Congenital Heart Anesthesia Intensive Care

CCAS-CHiP Network Journal Watch Collaboration

CCAS-CHiP Network Journal Watch Collaboration By: Nischal Gautam, MD   This edition of the CCAS-CHiP collaboration discusses relevant peer-reviewed publications between Jan 2021 and July 2021. Multiple insightful articles with overlapping anesthetic and intensive care interests were screened, and three original research articles caught our attention. These are a) Impact of hyperoxia during pediatric cardiopulmonary bypass on postoperative outcomes; b) Revisiting neutrophil-lymphocyte ratios in the current era of specific biomarkers, and c) Bivalirudin pharmacokinetics in children.   Volunteers from both subspecialties have evaluated the selected publications. These reviews are also available on the ChiP Network's Journal watch section.   The CHiP network is a rapidly growing multidisciplinary platform that allows for a multi-institution and multi-specialty seamless collaboration. The CHiP Network is also looking for volunteers and sponsors to support its mission. If you would like to support the CHiP Network through a donation, please click here.  

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The Role Of The Neutrophil-Lymphocyte Ratio For Pre-Operative Risk Stratification Of Acute Kidney Injury After Tetralogy Of Fallot Repair

Manuel V, Miana LA, Turquetto A, et al. Cardiol Young. 2021 Jun;31(6):1009-1014. doi: 10.1017/S1047951121001943. PMID: 34016219.   Take-Home Points Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass (CPB) in children. AKI can have long-term implications leading to chronic kidney disease. Therapeutic options for AKI after CPB are limited and, therefore, low-cost, easy-to-measure biomarkers may help to preoperatively identify patients at risk of AKI after CPB. The preoperative neutrophil/lymphocyte ratio may be useful in predicting serious AKI in children with tetralogy of Fallot (TOF) undergoing cardiac surgery. However, larger prospective studies are required to confirm these findings. Commentary by Ingrid Moreno-Duarte, MD Adult Cardiothoracic Anesthesiologist and Intensivist/Pediatric Cardiothoracic Anesthesia Fellow in Children’s Medical Center/UT Southwestern, Dallas, TX; Sana Ullah MD, Associate Professor in Anesthesiology, UT Southwestern Medical Center and Children’s Medical Center, Dallas, TX. Acute kidney injury (AKI) is a well-known complication after CPB. Children, particularly patients with congenital heart disease, have a higher incidence of AKI (5-45%). The presence of AKI is associated with increased in-hospital morbidity and mortality - including increased length of stay in the intensive care unit, increased mechanical ventilation, and increased mortality. Postoperative AKI is an independent risk factor for prognosis in surgical patients and can have long-term implications leading to chronic kidney disease (1). Although patients with Tetralogy of Fallot (TOF) have excellent long-term survival, more than half of these patients present with chronic kidney disease (CKD) in adulthood (2). Identifying which patients with AKI are at risk of CKD is challenging. Due to limited therapeutic options for AKI, the ability to prospectively identify high-risk patients could be very useful in implementing prevention strategies to reduce the impact of renal injury after congenital cardiac surgery.   The absolute neutrophil/lymphocyte count ratio (NLR) reflects the balance between inflammation (neutrophils) and immunity (lymphocytes) (3). An increase in the NLR suggests an acute or chronic inflammatory response that can suppress lymphocyte function. The NLR is simple, inexpensive, and easily calculated. The ratio has been used to predict multiple cardiovascular, respiratory, and hospital outcomes in adults but has not been studied in children. Higher NLR values are associated with disease progression and worse prognosis.   The authors explored the utility of the use of the preoperative NLR in predicting AKI in children undergoing TOF repair. A single center retrospective analysis of 116 patients less than 18 years old undergoing TOF repair between January 2014 and December 2018 was performed (4). AKI was defined according to the Acute Kidney Injury Network definition, where percentage changes in serum creatinine level from baseline are used to classify acute kidney injury as grade I (≥150–200%), grade II (≥200–300%), or grade III (>300%).   