalized for body weight at the time of VAD implant over 90 days. The recommended iron replacement therapy (IRT) dosing is 2–6 mg elemental iron/kg/d for 90 days.8,9 The data on blood transfusion volumes and IRT were also compared between P-VADs and CF-VADs. Allosensitization was assessed based on levels of panel reactive antibodies (PRAs), evaluated at the time of implantation, at 1 month postimplantation, and 3 months postimplantation.
Statistical analysis was performed using SPSS 22.0 software (IBM SPSS Statistics, Armonk, NY). Descriptive statistics included frequencies and proportions, or medians and interquartile ranges (IQRs) where appropriate. Univariable analysis was performed to test strength of association of predictor variables with outcomes, using χ2 test or nonparametric Kruskal–Wallis testing as statistically appropriate.
Seventy-six VAD implants in 74 patients met inclusion criteria: 45 P-VADs and 31 CF-VADs. Two patients were supported by VAD in two encounters. Baseline patient characteristics are summarized in Table 1. Continuous-flow VAD patients were older and had longer durations of VAD support. This is consistent with our clinical practice, as the P-VADs are generally implanted in younger and smaller patients, with these patients remaining in the hospital until recovery or transplant. There were no significant differences in the gender or ethnicity distributions nor the underlying etiology leading to HF between the cohorts. Pulsatile VAD patients were more likely to be interagency registry for mechanically assisted circulatory support (INTERMACS) stage 1 or 2 at the time of VAD implant, whereas a majority of the CF-VAD patients were INTERMACS stage 2 or 3. The P-VAD cohort had a higher proportion of patients needing extracorporeal membrane oxygenation (ECMO) support before transition to durable VAD (26.7% in P-VAD versus 9.7% in CF-VAD); however, this difference did not achieve statistical significance (p = 0.067). Most patients in each group had their VAD explanted at the time of transplant. At the time of analysis, six CF-VAD patients were being managed as outpatients.
Hematologic Characteristics at the Time of Ventricular Assist Device Implant
The hematologic laboratory findings of the patients are summarized in Table 2. Blood cell counts were not available on one patient in the P-VAD group. Overall, 50.7% (38/75) of the patients were anemic before VAD implantation, similar between CF-VAD and P-VAD groups. Further, 48% (36/75) of the patients were anemic at 24 hours post-VAD implant, with a higher prevalence in CF-VAD patients (67.7% vs. 34.1%; odds ratio (OR), 4.06; 95% confidence interval [CI], 1.53–10.79). None of the patients had microcytosis on peripheral smear. Iron deficiency at VAD implant was seen in 52% (39/75) of patients, as assessed by iron deficiency studies performed within 4 weeks of implantation. Iron studies at implantation were not available for two patients on CF-VAD support. The prevalence of iron deficiency was similar in both groups. The median values of serum iron, ferritin, transferrin, and transferrin saturation at implantation were also similar between the groups. Furthermore, there was no significant difference in the mean corpuscular volume (MCV) (mean [standard deviation]) of patients with or without iron deficiency (83.55 [3.62] vs. 84.65 [3.66], respectively; p = 0.203). There was no significant difference between the VAD cohorts regarding elevated lactate dehydrogenase (LDH) or plasma-free hemoglobin levels that would indicate hemolysis.
Renal dysfunction was assessed by estimating glomerular filtration rate (GFR) at the time of implant as well as at the explant based on the blood urea and creatinine concentrations. Serum markers of chronic kidney dysfunction or markers of decreased erythropoietic activity were unavailable. Overall, 54.7% (41/75) patients had decreased renal function at the time of implant, with a greater frequency in CF-VAD group (77.4% vs. 38.6%; OR, 5.44; 95% CI, 1.929–15.373). There was no association of anemia at 24 hours after VAD implant with preexisting renal dysfunction in P-VAD group (p = 0.603). However, in the CF-VAD group, anemia at 24 hours after VAD implant was associated with preexisting renal dysfunction, with 79.2% (19/24) of the patients with renal dysfunction being anemic when compared with 28.6% (2/7) of those with normal renal function (p = 0.022; OR, 9/5; 95% CI, 1.403–64.346).
