Madeleine Townsend, MD Cleveland Clinic Pediatric Cardiology Fellow Assessing Vasoplegia Syndrome After Heart Transplantation in Pediatric Patients Bridged with Ventricular Assist Devices vs Medical Therapy My name is Madeleine Townsend and I’m currently a Pediatric Cardiology fellow at Cleveland Clinic Children’s. Thank you for the opportunity to share my research with you today. Madeleine Townsend, MD Cleveland Clinic Pediatric Cardiology Fellow

Ventricular Assist Devices (VAD) Increasingly used as a bridge therapy to heart transplant Decrease waitlist mortality & improve survival to transplant 2 types: pulsatile and continuous Pulsatile, e.g. Berlin EXCOR Continuous, e.g. HeartWare, HeartMate Help failing heart pump blood to the body 3 uses - buying time to allow myocardial function to return (e.g. myocarditis), "destination therapy" in adult population, and bridge to heart transplant How each VAD functions Shuhaiber J et al. BMJ. 2010

VAD Prevalence in Pediatrics From Pedimacs database: Between 2012-2016, 42 hospitals implanted 432 devices in 364 patients less than 19 years of age Diagnoses included: Cardiomyopathy 61% Myocarditis 11% Congenital heart disease 21% ~50% underwent heart transplant within 6 months So what does the prevalence look like in Pediatrics? Blume ED, et al. IntenJ Heart Lung Transplant. 2018

Vasoplegia Syndrome Potential complication following cardiac surgery Risk factors include time on cardiopulmonary bypass (CBP), need for vasopressors prior to CBP, preoperative meds (ACEI, ARB, beta blockers) Pre-surgery VAD use in adult literature With known predisposing factors, rate 30-50% No universally accepted definition Generally within 6 hours of cardiopulmonary bypass The low SVR state described in vasoplegic syndrome is found in a number of disease entities, including sepsis, glucocorticoid deficiency, hepatic failure, or long-lasting severe shock of any cause.  Sepsis is the most common cause of vasoplegia Associated with a diffuse systemic inflammatory response and is mediated largely through cellular hyperpolarization, high levels of inducible nitric oxide, and a relative vasopressin deficiency. Cardiopulmonary bypass is a particularly strong precipitant of the vasoplegic syndrome, largely due to its association with nitric oxide production and severe vasopressin deficiency. Shaefi S, et al. J Cardiothorac Vasc Anesth. 2018

Vasoplegia Syndrome Decreased SVR with normal/high cardiac output Systemic vasodilation/hypotension Inadequate tissue perfusion Associated with a diffuse systemic inflammatory state -> deficit in smooth muscle contraction -Components: Within 48 hours of transplant, Significant arterial hypotension Adult: MAP <70 mmHg Pediatrics: age-dependent Normal or high cardiac output Low SVR Increased requirement for intravascular volume & vasopressors -Can also be resistant to catecholamines which carries a mortality of up to 25% Catecholamines Fluids Liu H, et al. J Clin Anesth. 2017 Chan JL, et al. Ann Thorac Surg. 2018 Omar S et al. Am J Med Sci. 2015

Vasoactive Index Score (VIS) Wernowsky Index Score (IS) = Dopa (μg/kg/min) + Dobutamine (μg/kg/min) +100× Epi (μg/kg/min) VIS = IS + 10× Milrinone (μg/kg/min) +10,000× Vasopressin (U/kg/min) + 100× Norepi (μg/kg/min) Evaluate inotropic score (IS) as a predictor of morbidity and mortality in the early post-operative period among infants who underwent a cardiac surgery with CPB (arterial switch operation). Max VIS level over the first 48 h was a good predictor of poor clinical outcome (death, cardiac arrest, prolonged mechanical circulatory support, renal replacement therapy and/or neurologic injury). High inotropic score was also associated with prolonged ICU stay, duration of mechanical ventilation and time to negative fluid balance A more comprehensive score: Davidson et al. performed a prospective observational study of 70 infants undergoing cardiothoracic surgery. Developed a modified inotropic score - VIS. They found that a higher VIS at 48 h after cardiothoracic surgery was strongly associated with increased length of ventilation and prolonged ICU and total hospital stay, and that VIS was more predictive of poor short-term outcome than IS. Davidson J, et al. Intensive Care Med. 2012

