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Pediatric Circulatory Support

Improved 6 Minute Walk Distance and Brain-Type Natriuretic Peptide After Continuous-Flow Ventricular Assist Device Placement in Children

Goldberg, Jason F.*; Schlosser, Robin S.; Walrath, James G.; Morris, Shaine A.; Elias, Barbara A.§; Price, Jack F.; Cabrera, Antonio G.; Denfield, Susan W.; Dreyer, Wiliam J.; Wang, Yunfei; Adachi, Iki§; Jeewa, Aamir

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doi: 10.1097/MAT.0000000000000865
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Abstract

The experience with continuous-flow (CF) ventricular assist devices (VADs) in children continues to grow in recent years, and for adults with end-stage heart failure, these devices have largely replaced pulsatile VADs.1,2 The pediatric experience has documented the use of the axial flow HeartMate II device (Thoratec Corp., Pleasanton, CA) in older children who are adult or near-adult size3,4; recent reports have shown the ability to implant smaller profile CF-VADs, specifically the centrifugal HVAD device (HeartWare Inc., Framingham, MA), in children as young as 4 years of age and weighing as little as 12 kg.5,6 The strategy of adapting adult intracorporeal VADs to children allows for the possibility of optimizing rehabilitation and functional recovery as well as avoidance of the higher mortality and morbidity associated with extracorporeal VADs used in smaller children.7,8

Although much attention has been given to the possibility of cardiac recovery with durable VADs, there are minimal pediatric data reporting the improvement in functional parameters in these patients.9–12 With the employment of a rehabilitation protocol, improvements in parameters such as 6 minute walk distance (6MWD) and brain-type natriuretic peptide (BNP) can be evaluated over time to assess functional recovery. Data among adults with CF-VADs have shown that poorer 6MWD and higher BNP levels during VAD support are associated with decreased survival, but there is little understanding of the trends in these values after device placement.13–17 We hypothesized that children with end-stage heart failure would demonstrate a longitudinal improvement in 6MWD and BNP after CF-VAD implantation and that there would be a time point after which improvement in 6MWD and BNP plateaus.

Methods

A retrospective cohort study was performed, including all patients less than 18 years of age who underwent CF-VAD placement from August 2008 to August 2016 at Texas Children’s Hospital. Patients were excluded if they did not have a 6MWD value collected during the first 365 days while the device remained in place. A center-specific rehabilitation protocol was employed, including physical, developmental, and occupational metrics at specified intervals. The assessment of 6MWD was specified at initial evaluation followed by post-VAD evaluation at time points of 2–3 weeks, 3 months, 6 months, and 1 year; while inpatient, 6MWD was performed weekly when appropriate. Institutional review board approval was obtained. Patient characteristics were collected, including age, sex, and CF-VAD type (axial vs. centrifugal flow). Six minute walk distance and BNP values were recorded during the first 365 days while the device remained in place; 6MWD was expressed as a percentage of the predicted (%P) value for sex, age, and height, using the formula published by Geiger et al.18

Statistical Analysis

The longitudinal change of 6MWD and BNP of each subject was first graphed for visual presentation with longitudinal spaghetti plots. Associations between potential predictor variables (time, age, sex, and device type) and the outcomes of 6MWD and BNP were then examined. The analyses were stratified by the first 90 days postimplantation and in the subsequent time period that the device remained because the longitudinal spaghetti plots showed a plateau of 6MWD and BNP values after 90 days. Mixed-effects linear modeling was first used to evaluate the univariate associations. Multivariate analyses using mixed-effects linear modeling were then performed accounting for repeated measures, using all covariates. Backward elimination was then used to exclude variables with p values >0.05 in stepwise fashion. Log transformation was applied to BNP values because the natural log of BNP demonstrated a better fit into the model than nontransformed BNP values. Post hoc subgroup analyses were performed according to specific statistically significant results from multivariate analyses: change in 6MWD with time was stratified by device type (given the association between device type and 6MWD after 90 days) and change in BNP with time was stratified by tertiles of age (given the association between age at implantation and BNP after 90 days). All analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC).

Results

Of the 34 patients with CF-VAD implanted at <18 years of age during the study period, seven were excluded as 6MWD data were not recorded. Twenty-seven patients were included in the analysis; 20 were males, and the median age was 12.7 (interquartile range [IQR], 7.9–15.1). Sixteen patients had the centrifugal HVAD device, and 11 patients had the axial HeartMate II device. Patient characteristics and outcomes are shown in Table 1. The sample included 92 6MWD and 341 BNP values. Patients had a median of three 6MWD values and 10 BNP values recorded during the study period. The median times to initial 6MWD and BNP values were 26.5 and 9 days, respectively. Six minute walk distance and BNP values throughout the study period are represented in Table 2. The median initial and final 6MWD values for each patient were 45 %P (IQR, 23–56 %P) and 63 %P (IQR, 56–70 %P), respectively. The median initial and final BNP values for each patient were 460 pg/ml (IQR, 250–1,133 pg/ml) and 134 pg/ml (IQR, 81.2–269 pg/ml), respectively. The longitudinal spaghetti plots of 6MWD and BNP of each patient over time are represented in Figures 1 and 2. At 90 days, there is a plateau observed of both increase in 6MWD and decrease in BNP.

