In children with severe heart failure caused by cardiomyopathy, myocarditis, or progressively worsening ventricular function after palliation of congenital heart disease, failure of maximal medical therapy leads to the requirement for temporary mechanical circulatory support (MCS).1 The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) began in the late 1960s but has had a significant increase in use since mid-2000.2 Unfortunately, ECMO is plagued with high rates of often fatal complications, including stroke, bleeding, coagulopathy, and infection.3 Furthermore, the occurrence rate of such complications is time-related with substantially increased rates in patients supported for more than 10–14 days, with studies suggesting only 13% survival on ECMO for >28 days.4 Another form of temporary MCS is a continuous-flow ventricular assist device (cfVAD), which is approved for short-term use (6 hours) in acute cardiogenic shock because of right heart failure, but may be extended up to 30 days as a Humanitarian Use Device. Off-label temporary centrifugal devices used in pediatrics are CentriMag and PediMag (Thoratec Corp., Pleasanton, CA) or RotaFlow (Maquet Holding B.V. & Co., Rastatt, Germany) pumps. Because of their ease of use, they are increasingly used for longer periods of support, especially for left ventricular failure.5,6 Despite the increase in temporary cfVAD use, the literature describing its use in pediatrics is limited.7–9
Materials and Methods
This was a retrospective study of patients <19 years of age undergoing nonemergent initiation of temporary MCS with either VA-ECMO or cfVAD (CentriMag or PediMag) at Duke University Hospital, Durham, NC. The study period was between January 1, 2011, and June 30, 2016. Before 2014, all patients at our institution in need of temporary MCS underwent ECMO cannulation. At the end of 2014, our institution began using temporary cfVADs for MCS according to the following general algorithm developed by cardiothoracic surgery, cardiology, and cardiac intensivist teams. If a patient were in acute cardiogenic shock, they would be cannulated for ECMO. If not in acute cardiogenic shock but declining with preserved pulmonary function, then a temporary cfVAD was placed. If not in shock but declining with poor pulmonary function, then either ECMO cannulation or temporary cfVAD with oxygenator could be used. Generally, if the patient had no or minimal recovery on ECMO after 10 days and no contraindications to heart transplant, then the patient would be converted to a temporary cfVAD. Once stable without bleeding or other significant end-organ injury, and no contraindications to heart transplant, then the patient would be converted a durable VAD.
Only patients placed on ECMO for clinically similar indications were included in the comparison cohort. To generate this cohort, patients placed on ECMO during the study period were excluded if they were cannulated for VA-ECMO during extracorporeal cardiopulmonary resuscitation, low cardiac output syndrome (within 14 days of cardiac surgery), respiratory failure, and uncorrected congenital heart disease. These exclusion criteria were chosen to create a cohort similar to those that underwent cfVAD implantation based on our institutional approach to MCS use, although no formal propensity score matching was employed because of the low numbers. It is important to note that cfVADs are not routinely used as a rescue for low cardiac output syndrome after cardiac surgery at our institution.
Preimplantation demographics, laboratory, and imaging data were collected. The primary endpoints were decannulation with survival to hospital discharge, transplant, or death. Secondary outcomes included length of inotropic support, mechanical ventilation, and adverse events associated with MCS: stroke, additional cardiac surgery, arrhythmia, mesenteric ischemia, pancreatitis, liver dysfunction, renal replacement therapy, bleeding, and infection. Inotropic support time was defined as number of 24-hour periods while on temporary MCS for which epinephrine, dopamine, or milrinone was infused. Mechanical ventilation support time was defined as number of 24-hour periods while on temporary MCS that the patient was mechanically ventilated with an endotracheal tube. Stroke was defined as either hemorrhagic or ischemic change detected by head ultrasound, computed tomography, or magnetic resonance imaging. Additional cardiac surgery was any thoracic surgical intervention after initial cannulation while on temporary support. Additional cardiac surgery does not include interventions concurrent with conversion to durable device or transplant, such as closure of small atrial septal defects or tricuspid valve repair. Arrhythmia was included if it required medical treatment or cardioversion. Mesenteric ischemia was defined as bloody stool, abdominal distention, and radiographic evidence consistent with the diagnosis. Pancreatitis was defined as three times the upper limit of normal elevation of amylase or lipase along with consistent symptoms. Liver injury was defined as elevated aspartate aminotransferase and alanine aminotransferase greater than five times of the upper normal limit for age. Significant kidney injury was recorded if patient underwent renal replacement therapy. Significant bleeding was defined as bleeding that required more than two transfusions in a 24-hour period or surgical exploration. Infection was defined by culture-positive bacteremia. Differences between groups (cfVAD vs. ECMO) were determined with the Student’s t-test for continuous data and the Fisher exact test for categorical data. Statistical significance was defined as a p value of 0.05 or less. The Duke University Health System Institutional Review Board approved the study and waived the requirement for individual patient consent.
