1. 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

2. 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

3. VAD Prevalence in Pediatrics
From Pedimacs database:
Between , 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

4. 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

5. 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

6. 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

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

8. Study Design
Retrospective chart review of the pediatric heart transplant patients ( 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

9. 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)

10. 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

11. 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%)

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

13. 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

14. 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 (0.99 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

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

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

17. 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

18. 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

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

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

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