Patients were excluded if they had any other hemodynamically significant concomitant congenital heart defect, pre-operative hemodynamic instability, surgical complications leading to increased CPB and cross-clamp times, suspected or evidenced infection (leukocytosis), prior antibiotic administration during the same hospital admission, primary hematological or other immunological diseases, or a positive viral screening.   The patients were assigned into two groups depending on the presence (n=39) or absence (n=77) of AKI according to the AKI Network definition. In the AKI group, the median neutrophil-lymphocyte ratio was 0.71 (interquartile range: 0.50–1.36); in the group without AKI, the neutrophil-lymphocyte ratio was 0.61 (interquartile range: 0.34–1.18).   There was no statistical difference in the NLR between groups. However, a subgroup analysis comparing the non-AKI group with the grade III AKI subpopulation (10 patients) showed an association between the NLR and its ability to predict more severe stages of AKI. A high preoperative NLR was also significantly associated with a high postoperative serum creatinine level. The study also re-confirmed the association of AKI with the presence of longer periods of postoperative mechanical ventilation, intensive care length of stay, hospital stay, and increased mortality during the first 48 hours after TOF repair.   The authors propose that the higher level of the pre-operative NLR may be influenced by the presence of cyanosis and chronic vascular stress, which may lead to a chronically activated innate immune system. CPB may exacerbate this activation and lead to adverse outcomes, including AKI. The authors conclude that the pre-operative NLR can be used to identify patients at risk of developing grade III acute kidney injury after TOF repair.    The NLR is inexpensive and easy to measure; however, it is not truly specific to AKI. Many other conditions unrelated to the kidney may increase this ratio. This retrospective study included a small sample size and the groups were numerically unbalanced (39 vs. 77 patients), which limits the study’s conclusions. In addition, the retrospective design, the relatively small number of patients, and a sensitivity and specificity of approximately 70% undercuts the utility of this test as a predictor of renal injury after CPB. Since measuring the white cell count is a routine blood test before cardiac surgery, it should be relatively easy to conduct a much larger prospective study to assess the usefulness of the NLR as a predictive risk-stratification tool.   Nonetheless, AKI does affect outcomes after congenital heart surgery. A low-cost, easy-to-measure biomarker such as the NLR may have a role in identifying high-risk patients with congenital heart disease that could develop AKI after cardiopulmonary bypass. Identifying such patients could lead to early prevention strategies, such as avoidance of fluid depletion, hypotension, mindful use of nephrotoxic agents, and prophylactic dialysis catheters placed at the time of surgery (5, 6).   References: 1. Trongtrakul K, Sawawiboon C, Wang AY, Chitsomkasem A, Limphunudom P, Kurathong S, et al. Acute kidney injury in critically ill surgical patients: Epidemiology, risk factors and outcomes. Nephrology (Carlton). 2019;24(1):39-46. 2. Buelow MW, Dall A, Bartz PJ, Tweddell JS, Sowinski J, Rudd N, et al. Renal dysfunction is common among adults after palliation for previous tetralogy of Fallot. Pediatr Cardiol. 2013;34(1):165-9. 3. Song M, Graubard BI, Rabkin CS, Engels EA. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci Rep. 2021;11(1):464. 4. Manuel V, Miana LA, Turquetto A, Guerreiro GP, Fernandes N, Jatene MB. The role of the neutrophil-lymphocyte ratio for pre-operative risk stratification of acute kidney injury after tetralogy of Fallot repair. Cardiol Young. 2021:1-6. 5. Koo CH, Eun Jung D, Park YS, Bae J, Cho YJ, Kim WH, et al. Neutrophil, Lymphocyte, and Platelet Counts and Acute Kidney Injury After Cardiovascular Surgery. J Cardiothorac Vasc Anesth. 2018;32(1):212-22. 6. Vanmassenhove J, Kielstein J, Jörres A, Biesen WV. Management of patients at risk of acute kidney injury. Lancet. 2017;389(10084):2139-51.   