Thirteen patients underwent initiation of temporary cfVAD during the study period. One-hundred and sixty-five patients underwent ECMO cannulation during the study period. After applying exclusion criteria, 16 patients were identified who were cannulated to ECMO for similar indications as in the cfVAD cohort. Five of the patients initially supported with ECMO received a cfVAD during their hospitalization and were included in the cfVAD cohort only. The remaining 11 patients comprised the ECMO cohort for comparison. Demographics and precannulation data are presented in Table 1.
Diagnoses for the patients cannulated for cfVAD included myocarditis, dilated cardiomyopathy, and complex congenital heart disease (two with single ventricle physiology). Seven of the 13 were female with a median age of 32 months (range 16 days to 18 years) and median weight of 13.3 kg (range 4.5–77 kg). Eight of the 13 who received cfVAD support were already listed for heart transplant at the time of cannulation.
Diagnoses for patients cannulated for ECMO included presumed myocarditis (biopsy not performed), dilated cardiomyopathy, and one with progressive ventricular dysfunction after surgical palliation of complex two ventricle congenital heart disease. Four of the 11 patients were female with a median age of 12 months (range 1 day to 16 years) and median weight of 9.6 kg (range 2.1–85 kg). Only two of the 11 who were cannulated to ECMO were listed for heart transplant at the time of cannulation.
The only significant differences between the groups were biomarkers indicating the severity of acute illness immediately before cannulation. Precannulation lactate was significantly higher with a median of 10.6 mmol/l for patients cannulated to ECMO compared with 2.7 mmol/l for patients placed on cfVAD (p < 0.01). Similarly, precannulation arterial pH was significantly lower with a median of 7.23 for patients going on ECMO compared with 7.36 for those going on cfVAD (p < 0.01). None of the patients in the ECMO cohort were receiving cardiopulmonary resuscitation during cannulation. Indicators of end-organ dysfunction, including urea nitrogen, creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, mechanical ventilation, and stroke, were not significantly different between the groups. Echocardiographic features were not statistically different between the cohorts. Too few patients underwent cardiac catheterization before initiation of temporary MCS to evaluate.
Primary and secondary outcomes for both groups are presented in Table 2. Median length of cfVAD support was 20 days (6–227 days) compared with 9 days (1–15 days) on ECMO (p = 0.02). Figure 1 shows the primary outcomes compared with length of temporary support. Primary outcomes for patients cannulated with cfVAD included one bridged to recovery, six bridged to transplant, and six deaths. Of the six who were transplanted, three underwent conversion to durable VAD—all Berlin Heart EXCOR (Berlin Heart GmbH, The Woodlands, TX) left ventricular support. Median length of cfVAD support for survivors was 16 days (6–227 days). Of the six nonsurvivors, three were converted to durable VAD before death, one was converted to Berlin Heart EXCOR biventricular support, two were converted to HeartWare HVAD (HeartWare International Inc., Framingham, MA) left ventricular support, and one death occurred after conversion from cfVAD to ECMO for worsening respiratory failure. Furthermore, median length of cfVAD support for those who died was 46 days (19–130 days), and median time between cfVAD cannulation and death was 70 days (27–241 days). This difference in time of support compared with time until death is caused by several deaths that occurred after conversion to either VA-ECMO or durable VAD. Biventricular support was more commonly associated with death as 5/7 (71%) in the biventricular VAD (BiVAD) group died versus. 1/5 (20%) in the left ventricular assist device (LVAD) group. Individual course and outcomes for each patient supported with cfVAD are presented in Table 3.
Primary outcome for the cohort supported on ECMO included five bridged to recovery, three bridged to transplant, and three deaths. All three who were transplanted were converted to VAD: one to Berlin Heart EXCOR LVAD, one to PediMag LVAD followed by Berlin Heart EXCOR LVAD, and one to PediMag LVAD. Median length of ECMO support for survivors was 8 days (4–15 days). All three patients who died were not converted to other MCS. Median length of support for those who died was 9 days (1–12 days).
When the two groups were compared, the only significant statistical difference was the length of support. There was no statistical difference in days on inotropic support, days on mechanical ventilation, incidence of stroke, additional cardiac surgery, arrhythmia, mesenteric ischemia, pancreatitis, liver injury, renal replacement therapy, significant bleeding, or bacteremia. Although no patients in the ECMO cohort were on renal replacement therapy before cannulation, two of the three who went on cfVAD were able to wean off renal replacement therapy.