Hematologic Characteristics at the Time of Ventricular Assist Device Explant
At explant, 70.67% (53/75) overall had anemia. The prevalence of anemia was similar in both groups. However, the patients on P-VAD had a greater risk of conversion to anemia over the course of the VAD duration (OR, 0.35; 95% CI, 0.125–0.98; p = 0.053). This is also consistent with the finding that patients on P-VADs had a lower median hemoglobin at the time of explant, given that they are a younger population than the CF-VAD patients, and have a higher value of normal ranges of hemoglobin.
Renal dysfunction was present in 26.7% (20/75) of the patients overall at the time of VAD explant, which was significantly lower than the prevalence at the time of implant (p = 0.033; OR, 3.35; 95% CI, 1.068–10.486). The prevalence of renal dysfunction at explant was higher in the CF-VAD group (38.7%, 12/3) when compared with the P-VAD group (18.2%, 8/44), with the p value approaching significance at 0.048 (OR, 2.84; 95% CI, 0.991–8.148). Renal dysfunction at the time of VAD explant was not associated with anemia in the P-VAD (p = 0.082) or CF-VAD group (p = 1.000).
Hematologic Characteristics After Supplemental Oral/Intravenous Iron
Characteristics of IRT and the hematologic characteristics after IRT in the study cohort are summarized in Table 4. Ten iron-deficient P-VAD patients received oral iron in the form of multivitamins or iron supplements. Ten iron-deficient CF-VAD patients received IRT—nine in the form of oral supplements/multivitamins and one as intravenous iron dextran. Of these, only one P-VAD patient and three CF-VAD patients received oral/intravenous iron at an adequate dose recommended for goal IRT (2–6 mg elemental iron/kg/d × 90 days). When comparing all subjects, there was no difference in the dosing of iron between cohorts.
Follow-up iron studies were available on six patients only (two P-VADs, four CF-VADs). After IRT, there was no significant change in the median hemoglobin, MCV, serum iron, ferritin, transferrin, and transferrin saturation (Tables 3 and 5). The levels of hemoglobin, iron, ferritin, transferrin, and transferrin saturation were similar among the two cohorts as measured after the last dose of IRT. When comparing only the four patients who received goal IRT, two of the CF-VAD patients were still anemic after the recommended “adequate” therapy, and one of these was still iron deficient.
Burden of Packed Red Blood Cell Transfusion
Pulsatile VAD patients received higher volumes of pRBC transfusions when standardized in ml/kg/d over the course of the VAD implantation (p < 0.001) (Table 4). When taking into account the iron administered through pRBC transfusions, the elemental iron administered in mg/kg/d was higher for the P-VAD group (p < 0.001). Thirty-nine patients received a volume of pRBC transfusions over duration of VAD support which alone accounted for elemental iron supplementation equivalent to goal IRT. There was no association of anemia or iron deficiency at implant with blood transfusion volumes (p = 0.178 and 0.272, respectively).
Progression of Anemia Over Course of Ventricular Assist Device Support
Twenty-seven patients were anemic at the time of explant, but not at implant. When comparing the median hemoglobin at the time of explant with the median hemoglobin at the time of implant, there was a significant drop in hemoglobin for the P-VAD group, but no significant change for the CF-VAD group (Table 5). There was no significant association of development of anemia over course of VAD implant with underlying cardiac diagnosis or preexisting iron deficiency. In addition, there was no significant association of mortality with anemia or iron deficiency at the time of implant, with mortality in P-VAD or CF-VAD cohorts (Table 6).
There was no significant change in the PRA levels (class I or class II) at 1 month and 3 months of post-VAD implantation in the CF-VAD group (p > 0.1) (see Supplement Table, Supplemental Digital Content, http://links.lww.com/ASAIO/A224). In the P-VAD group, the class I PRA levels at 1 month and 3 months were successively trending higher (p = 0.05 and p = 0.05), but there was no significant change in the class II PRA. There was no association of change in PRA levels with anemia or iron deficiency. There was no correlation between change in PRA levels and transfusion volumes.