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Hyperoxia During Cardiopulmonary Bypass Is Associated With Mortality in Infants Undergoing Cardiac Surgery

Asaad G Beshish 1, Ozzie Jahadi 2, Ashley Mello 3, et al. Pediatric Critical Care Med.2021 1;22(5):445-453. DOI: 10.1097/PCC.0000000000002661 PMID: 33443979   Take Home Points Hyperoxia during CPB is an independent risk factor associated with 4-fold greater odds of 30-day mortality. Infants with hyperoxia are more likely to have acute kidney injury, prolonged post-operative stays, and mortality, but the authors failed to identify an association with development of acute kidney injury or prolonged postoperative length of stay when controlled for covariables. A PaO2 of greater than 313 mmHg on CPB has the highest sensitivity with specificity greater than 50% for association with operative mortality. Hyperoxia is associated with greater odds of mortality in neonatal patients. No generally accepted level for pathological hyperoxia exists. Commentary by Matthew A. Lilien, MD and Laura Downey, MD, Children’s Healthcare of Atlanta Department of Pediatric Cardiac Anesthesiology. Currently, there are no clearly defined numerical cutoffs for hypoxia, normoxia, or hyperoxia for pediatric patients undergoing cardiopulmonary bypass. Even adequate oxygenation is poorly defined but usually accepted as the balance between oxygen delivery and consumption.1 During metabolism, oxygen (O2) combines with hydrogen (H) in mitochondria to form water (H2O). However, there can be leakage of the enzyme chain creating highly reactive molecule species referred to as reactive oxygen species (ROS).2  The body has an antioxidant system to balance free oxygen, but if the antioxidant system is overwhelmed by high levels of free oxygen, ROS interact with lipids, DNA, and proteins. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury resulting in cell necrosis or apoptosis.4 Premature infants are especially susceptible to ROS-induced damage for two major reasons. First, adequate concentrations of antioxidants may be absent at birth since developmental increases in antioxidant capacity (maternal-fetal placental transfer, endogenous production) occur in the latter part of gestation in preparation for the transition to extrauterine life. Second, the ability to increase the synthesis of antioxidants in response to hyperoxia or other oxidant challenges is deficient.5 Given that other risk factors like age, weight, and STAT score are not easily modifiable, this paper looks to identify hyperoxia as a modifiable practice-based risk factor that may lead to improved outcomes.   This is a single-center retrospective cohort study of 469 infants undergoing cardiac surgery with CPB from January 2015 to December 2018. Patients were excluded if ECMO was initiated in the operating room and for patients with corrected gestational age less than 35 weeks. The primary objective was to determine if hyperoxia is an independent risk factor for all-cause inpatient mortality. Secondary outcomes were to determine if hyperoxia is associated with acute kidney injury (stage II or III) or prolonged post-operative length of stay (PPLOS) defined by > 14 days. To control for bias of early mortality appearing as a shortened PPLOS, two methods were used: 1) all patients with post-operative mortality were counted as PPLOS regardless of when the death occurred; 2) a composite rank-based outcome was created for days alive ICU free. PaO2 on CPB was determined at the discretion of the perfusionist. PaO2 for individual patients were determined as an average of all arterial blood gas samples while on CPB.   