Table 1.
Table 1.:
Patient Characteristics and Number of Recorded 6MWD and BNP Values Per Patient (n = 27)
Table 2.
Table 2.:
6MWD and BNP Throughout Study Period for Each Patient (n = 27)
Figure 1.
Figure 1.:
Longitudinal spaghetti plot of each patient’s 6 minute walk distance values (expressed as percent predicted for age, sex, and height) over time throughout the study period. Dashed red line represents an inflection in slope of the plots, with a plateau of values after 90 days. CF-VAD, continuous-flow ventricular assist device.
Figure 2.
Figure 2.:
Longitudinal spaghetti plot of each patient’s BNP values (expressed as percent predicted for age, sex, and height) over time throughout the study period. Dashed red line represents an inflection in slope of the plots, with a plateau of values after 90 days. BNP, brain-type natriuretic peptide; CF-VAD, continuous-flow ventricular assist device.

Univariate and multivariate analyses for 6MWD are shown in Table 3. In the first 90 days, there was a significant association between time and 6MWD by univariate analysis (P < 0.01, Figure 3), and in multivariate analysis, time was the only variable that remained associated with 6MWD. The mean change (slope) of the univariate regression line in the first 90 days was +0.39 %P per day, or an increase of 12 %P per 30 days (Figure 3). After 90 days, there was no longer a correlation between time and 6MWD, with a mean increase of only 0.02 %P per day, or 0.6 %P per 30 days (P = 0.482, Figure 3). After 90 days, the only variable (upon both univariate and multivariate analysis) significantly associated with 6MWD was device type. The presence of an axial flow device, as compared to a centrifugal flow device, was associated with a higher 6MWD after 90 days (P = 0.019). Median 6MWD after 90 days among patients with axial flow devices was 73 %P (IQR, 66–84 %P) versus those with centrifugal pumps was 64 %P (IQR, 59–64 %P). The interpretation of this difference is complicated by the fact that the number of 6MWD values after 90 days is small (axial: 12 6MWD values among five patients; centrifugal: 13 6MWD values among 10 patients) and that the individual regression lines of each device type did not show a significant positive or negative slope (axial: slope (%P/day) = −0.02, 95% CI = −0.1 to 0.06, p = 0.566; centrifugal: slope (%P/day) = 0.05, 95% CI = −0.08 to 0.18, p = 0.254).

Table 3.
Table 3.:
Univariate and Multivariate Analysis of 6 Minute Walk Distance
Figure 3.
Figure 3.:
Regression lines of the univariate analysis of 6MWD with time, with significant increase in slope in the first 90 days and without significant increase after 90 days. *Slope (% predicted/day) = 0.39, 95% CI = 0.23–0.56. ‡Slope (% predicted/day) = 0.02, 95% CI = −0.04 to 0.07. 6MWD, 6 minute walk distance; CF-VAD, continuous-flow ventricular assist device.

Univariate and multivariate analyses for BNP are shown in Table 4. In the first 90 days, there was a significant association between time and BNP by univariate analysis (P < 0.01, Figure 4), and in multivariate analysis, time was the only variable that remained associated with BNP. The mean change (slope) of the univariate regression line in the first 90 days was −1.98% of the preceding BNP per day, or a decrease of 59% per 30 days (Figure 4). After 90 days, there was no longer a correlation between time and BNP, with a mean increase of only 0.06% of the preceding BNP per day, or 1.8% per 30 days (P = 0.341, Figure 4). After 90 days, the only variable (upon both univariate and multivariate analysis) associated with a lower BNP was older patient age (P = 0.013). Further evaluation of this relationship was conducted by dividing the sample into tertiles of age. Those patients with age <9.9 years of age showed longitudinal increase in BNP after 90 days, whereas the remainder of the sample showed longitudinal decrease in BNP after 90 days, as shown in Figure 5.

Table 4.
Table 4.:
Univariate and Multivariate Analysis of BNP (Log Transformation)
Figure 4.
Figure 4.:
Regression lines of the univariate analysis of BNP (log transformation) with time, with asymptotic decrease in slope in the first 90 days and without significant change after 90 days. *Slope (pg/ml/day) = −1.98, 95% CI = −2.41 to −1.56. ‡Slope (pg/ml/day) = 0.06, 95% CI = −0.07 to 0.20. BNP, brain-type natriuretic peptide; CF-VAD, continuous-flow ventricular assist device.
Figure 5.
Figure 5.:
Regression lines of the univariate analysis of BNP (log transformation) with time, for the three tertiles of age, before and after 90 days post-VAD implantation. All 27 patients had available BNP data in the first 90 days but only 17 of 27 patients had available BNP data after 90 days. The two oldest tertiles show negative slope, while the youngest tertile shows positive slope. *Slope after 90 days (lnpg/ml/day) = 0.21, 95% CI = 0.04–0.39, P = 0.019; ‡slope after 90 days (lnpg/ml/day) = −0.32, 95% CI = −0.54 to 0.11, P < 0.01; αslope after 90 days (lnpg/ml/day) = −0.26, 95% CI = −0.48 to 0.04, P = 0.022. BNP, brain-type natriuretic peptide; VAD, ventricular assist device; CF-VAD, continuous-flow ventricular assist device.