Changes Over the Duration of Study
To assess the impact of time of VAD implantation, we divided the cohort into VADs implanted from 2006 to 2010, and those implanted from 2011 to 2015. There was no significant difference in the distribution, weight, or ages of P-VADs and CF-VADs before or after 2010 (Table 1, data not shown). Although the patients with P-VADs implanted 2011–2015 were more likely to be supported on ECMO initially (41.7% vs. 9.5%; p = 0.015), there was no difference noted in CF-VAD cohort. There was no significant difference between the groups regarding the distribution of patients among the INTERMACS stages in the P-VAD or CF-VAD cohorts (data not shown). Evaluation of hematologic indices demonstrated that patients with P-VADs implanted 2011–2015 had a similar frequency of anemia or iron deficiency at implant; however, they were more likely to become anemic at VAD explantation than their counterparts from 2006 to 2010 (83.3% vs. 55.0%; p = 0.040). In contrast, there was no significant difference in the CF-VAD group in the frequency of anemia or iron deficiency at the time of implant or explant, either before or after 2010.
Little is known about the prevalence of anemia and iron deficiency in pediatric HF patients on VAD support. Previously, our center reported the prevalence of anemia in children presenting in acute decompensated HF.3 Forty-six percent of children who died or needed transplant/MCS, and 33% of those who survived and did not need transplant/MCS were found to be anemic.3 In this study, almost 50% of patients were anemic at the time of VAD implantation with a significantly higher prevalence of anemia in CF-VAD patients. This finding in the CF-VAD patients may possibly be attributed to a higher intraoperative transfusion threshold, or greater clinical stability postoperatively, thereby able to be managed with a higher threshold for transfusion.
We were unable to demonstrate improvement in anemia after VAD support, even in the setting of improving end-organ function. Almost 71% of patients were anemic at the time of VAD explant, which was higher than at implant. Adult studies have shown that anemia is a significant morbidity in VAD patients and is independently associated with higher rates of readmissions and poorer survival.4,10 In this study, we did not find an association of anemia with mortality in either of our cohorts. However, this difference may be due to smaller sample size of this population.
Furthermore, the significant pRBC transfusion volumes may also be masking the true prevalence of anemia in this cohort and the morbidities associated with it. Although we had a higher prevalence of anemia in our CF-VADs at baseline, over the course of the VAD support, progressive development of anemia was higher in the P-VAD group, which incidentally also received significantly higher volumes of pRBC transfusions. The hematologic indices at explant reflect the impact of these blood transfusions on the anemia. The high prevalence of anemia at the time of explant in spite of these blood transfusions indicates that the etiology of this anemia merits investigation, especially as iron deficiency would be a highly suspected and highly treatable cause.
We found that the prevalence of renal dysfunction seemed to improve over the course of VAD support. However, the prevalence of anemia was significantly greater at explant, and renal dysfunction at explant was not associated with anemia at the time of explant. This may not be unusual; Nassif et al.11 have shown no significant association between lower levels of erythropoietin and anemia in adults with a VAD.
About 53% of our patients were iron deficient at the time of VAD implantation, with no difference in iron deficiency indices between P-VAD and CF-VAD cohorts. Much of the previously published literature on iron deficiency and its impact on outcomes is from ambulatory adults in chronic HF.2,12,13 Lower serum iron levels have been shown to be associated with higher cardiovascular and all-cause mortality, frequent readmissions, and poorer functionality in adults with chronic HF.2,12 However, we were unable to find any association of iron deficiency with mortality in our patients, perhaps accounting for the differences in comorbid conditions between adult and pediatric VAD recipients.
Microcytosis is used as a surrogate marker for iron deficiency. However, none of our patients had microcytosis, not even the ones with definite iron deficiency on serum testing. This may reflect the burden of pRBC transfusion in this population, making MCV measurements unreliable. It may also reflect coexistent micronutrient deficiency (i.e., vitamin B12 deficiency, folate deficiency), which may result in normocytosis. The absence of microcytosis suggests that specific iron studies are essential to detect iron deficiency in this population.
Transfusions of platelets- and leukocyte-containing blood products have been shown to be risk factors for development of allosensitization.13 Leukocyte-reduced pRBC transfusions are not typically considered to impart additional risk of increased allosensitization.14,15 Concordant with these reports, we did not find an impact on PRA levels with volumes of blood transfusions. We also did not find any association of anemia or iron deficiency with a significant change in PRA over time. Appropriate treatment of anemia and iron deficiency at the front end before and during VAD implant are relatively risk-free interventions that may help limit pRBC transfusions.