The study included 471 infants undergoing cardiac surgery with CPB. Two patients were excluded due to initiation of ECMO in the OR. Patients had a median age of 97 days, median weight of 4.9kg, and a STAT score of 4 or 5 in 48% of patients. Median duration of CPB and cross clamp were 128 minutes and 54 minutes, respectively. PaO2 levels on CPB were averaged for each individual patient with a mean of 314 mmHg (IQR 287-340 mmHg). Of the 469 patients, 25 died from various causes (HF, cardiac arrest, multiple organ failure, ECMO).   In order to determine the average intraoperative PaO2 which was most predictive for the primary outcome (30-day mortality), a receiver operating characteristic (ROC) curve was used. The optimal cutoff value of PaO2 of 313 mmHg was selected due to the best combination of sensitivity (80%) and specificity (greater than 50%) for 30-day operative mortality. The area under the curve for PaO2 to predict mortality was 0.67 (95% CI, 0.56-0.77, p=0.003). Of the patients included in the study 237/469 fell under the author’s definition of hyperoxia while on CPB. The hyperoxia group was younger in age, weighed less, underwent more complex surgical procedures (median STAT 4 vs. 3), and had longer CPB and cross clamp durations. In multivariable regression, hyperoxia during CPB was associated with greater odds to predict mortality (OR=3.9, 95%CI, 1.4-10.5, p=0.008) when controlled for age, weight, and STAT mortality score. Survivors had a lower median PaO2 while on CPB than non-survivors (311 mmHg IQR, 286-339 vs 339 mmHg IQR 315-355, p=.003). A subgroup analysis was performed for neonates that demonstrated patients with hyperoxia were more likely to have operative mortality (19% vs 6%, p=0.04) when controlling for weight and CPB time (OR =3.8, 95% CI, 1.02-14.0 p=0.04). Univariable and multivariable analysis failed to find association between hyperoxia and development of AKI or PPLOS.   The results show that there may be an independent association with hyperoxia and mortality. Other studies have also demonstrated hyperoxia as an independent risk factor. Synycer-Taub et al showed worse 30-day mortality and need for dialysis in ECMO for cardiac arrest patients with hyperoxia defined as >198 mmHg.6 Rabi et al showed that in asphyxiated infants, neonates in the room air resuscitation group had a lower mortality than those that received 100% oxygen during resuscitation at both the first week of life (odds ratio 0.70, 95% CI 0.50, 0.98) and at one month and beyond (odds ratio 0.63, 95% CI 0.42, 0.94).7 The Beshish et al study does not claim hyperoxia on CPB directly leads to death, but “hyperoxia may have led to a postoperative course that was more likely to have comorbidities and complications that would lead to mortality.”   This study has several limitations that make it difficult to make any changes or recommendations based on these results. This is a single institution study with a small number of patients. Evidence from a large multicenter study may help elucidate the risk of hyperoxia on bypass. This study does not include all variables that could contribute to morbidity, and hyperoxia on CPB may have been a surrogate for disease severity. Hyperoxia has not been established across patient populations or disease states. These authors used a cut point analysis to define hyperoxia. However, a PaO2 of 313 mmHg is generally much higher than intensivists and anesthesiologists target for infants and neonates perioperatively. Oxygen levels are continuously changing based on patient tissue needs with delivery and consumption while on bypass. These samples are arterial gases. The authors did not measure venous oxygen levels to determine tissue oxygen consumption and need for hyperoxia. There is no data that antioxidant levels and the ability to clear free radicals is consistent between individuals. A specific concern for this patient population is whether patients with cyanotic heart disease have the same ability to cope with free radicals as non-cyanotic patients. There was no clearly defined protocol