Hypothesis VAD use may predispose patients to an increased rate of vasoplegia syndrome following pediatric heart transplantation relative to medical therapy alone. Paraphrase

Study Design Retrospective chart review of the pediatric heart transplant patients (0 - 21 years of age) at Cleveland Clinic Children’s Hospital from December 2010 to December 2016 Patients divided based on VAD use pre-transplant vs medical therapy. VAD group subdivided into continuous vs pulsatile type

DATA COLLECTION & ANALYSIS Statistical analysis was used to compare VAD vs medical therapy patient groups, as well as between continuous vs pulsatile VADs Study data were collected and managed using REDCap. Study groups were compared on continuous and categorical outcomes using Kruskal-Wallis tests and Chi-square or Fisher’s exact tests, respectively. Kruskal-Wallis tests for continuous and ordinal characteristics Chi-square or Fisher’s exact tests for categorical characteristics SAS version 9.4 (The SAS Institute Cary, NC)

Vasoplegia Calculation VIS calculated pre-operatively and highest score within 48 hours post-transplant Inclusion: Post-op VIS score >8 to account for post- transplant protocol drugs including milrinone and low- dose epinephrine Exclusion: significant post-operative bleeding and/or decreased cardiac function

Pediatric Heart Transplant Patients N=38 Ventricular Assist Device N=14 Medical Therapy N=24 Pulsatile Flow Device N=7 Continuous Flow Device N=7 Vasoplegia N=16 (79%) P-value 0.87 Vasoplegia N=6 (86%) Vasoplegia N=5 (71%)

Medical Therapy (total 24): 13 cardiomyopathy 9 CHD 2 other - coronary vasculopathy, 2nd transplant VAD (total 14) 12 cardiomyopathy 2 CHD

Medical Therapy vs VAD Medical (N=24) VAD (N=14) P-value Male 12 (50%) 10 (71%) Age at Transplant (years) 12 (0,20) 14 (1,18) 0.58 Weight (kg) 37 (4,89) 38 (8,68) 0.95 Time on VAD pre-transplant (days) 45 (3,232) Inotrope score pre-op 6 (0,15) 5 (0,40) 0.016 Inotrope score post-op 16 (7,50) 16 (9,58) 0.53 Time on cardiopulmonary bypass (min) 118 (71,364) 101 (74,208) 0.62 Ischemic time of donor heart (min) 197 (101,293) 189 (92,218) 0.35 Post-operative bleeding 4 (17%) 1 (7%) 0.63 Inotrope scores -higher preoperative inotrope score in medical group

Pulsatile vs Continuous VAD Male 5 (71%) Age at Transplant (years) 5 (1,14) 15 (14,18) Weight (kg) 20 (8,31) 52 (45,68) Pre-op time on VAD (days) 99 (32,232) 44 (3,127) Inotrope score pre-op 5 (0.40) 5 (0,10) Inotrope score post-op 16 (12,45) 16 (9,58) Time on cardiopulmonary bypass (min) 138 (84, 208) 97 (74,136) Ischemic time of donor heart (min) 197 (139,218) 185 (92,215) Average age of transplant younger in pulsatile group Inotrope scores not difference (pre-op trend toward lower inotrope score with continuous VAD) Death – p-value 0.61 (0.99 if comparing medical vs VAD total) 1 Medical (CHD pre-op, NEC & PE?) -> 4% 1 Pulsatile (CHD pre-op, Ab mediated rejection) -> 14% 0 Continuous

What we also looked at was length of stay post-transplant ICU post-op: p=0.047 Hospital post-op: p=0.51

Medical Therapy: 16/24 Pulsatile VAD: 6/7 Continuous VAD: 5/7 p=0.87

Conclusion High incidence of vasoplegia syndrome in pediatric post-transplant patients No significant difference between medical therapy & VAD groups Trend toward increased rate in VAD group, small sample size may be impacting results Similar finding to that seen in adult literature Paraphrase

Limitations Small sample sizes Retrospective review No universally accepted definition of vasoplegia syndrome Small sample sizes limited conclusions that could be drawn from the data

Future Directions Multicenter prospective design or use of the current heart transplant databases could contribute a larger population size

Thank you to Dr. Boyle and the Pediatric Heart Transplant team, as well as the support of the CCF Biostatistics department

Thank you, and I’ll be happy to answer any questions now.