Iron deficiency can be treated with iron supplementation in the form of oral iron (ferrous sulfate, ferrous fumarate, and ferrous gluconate) or intravenous iron (iron dextran, ferric carboxymaltose). There is inconsistent recognition and treatment of iron deficiency, especially in the absence of anemia, in the VAD population. The absence of microcytosis, a familiar surrogate for iron deficiency anemia, often leads to variation in interpretation of testing and the necessity to treat. In our cohort, we had a small number of patients who received oral/intravenous iron, of whom only four received goal IRT. One of the CF-VAD patients received intravenous iron in addition to oral iron; however, this was the only patient among our cohort who received parenteral iron supplementation. Among the four who received appropriate therapy (three oral and one both oral and intravenous), two patients continued to remain iron deficient after therapy. Although these numbers are too small to make any conclusions, the question arises whether the “recommended” dose of oral iron is adequate treatment for iron deficiency in the pediatric VAD population, and whether parenteral formulations may be more efficacious in these patients.
Management of iron deficiency is already challenging in the general pediatric population, and this is amplified in children on VAD support.16 Oral iron therapy is challenging because of its side effect profile, potentially limited absorption in patients with HF, and poor compliance with multiple daily dosing.16 Furthermore, the perceived risks of anaphylaxis with parenteral iron cause hesitation among cardiologists. Newer alternatives to iron dextran, like iron sucrose and ferric carboxymaltose, are shorter infusions with lower theoretical risk of anaphylaxis.
Limitations and Future Directions
Our study was limited by the retrospective nature of the data collection and analysis from a single center. We did not have serial iron studies on many of our patients. Markers of decreased erythropoiesis or measures of other micronutrient deficiencies were not obtained, another potential source for anemia in this population.
Our hematologic criteria were adjusted for age and gender; however, pRBC transfusion load is affected by provider discretion and individual (variable) target hemoglobin goals. We do not currently have a standardized protocol to guide transfusion at a specific hemoglobin threshold. The increased rate of development of anemia over the course of VAD implantation in the P-VAD group, coupled with the higher pRBC transfusion volumes in this group, suggests that low or dropping hemoglobin levels may have been a driving factor for transfusion in this population. Patients on P-VAD were also younger, and hence providers may have had a more conservative threshold for transfusion. The P-VAD patients were also more likely to be at a more decompensated INTERMACS stage at the time of implant, and hence may have received more liberal transfusions to maximize their oxygen carrying capacity. The P-VAD protocol at our institution involves frequent phlebotomy for close monitoring, resulting in greater iatrogenic blood losses. It is difficult to quantify iatrogenic blood losses in a retrospective fashion. There were relatively small numbers of CF-VAD patients in this cohort as outpatients to assess the impact of anemia or iron deficiency on readmission rates. However, as our pediatric VAD patients transition to outpatient, we plan to evaluate the association of iron deficiency with frequency of readmissions, phlebotomy volumes, and functional status. We did not have sufficient number of patients in this study who received body weight appropriate IRT to assess any impact of this therapy on outcomes. Our next step would be to systematically diagnose anemia and iron deficiency in this high-risk population and trial therapy protocols for efficacy. Assessing the serum micronutrients and renal erythropoietic markers prospectively in this growing population may also further help elucidate any additional causes of the widely prevalent anemia in this cohort. Iron deficiency indices would be monitored prospectively, allowing us to examine the efficacy of iron therapy in these patients, and its impact on pRBC transfusion volumes as well as on morbidity and mortality. Incorporation of iron deficiency indices in multicenter registries may help delineate outcomes of iron deficiency and treatment in this population. It is also worth noting that the patients in this cohort were chronic HF patients who progressed to need a VAD for support. They represent a potential intervention group who could have been optimized further by treating their iron deficiency and anemia before VAD implantation.
Anemia is a common comorbidity in pediatric VAD patients, with many on a pulsatile device developing anemia over the course of support. Majority of pediatric VAD patients are iron deficient. Children with a VAD, especially pulsatile devices, receive significant volumes of pRBC transfusions. Specific iron studies are needed to diagnosis iron deficiency in this population, as low hemoglobin and microcytosis in iron-deficient pediatric VAD patients may be masked by pRBC transfusions. Based on our findings, we recommend routine screening and scheduled monitoring for management of anemia and iron deficiency in the pediatric HF and VAD population.
The authors acknowledge the Blood Bank staff at Texas Children’s Hospital for allowing access to blood product data.
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