for perfusionists that dictated parameters for patients to receive higher levels of delivered oxygen, such as decreased Near Infrared Spectroscopy (NIRS), decreased mixed venous oxygen saturation, or increasing lactate. Perfusionists could take samples at set times and periods of CPB cases. It is not clear from this study if sicker patients required higher levels of oxygen. Of the subgroup of neonates, the survivors have a wide distribution of PaO2. However, the distribution of PaO2 in the neonatal deaths had overall higher PaO2 levels. It is not clear from this study that hyperoxia is a risk factor for mortality, but instead hyperoxia may be a surrogate for severity of illness. The authors considered STAT scoring as a variable but that doesn’t account for patient’s overall disease state. Based on this paper and others that are referenced throughout this study, it is suggested that delivering higher levels of oxygen may have a detrimental effect on patient outcomes. This is particularly seen when ischemic tissue, as in post cardiac arrest and brain ischemia, is resuscitated with hyperoxia causing reperfusion injury. Similar situations can be extrapolated to CPB and patients with cyanotic heart disease. Congenital heart patients that are chronically hypoxic will partially switch to anaerobic metabolism, resulting in acidosis, depending on the level of hypoxia. Whether this hypoxia is acute or chronic, there is a lower antioxidant reserve due to increased ROS production.8 The result of CPB with hyperoxia will be increased ROS with decreased capacity of the antioxidant system. Thus, it is a logical jump to think hyperoxia on CPB may lead to reperfusion injury and cell death. More research is required on the subject, and current studies are limited to suggest a change in practice. However, the consequences of hyperoxia are not clearly balanced by the benefits of higher PaO2 levels with the potential for cell injury. There is research that suggests normoxia during CPB procedures in adults results in reduced myocardial oxidative stress compared to hyperoxia9. However, the concept of controlled reoxygenation and the practice of aiming for lower levels of oxygen on CPB are not common in the pediatric population. Nevertheless, both are worth investigating given the existing evidence of reperfusion injury.   Reference Pediatric Oxygen Therapy: A Review and Update. Brian K Walsh and Craig D Smallwood Respiratory Care June 2017, 62 (6) 645-661; DOI: https://doi.org/10.4187/respcare.05245 Hyperoxia in anaesthesia and intensive care E. Horncastle1 and A.B. Lumb1,2, * 1 St James’s University Hospital, Leeds, UK and 2 University of Leeds, Leeds, UK Oxygen Toxicity Louise Thomson MBChB, MRCPH, James Paton MD* School of Medicine, University of Glasgow Pacher P., Beckman J.S., Liaudet L.: Nitric oxide and peroxynitrite in health and disease. Physiological reviews 2007; 87: pp. 315-424. Maturation of the antioxidant system and the effects on preterm birth Jonathan M. Davis a,*, Richard L. Auten b Sznycer-Taub NR, Lowery R, Yu S, et al: Hyperoxia is associated with poor outcomes in pediatric cardiac patients supported on venoarterial extracorporeal membrane oxygentation. Pediatr Crit Care Med 2016; 17:350-358 Rabi Y, Rabi D, Yee W: Room air resuscitation of the depressed newborn: A systematic review and meta-analysis. Resuscitation 2007; 72:353-363 Mokhtari, Amir, and Martin Lewis. “Normoxic and Hyperoxic Cardiopulmonary Bypass in Congenital Heart Disease.” BioMed Research International, Hindawi Limited, 2014, pp. 1-11. Crossfer, doi: 10.1155/2014/678268. Topcu AC, Bolukcu A, Ozeren K, Kavasoglu T, Kayacioglu I. Normoxic management of cardiopulmonary bypass reduces myocardial oxidative stress in adult patients undergoing coronary artery bypass graft surgery. Perfusion. 2021;36(3):261-268. doi:10.1177/0267659120946733  