Discussion

Improvement in 6MWD and BNP may be markers of adequate ventricular unloading and functional recovery after CF-VAD placement. The data from this study show a significant improvement in 6MWD and BNP within the first 90 days after CF-VAD placement in children, without significant change in these parameters after 90 days. This relationship may suggest that optimal rehabilitation is most likely to be evident within the first 90 days after device placement.

This study highlights the potential value of using BNP and 6MWD during a VAD rehabilitation and recovery protocol as adjunct tools to other investigations, such as echocardiography and cardiac catheterization. Brain-type natriuretic peptide has been long accepted as a marker of acute and chronic heart failure in children and adults.19–24 It has also been used as a marker of improvement in adult VAD patients, with evidence showing decrease in BNP after VAD placement25,26 as well as using BNP to predict shorter length of stay27 and decreased mortality after VAD placement.14 Among adult VAD patients, 6MWD has been used to assess rehabilitation and functional capacity, and 6MWD below a normative value has been associated with higher mortality in the adult VAD population.13,28,29

After CF-VAD placement, many parameters may be used to determine functional improvement. Our center has previously described the rehabilitation and myocardial recovery of pediatric CF-VAD patients resulting in device explantation, similar to that seen with reports of device explantation in adults with CF-VADs.16,30–32 With the early adoption of a cardiac rehabilitation protocol as well as regular, routine assessment of 6MWD and BNP, the clinician can gain insight with respect to the longitudinal trends in these values, which can assist the clinician in planning the patient’s therapeutic course. Patients showing improvement in BNP and 6MWD may be indicating optimal cardiac rehabilitation and readiness for activation or listing for heart transplantation. The challenge still exists in differentiating between children with adequate ventricular unloading and rehabilitation and those that achieve true myocardial recovery with VAD support.

There is a tendency at pediatric centers to list a durable VAD patient for transplant shortly after device implantation, rather than after a period of assessment for recovery.1 Our center’s practice regarding children with intracorporeal VADs involves waiting at least 3 months after device implantation before listing the patient for transplantation. This period allows for the opportunity to rehabilitate a deconditioned child with physical and occupational therapy after implantation, evaluating the appropriate timing for listing. A recent publication by VanderPluym et al.33 describes cardiac rehabilitation regimens being utilized in many pediatric centers, before and after VAD implantation, including the use of 6MWD. Our center’s protocol involves physical therapy, which allows the child to ambulate and exercise while supporting the weight of the device controller and batteries, as well as occupational therapy, which aids in incorporating the device into activities of daily living, allowing children to live safely at home and in the community. Frequent outpatient follow-up during this process allows the medical team to assess the patient’s longitudinal rehabilitation, which can be augmented by serial assessment of 6MWD and BNP. Given the overall paucity of data regarding functional recovery in pediatric VAD patients, our study was able to demonstrate that a period of approximately 3 months after VAD implant may be a suitable time point to assess for optimized rehabilitation or functional recovery, barring any significant device-related complications.

An unexpected finding in the analysis was the association between younger age and increase in BNP after 90 days. Subgroup analysis showed that the youngest tertile (<9.9 years of age) indeed had increase in BNP, whereas the older groups showed decrease in BNP after 90 days. This may suggest that younger patients are less able to rehabilitate and achieve functional recovery than older patients.

There are several important limitations to this study. It is retrospective in nature and comprises a small dataset of one center. Although our center has developed a functional recovery protocol, 6MWD and BNP values in this dataset were often obtained on the basis of clinical need and not always per the standardized protocol. In addition, the population in this study is heterogeneous, comprising patients of different ages and different etiologies of cardiomyopathy, including some patients with congenital heart disease. Six minute walk testing can also be difficult to interpret in younger children although the referenced normative data included children as young as 3 years of age; our dataset included four patients of 3–6 years of age.18

Conclusions

In the current study, improvement in 6MWD and BNP was significant in the first 90 days after CF-VAD placement in children, without subsequent significant improvement thereafter. This time course suggests a greater potential for functional recovery in the first 90 days after VAD placement. Although data exist regarding 6MWD and BNP in the adult VAD population, this is the largest study to describe these parameters in pediatric CF-VAD patients. The standardization of post-VAD rehabilitation protocols may offer better opportunities to characterize the time course of rehabilitation and functional recovery in children on device support.

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Keywords:

mechanical circulatory support; heart-assist devices; pediatrics; heart failure; rehabilitation

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