Study Design and Randomization Protocol: After parental informed consent, eligible subjects were enrolled at Penn State Health Children’s Hospital (Penn State College of Medicine IRB Study ID: PRAMS019299-A, last approval date: 04/14/2022). To be eligible for the present study, patients must have been less than 18 years of age at the time of enrollment, and were scheduled to undergo cardiac surgery requiring CPB for congenital heart defects. Additionally, patients utilizing only 8–14 Fr arterial cannulas were included in the study to create more homogeneous groups for comparison. Patients meeting the inclusion criteria were randomized to undergo CPB using either pulsatile or non-pulsatile perfusion settings. Details explaining the randomization process are presented in Supplemental Fig. 1 and Supplemental Methods section of our previously published study [16]. For the present analysis, patients were split into groups based on type of heart disease (acyanotic vs. cyanotic), and each group was then studied to determine the impact of the type of perfusion-modality settings (non-pulsatile vs. pulsatile). All methods in this manuscript were carried out in accordance with relevant guidelines and regulations. Penn State College of Medicine, Institutional Review Board, approved all experimental protocols.
Anesthesia and Perfusion
Isoflurane, pancuronium, and fentanyl were utilized to achieve general anesthesia. A median sternotomy incision was used as the primary approach in all surgeries. The CPB circuit comprised of a Maquet-HL-20 heart-lung machine (Maquet Cardiopulmonary, Getinge Group), Capiox hollow-fiber membrane oxygenator, Capiox pediatric 32-mm arterial filter (Terumo Cardiovascular Systems), cardioplegia set (66483-01, Terumo), Minntech hemoconcentrator (HemoCor HPH400TS, Medivators, Inc), polyvinyl chloride tubing (LivaNova Smart Perfusion Pack), Stockert heater-cooler system (Sorin Group USA), and arterial cannulas selected from the DLP series (Medtronic), Sarns Tender Flow series (Terumo Cardiovascular Systems), or Fem-Flex II series (Edwards Lifesciences Corp). The CPB circuit was primed with 400 mL of Plasmalyte-A, 50 mL of 25% Human Albumin, 15 mEq NaHCO3, and 1000 U of Heparin. Approximately, 120–180 mL of priming solution was removed, which was used as additional volume as needed during the surgery, and 250 mL of packed red blood cells were added. Hematocrit goal during CPB was set to ≥ 26%. Additionally, a 0.5 g/kg dose of mannitol was administered after the initiation of CPB. Lastly, all patients underwent modified ultrafiltration prior to discontinuation from CPB.
Patients in the pulsatile perfusion group were placed on CPB at the following settings: 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 < 6.9 kg, 120 beats/min.
Intraoperative Monitoring of Cerebral Hemodynamics and Oxygen Saturation:
Transcranial Doppler. To measure cerebral flow velocities, quantify pulsatility index, and detect the presence of gaseous microemboli (GME) counts during CPB, Transcranial Doppler (TCD) ultrasound (Pioneer TC8080; Nicolet Biomedical Inc) was utilized. One TCD ultrasound sensor was attached to the patient’s right temporal window above the zygoma to insonate the right middle cerebral artery (MCA). Additionally, a second TCD ultrasound sensor was also placed on the CPB circuit tubing before the aortic cannula. Using a 2-MHz pulsed-waved transducer, simultaneous M-mode and spectrogram readings were generated. The insonation depth was set between 25 and 50 nm.
Near-Infrared Spectroscopy. Quantification of regional cerebral oxygen saturation was completed with the INVOS 5100B Near-Infrared spectroscopy (NIRS) monitor (Somanetics, Troy, MI). NIRS is a noninvasive method of measuring real-time changes in the percentage of oxyhemoglobin to total hemoglobin of cerebral blood. Pediatric SomaSensors (Somanetics) were attached to the forehead below the hairline to collect NIRS data. Both TCD and NIRS data were collected at the following times: baseline (pre-incision), on bypass (before cross-clamp), and on bypass (after cross-clamp) at 5, 20, 40, and 60 minutes.
Postoperative Outcomes
Postoperative vital organ injury was quantified using the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score [17, 18], which was calculated at 24, 48, and 72 hours after surgery for all patients remaining in the PICU at the collection time. The Pediatric Risk of Mortality (PRISM) 3 score [19] was utilized to estimate mortality risk in children admitted to the PICU based on data collected within the first 12 hours of admission to the PICU. The Vasoactive-Inotropic (VIS) score [20] quantifies the cardiovascular support required by patients in the postoperative period and was assessed at 24 and 48 hours after surgery. Additional outcomes included intubation duration, ICU length of stay, hospital length of stay, and mortality within 180 days. Details about the organ dysfunction scoring systems are available in the Supplemental Methods section.
Statistical Methods:
Chi-square tests, or Fisher’s exact tests if expected cell counts were small, were used to compare groups for categorical characteristics (e.g., sex). General linear models allowing for heterogeneous variance having fixed factors of patient status (i.e., cyanotic, acyanotic), pulsatility mode (i.e., pulsatile, non-pulsatile) and their interaction were fit to continuous characteristics collected at one point in time (e.g., aortic cross-clamp time). Mixed models having a random subject effect and fixed effects for patient status, pulsatility mode, time, and their interactions were fit to continuous characteristics collected at multiple points in time (e.g., VIS score at 24 and 48 hours). Mixed models account for the within-subject, as well as the between-subject, variability inherent in data collected at multiple time points (i.e., repeated measures). Contrasts were constructed from the models to test hypotheses of interest. All hypothesis tests were two-sided and all analyses were performed using SAS software, version 9.4 (SAS Institute Inc., Cary, NC).