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Dose Estimation For Bivalirudin During Pediatric Cardiopulmonary Bypass

Wolstencroft P, Arnold P, Anderson BJ. Pediatric Anesthesia. 2021;31:637-43. DOI: 10.1111/pan.14125 PMID: 33423355   Take Home Points Bivalirudin clearance rates decrease with age Higher bivalirudin infusion rates in children will achieve target blood plasma concentrations without the need for dose titration After loading dose of 2.5 mg/kg, bivalirudin infusion at a rate of 4.5 mg/kg/hour in a 10 kg child, 4 mg/kg/hour in a 20 kg child, and 3.5 mg/kg/hour in a 30-40 kg child will produce an ACT < 400 seconds Children ≥ 50 kg should follow adult dosing protocols   Commentary by Kelly A Machovec, MD, MPH, Associate Professor of Anesthesiology, Duke University Hospital. Bivalirudin is a direct thrombin inhibitor used as an alternative to heparin anticoagulation in cases of heparin induced thrombocytopenia with thrombosis, severe antithrombin deficiency, or anaphylaxis to protamine. Bivalirudin is metabolized by intracellular proteolysis, with 20% excreted unchanged by the kidneys. Wolstencroft, Arnold and Anderson present a study using allometry to determine appropriate bivalirudin infusion rates for pediatric patients requiring bivalirudin for cardiopulmonary bypass (CPB) anticoagulation1.   Previous studies in healthy adults demonstrate that a target bivalirudin plasma concentration of 10-15 mg/L is sufficient to maintain effective anticoagulation, as guided by activated clotting time (ACT)2. Bivalirudin anticoagulation reaches a ceiling ACT value of about 450 seconds in the adult population. However, pharmacokinetic and pharmacodynamic studies for bivalirudin in adults undergoing procedures with CPB have not been widely conducted; dosing in this population is extrapolated from studies of both healthy adults and those having percutaneous cardiac procedures2,3. For CPB, generally accepted dosing in adults is a loading dose of 1 mg/kg followed by an infusion of 2.5 mg/kg/hour, to achieve a target ACT of 350-500 seconds.   Bivalirudin pharmacokinetics have been studied in children with congenital heart disease having cardiac catheterization procedures, who received a bolus loading dose of 0.75 mg/kg, then infusion of 1.75 mg/kg/hour4. The authors of this PK study demonstrated that bivalirudin clearance decreases with age, with neonates and infants (less than 2 years) having the highest clearance. Interestingly, the authors postulate that the immature renal system in neonates and young infants, which should decrease bivalirudin clearance, is likely balanced by enhanced proteolytic degradation in the blood. As in adults, bivalirudin has a ceiling effect on the ACT, with maximum ACT of approximately 400 seconds4.   Neither adult dosing regimens nor pediatric percutaneous cardiac dosing regimens are appropriate for dosing bivalirudin in children undergoing cardiac procedures with CPB. Wolstencroft, Arnold and Anderson address this knowledge gap by using allometry to determine pediatric dosing of bivalirudin5. Allometric theory states that the clearance of bivalirudin should be the same in children as in adults, as long as the dose is scaled for the child’s weight using the following equation:   Infusion rateChild = Infusion rateAdult x (WeightChild/70)0.75   The authors propose that, given the derangements to hemostasis and coagulation induced by CPB, the following infusion rates should be used after bivalirudin loading dose: 10 kg – 4.5 mg/kg/hour 20 kg – 4 mg/kg/hour 30-40 kg – 3.5 mg/kg/hour 50 kg – adult dosing These rates will produce an ACT less than 400 seconds. However, the authors emphasize the importance of avoiding changes to the infusion rate to chase a given ACT. After increasing the infusion rate, it takes about 3-5.5 half-lives to reach a new steady-state, so changes based on the ACT will eventually accumulate and risk excessive anticoagulation and bleeding complications.   What this means for our practice Bivalirudin dosing in children having cardiac surgery with CPB cannot simply be adopted from adult protocols. Adult dosing does not consider developmental hemostasis and its impact on coagulation and fibrinolysis. Further, adult regimens do not account for unique aspects of pediatric cardiac procedures, including hypothermia, prolonged aortic cross-clamp times, and the use of ultrafiltration. Each of these aspects of pediatric CPB affects bivalirudin clearance.   Using allometric theory, bivalirudin infusion rates can be extrapolated from adult data and applied to children of a given body weight. After a loading dose of 2.5 mg/kg, the infusion should be started at the rate indicated by the child’s weight and then not adjusted, despite ACT values that are out of the intended range for CPB. Doing so may result in unintentional over- or under-dosing with potentially deleterious consequences. Unfortunately, no point-of-care tests for bivalirudin efficacy are yet available for clinical use.   The dosing regimen for neonates and infants is still uncertain despite the allometric methods applied in this study. The combination of immature renal function and immature coagulation/fibrinolytic systems will affect bivalirudin clearance, but research to date does not demonstrate the magnitude of these effects. This is a topic in need of further investigation.   References 1. Wolstencroft P, Arnold P, Anderson BJ. Dose estimation for bivalirudin during pediatric cardiopulmonary bypass. Paediatr Anaesth. 2021;31(6):637-643. 2. Zhang DM, Wang K, Zhao X, et al. Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers. Acta Pharmacol Sin. 2012;33(11):1387-1394. 3. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther. 2002;71(6):433-439. 4. Forbes TJ, Hijazi ZM, Young G, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2011;77(5):671-679. 5. Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12(3):205-219.   

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Impact of Specialized Electrophysiological Care on the Outcome of Catheter Ablation for Supraventricular Tachycardias in Adults with Congenital Heart Disease: Independent Risk Factors and Gender Aspects

Impact of Specialized Electrophysiological Care on the Outcome of Catheter Ablation for Supraventricular Tachycardias in Adults with Congenital Heart Disease: Independent Risk Factors and Gender Aspects. Fischer AJ et al. Heart Rhythm. 2021; 18:1852-1859.   Take...

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