In a select population of pediatric patients with progressive acute heart failure in urgent need of MCS, temporary cfVAD is an additional option to bridge to recovery, bridge to decision, or bridge to transplant. In a recent study by Yarlagadda et al.,9 the Organ Procurement and Transplantation Network data were reviewed for survival to heart transplant with temporary circulatory support. Using all temporary VAD patients waiting for heart transplant compared with a propensity-matched cohort of patients waiting on ECMO, the authors found significantly longer waitlist survival and longer overall survival, despite no difference in postheart transplant survival. This translated to a modest reduction (39% VAD compared with 45% ECMO, p = 0.003) in 90-day mortality after initiation of MCS. Furthermore, the authors noted that the CentriMag-PediMag system “conferred the longest support durations with a significant survival benefit.” This retrospective review provides additional evidence that temporary cfVAD implantation can support pediatric patients more than longer periods of time than ECMO, with the potential to transition to durable VAD and transplant.
None of the patients in this study received a heart transplant directly from ECMO, but some patients on ECMO were transplanted after conversion to VAD (temporary or durable). Even for the patients on cfVAD who died, the support times exceeded the highest support times in the ECMO cohort. Based on our data, though, median length of cfVAD support for survivors was still only 16 days, compared with 46 days for nonsurvivors. This suggests that temporary cfVAD remain a temporary support in a bridge to decision, durable device, or transplant. This additional survival time is likely beneficial considering pediatric patients listed status 1A in the United States have an average wait time of 25 days (based on Organ Procurement and Transplantation Network data as of June 30, 2015).
Additional benefits of temporary cfVAD include ease of handling and implantation, lower priming volumes than ECMO, low device complications, ability to integrate oxygenator into the circuit, approval for use without listing for transplant, and reduced expense compared with durable devices.5,10 As compared with durable VADs, temporary cfVADs can almost always be implanted without need for cardiopulmonary bypass or aortic crossclamping, which may be of particular benefit in a patient with compromised right ventricular function. Many of these benefits were seen with our cfVAD cohort as well. Ease of handling is largely dependent upon the surgical expertise. Lower priming volumes were always the case given significantly less tubing necessary for the cfVAD system compared with ECMO. This theoretically reduces exposure to blood products and thereby reduces risk of sensitization for future transplant. Two patients in the cfVAD group benefited from an oxygenator as part of their circuit. Five patients were cannulated for cfVAD without being listed for transplant. Cost comparisons were not performed as part of this study.
Unfortunately, similar risks associated with all VADs remain, including bleeding, infection, and residual sequelae from low cardiac output. These risks appear to be exacerbated in patients with biventricular support versus univentricular support, as the majority of nonsurvivors in our cohort had BiVAD support. This difference is consistent with increased risk of death with BiVAD support compared with LVAD only, which is seen in both adult and pediatric patients.11,12 Many believe that patients requiring BiVAD support reflects more severe disease at the time of implantation. However, this has not always borne out in the literature.11 It is also intuitive that two devices are more likely to lead to complications than one. Whatever the underlying etiology and regardless of device selection, BiVAD support appears to increase morbidity and mortality. However, it is unclear whether VA-ECMO would be a safer option in patients currently receiving BiVAD support. Arguably, with both experience and improvement in technology, those risks may decrease.
This study has several limitations. A single pediatric center experience will almost always suffer from low patient numbers, and our study was no different. The single-center study experience, however, lends to more granular data regarding each individual patient. There was also heterogeneity to the patients. Several patients were included with complex congenital heart disease and prior cardiac surgeries that may present unique challenges not captured when grouping them with patients with acquired heart disease. There were also clinical differences between the groups, most notably higher lactate and lower pH seen in the ECMO cohort. This likely reflects a more acutely critically ill cohort of patients before ECMO cannulation compared with those for VAD, which in itself portends worse outcomes.13,14 Finally, there was a lack of standardization of therapeutic decision-making throughout the study period, owing largely to the novelty of cfVAD use.
Future prospects for temporary cfVAD use will depend on further study. One important area of study will be improving patient selection. Which pediatric patients will benefit compared with the relative risks associated with MCS? Smaller patients may be one group that could benefit because cardiac output may be easier to titrate with cfVAD than the fixed-volume pulsatile devices. Another group that may benefit is children with severe ventricular dysfunction because of myocarditis where recovery may be anticipated but could take weeks. Another important area of study is the improvement of the intensive care management of children on cfVAD devices. Advances in anticoagulation and antiplatelet therapy, both new drugs and improved protocols, could lead to significant reductions in the most common VAD-related complications of hemorrhage and thromboembolic events. Further understanding of right and left ventricular interactions could also lead to reduction of morbidity and mortality by either improving BiVAD outcomes or reducing the need for right ventricular support.
Temporary cfVAD use in pediatric patients with progressive acute heart failure may have specific advantages, including longer support time and lower priming volumes compared with ECMO (while retaining the option to add an oxygenator to the circuit), and implant without listing for heart transplant when compared with durable devices. Because of these advantages, it is an additional option to bridge to recovery, decision, or transplant.
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