Clinical Assessment of the Utility of Pulsatile Over Nonpulsatile Flow for Neonatal and Pediatric Cardiopulmonary Bypass Procedures Using Multidisciplinary Translational Research at a Tertiary Care Center

Introduction

Over the past 20 years, the Pediatric Cardiovascular Department at Penn State Health Children's Hospital and College of Medicine has been researching ways to improve the safety and efficacy of pediatric cardiopulmonary bypass (CPB) for neonates and children requiring congenital heart surgery. One of the long-standing projects within our research group has been the assessment of pulsatile flow during CPB. The purpose of this essay is to summarize our findings of pulsatile flow during CPB and to describe how this may facilitate improved clinical outcomes for neonates and children undergoing congenital heart surgery.

Safety and Design of CPB Circuit for Pulsatile Flow

Before proceeding with pilot clinical studies to evaluate pulsatile flow, we optimized the safety and design of the CPB circuit using a multidisciplinary research team, confirmed through in vitro simulated patient experiments.^1,2 Based off of this collaboration, the following settings were used to demonstrate pulsatile perfusion: 10% of the base flow, 20% of the pump head start point, and 80% of the pump head stop target. The pump rate was set based on the patient's weight: >15 kg, 90 beats/min; 7 to 15 kg, 100 beats/min; and <7 kg, 120 beats/min. The basis of theses settings was derived from our previous research for producing adequate quality of pulsatility. This model was then tested in a randomized clinical trial (RCT) in 159 patients receiving pulsatile and nonpulsatile flow. This showed pulsatile perfusion did not increase plasma free hemoglobin or gaseous microemboli (GME) counts and maintained safe arterial line pressures, indicating that pulsatile flow is a safe modality on CPB. ³ While this RCT did not demonstrate any clinical benefits with pulsatile flow in terms of intubation time, intensive care unit length of stay (ICU LOS), and hospital LOS, the study cohort included patients in the low to middle STAT categories which may potentially generate different outcomes in patients with higher risk profiles.

Other important clinical considerations in utilizing pulsatile flow involve optimization of the entire CPB circuitry including the arterial cannula to reduce excessive arterial cannula pressure drops during CPB. In previous studies, we showed that using the same size (6F and 8F) arterial cannula with different cannula geometry can result in excessive arterial line pressures and pressure drops. ² Additionally, we found that certain brand name oxygenators with identical clinical settings may have significantly different pressure drops and microemboli counts. ² Given these findings, we recommend that investigators optimize the entire CPB circuitry, including the pump, oxygenator, and arterial cannula, for pulsatile flow to ensure safety and performance before clinical applications.

Pulsatile Flow and Real-Time Intraoperative Neurologic Monitoring

Through application of translational research from in vitro hemodynamic studies to in vivo animal studies and small pilot clinical trials, our research group at Penn State Health has shown that total hemodynamic energy is greater in patients receiving pulsatile over nonpulsatile flow during CPB and that pulsatile flow settings have a direct impact on the quality of pulsatile waveforms. ¹ To further evaluate this effect, our research group utilized transcranial doppler (TCD) and demonstrated that the pulsatility index is significantly increased using pulsatile flow at the level of the middle cerebral artery (MCA) and arterial line of the CPB circuitry when compared to patients with nonpulsatile flow on CPB.^4,5 While clinical studies are currently ongoing, our hypothesis is that increased pulsatility will correlate with improved cerebral biomarkers which may manifest as improved postoperative neurologic outcomes over time.

Moreover, the use of TCD in the operating room allows for real-time neurologic monitoring that is vital for determining clinical outcomes. We have shown that TCD can accurately measure the GME count during CPB and that high-risk STAT 5 mortality category patients have a significantly higher GME burden than patients with a lower risk profile. ⁵ Overall, we have currently not found any significant difference in the GME burden in patients with pulsatile versus nonpulsatile flow; however, this could potentially have a more clinically significant impact for patients with high-risk profiles.^3,5 While most centers do not employ the use of TCD during congenital heart surgery, our group strongly recommends using this powerful imaging tool to assess cerebral and circuitry hemodynamics as well as GME count for patients receiving pulsatile and nonpulsatile flow.

Neurodevelopmental Biomarkers

One of the goals of our research group is to improve neurologic outcomes from modifiable components of CPB. Previous studies suggested that low levels of apolipoprotein E (ApoE) may be predictive of adverse neurodevelopmental outcomes following CPB. ⁶ Within our research group, preliminary studies have shown that ApoE levels are maintained at higher physiologic levels while patients are on pulsatile flow over nonpulsatile flow during CPB. ⁷ Additionally, a previous pilot study performed at our center found there was greater fibrinolytic balance (ratio of plasminogen activator inhibitor-1: tissue plasminogen activator) with patients on pulsatile over nonpulsatile flow. ⁷ If pulsatile flow demonstrates better physiological levels of neurodevelopmental biomarkers, this may provide further support for adopting this modality, considering neurodevelopmental changes occur over long periods, which cannot be adequately assessed in the relatively short-term postoperative ICU setting.

Steps to Applying Pulsatile Flow to Clinical Practice

For any clinician who desires to critically assess and apply the findings of pulsatile flow under CPB to generate meaningful outcomes in neonates and children undergoing congenital heart surgery, our research group recommends the following:

Perform an extensive literature review to understand the mechanism of action of pulsatile flow as well as its potential benefits and harm during CPB.

Visit or collaborate with tertiary care centers that routinely utilize pulsatile flow in a clinical setting and conduct experimental in vitro and in vivo models for optimizing the entire CPB circuitry.

Perform in vitro experiments to understand arterial pressure changes and quantify plasma free hemoglobin levels using consistent CPB circuitry (if institutional facilities are available for in vitro studies).

Perform in vivo experiments in a piglet model to further assess hemodynamics using consistent CPB circuitry (if institutional facilities are available for in vivo studies).

Adopt or create a clinical protocol for utilizing pulsatile flow based on evidence-based research performed by the local team or other investigators worldwide.

Perform pilot clinical trials in neonates and children comparing pulsatile and nonpulsatile flow on CPB.

Perform RCTs with a larger cohort size to evaluate the efficacy of pulsatile flow.

Conclusions

Through a multidisciplinary and translational research approach, our research group has identified that pulsatile flow is a safe modality which shows statistical significance in increasing the pulsatility index in the MCA and CPB circuit during CPB. However, there does not appear to be any short-term clinical benefits in terms of Pediatric Logistic Organ Dysfunction-2 score along with intubation time, ICU LOS, and hospital LOS when comparing the use of pulsatile flow over nonpulsatile flow in a randomized control trial of patients with low- to middle-risk STAT categories. Despite this our research group has documented that pulsatile flow increases hemodynamic energy and maintains physiologic levels of neurodevelopmental biomarkers compared with nonpulsatile flow. It will therefore be important to continue to assess the long-term clinical impact of pulsatile flow using TCD among our current cohort as well as patients with higher risk profiles. Overall, our data confirm that pulsatile flow is not a “magic bullet” for CPB; instead it involves optimization of the entire circuit through use of a multidisciplinary research team. Future multicenter randomized control trials are needed to reassess these findings and to confirm any long-term neurodevelopmental impact pulsatile flow might have on the neonate and child requiring congenital heart surgery. Lastly, our Pediatric Cardiovascular Research Department at Penn State Health Children's Hospital and College of Medicine is open to collaboration across different centers to begin conducting multicenter analysis on this important subject.