Ambulatory Intravenous Inotropic Support in Pediatric and ... · •14 pts on home IV milrinone...

Ambulatory Intravenous InotropicSupport in Pediatric and Congenital

Heart Failure: How to Evaluate Outcomes

Sotiria Apostolopoulou

Department of Paediatric Cardiology and Adult Congenital Heart Disease

Onassis Cardiac Surgery Centre, Athens, Greece

Background

• CHD and CM cause end-stage HF in children and adults CHD patients

frequently requiring inotropes and MCS as a bridge to transplant in up

to 57% of cases

• Children on MCS, even for a short time, have:

- survival rates to transplant or recovery as low as 75%

- risk for thromboembolic, hemorrhagic, neurologic events, respiratory

failure and multisystem organ failure

• In the absence of heart transplantation, end-stage HF has significant

morbidity and mortality, poor quality of life, complicated management,

and frequently, long-term continuous inotropic support in the ICU

• Post myocarditis dilated CM, even if needing inotropic or MCS, has a

significant chance of recovery within 2 years → should these patients

receive long-term inotropic support prior to referral for transplant?

Ambulatory inotropic therapy in end-stage HF in adults

• AI therapy is advocated in stage D HF for 1) pts awaiting heart

transplant or MCS or 2) palliative care in non eligible pts

• Older studies showed that home inotropic therapy in adults, despite

improving clinical status and lowering cost, increases mortality and

morbidity probably related to arrhythmic events•

• Low dose PO enoximone is safe but does not improve mortality,

cardiovascular hospitalization or 6MWTD

• 112 inotrope dependent pts (not transplant candidates)

- median F/U: 130 days (2-2345 days)

- High mortality (76%), rehospitalization 49%

• Trend towards MCS with the significant risks of thromboembolic

events, bleeding, cerebral hemorrhage, pump malfunction, etc

ACCF/AHA guideline for the management of heart failure JACC 2013

ESSENTIAL trials. Metra et al. Eur Heart J 2009

Gorodeski et al. Circ Heart Fail 2009

Packer et al. N Engl J Med 1991

Hampton et al. Lancet 1997

Cohn et al. N Engl J Med 1998

Park et al. Circ Heart Fail 2012

Experience with ambulatory inotropic therapy in children with end-stage HF

• 14 pts on home IV milrinone and/or dobutamine, age 6-18 yrs

- Duration 14-476 (median 68) days

- 8 palliative care, 6 awaiting heart transplant

- Safe, cost, family dynamics with hospitalization

• 7 pts on home IV inotropes, age 14.6 ±3.7 yrs

- Duration 4-84 (median10) wks

- 1 death, 5 complications in 2 pts, 6 pts bridged to transplant

- EF from 30 to 39% on therapy

• 106 pts on home IV inotropes, age 10.1±6.4yrs

- Duration median 47 days (4–323 days)

- 85% transplant

- 8% weaned from support

- 6% deaths

Berg et al. J Heart Lung Transplant 2007

Price et al. J Card Fail 2006

Birnbaum et al. Circ Heart Fail 2015

Criteria for IV ambulatory inotropes (AI) and/or Levosimendan (LS)

• Intractable CHF despite maximum oral therapy

• Cause: myocarditis, dilated CM, restrictive CM, CHD

• Inability to wean IV inotropes after multiple attempts of slow weans over at least 4 weeks

• Stabilization on IV inotropes without need for ICU

• Without significant arrhythmia–Defibrillator if indicated

• Local Transplant Team → negative for mechanical assist device, mostly due to age and size

Apostolopoulou SC, et al. Pediatr Cardiol. 2018 Oct;39(7):1315-1322

Protocol for ambulatory inotropes

• Maximal tolerated oral therapy, including β-blockers, diuretics

and ACE inhibitors along with the IV inotropes

• Subsequent initiation of levosimendan infusions q 2-3 wks

• Stable in hospital for at least 4 weeks

• Insertion of central Hickman catheter

• Education of 2 caretakers (incl. the pt if >12 yo) in sterile

procedures, infusion preparation, pump function etc

• Patients stay locally for 2 additional weeks

• Periodic attempt at slow wean of inotropes


Population Demographics

Characteristics No (%)

Patients 27

Gender

Male 16 (59%)

Female 11 (41%)

Age at initiation of therapy 9.4 (0.1-26.1) years

NYHA Class at initiation of therapy III-IV

NT- proBNP at initiation of therapy 2542 (320-16166) pg/ml

Inotropic therapy

Ambulatory Inotropes alone 7 (26%)

Levosimendan alone 6 (22%)

Combined Ambulatory Inotropes and Levosimendan 14 (52%)


Diagnosis No (%)

Myocarditis 6 (22%)

Dilated cardiomyopathy 13 (48%)

Restrictive cardiomyopathy 2 (8%)

Postoperative CHD 6 (22%)

Single ventricle s/p Fontan 1

Single ventricle s/p Glenn 1

Aortic stenosis s/p Ross operation 1

Anomalous LCA origin from PA s/p reimplantation 1

CCTGA s/p tricuspid valve replacement 1

CAVC s/p biventricular repair and mitral valve replacement 1

Diagnoses


Diagnosis –Age at initiation

0

2

4

6

8

10

12

14

Myocarditis Dilated CM Restrictive CM CHD

Diagnoses

22%

48%

8%

22%

Nu

mb

er o

f p

atie

nts

0

2

4

6

8

10

12

0-1yo 1-5yo 5-10yo 10-18yo >18yo

Age at initiation of AI/LS

Nu

mb

er o

f p

atie

nts

22%

15%

37%

7%

19%


Results – Summary (27 pts)

• Median F/U 2.1 (0.3-21.3) years

• 4 pts (2 DCM, 2 RCM): prolonged hospitalization and death after 0.8-2.1 years (mortality 15%)

• 6 pts (22%): heart transplantation after 0.3-2.3 years

• 17 pts stable for 4mos to 3.4 yrs

• WHO class I-II, good QoL, good social life, attending school, playground

• AI weaned and discontinued in- 6 improved myocarditis pts after 1.2 (0.4-2.3) yrs - 2 CM pts after 0.7 and 3.7 years (still on LS infusions)- 1 CM pt with LVAD and was transplanted 3.5 yrs later


AI as bridge to recovery

• 6 patients

• 3 Parvo B19

• 4 pts received:

- AI for 0.3-1.3 yrs

- LS for 0.3-1.2 yrs

• 2 pts received:

- only LS for 1.1-2.3 yrs

• Post discontinuation:

stable without HF or

deterioration and LVEF >

60% over 2.8 (0.6-3.4) yrs0 5 10 15 20 25

6

5

4

3

2

1

AI

LS

Bridge to recovery

Pat

ien

ts

Months


AI and/or LS as bridge to recovery

1 mo after discontinuation of HI,

SF 33%

Initial SF 16% 9 mos HI, SF 26%

2.7 yrs after discontinuation of HI,

SF 40%

6 mos HI, SF 14%

1 yr after discontinuation of HI,

SF 33%


Home inotropes as bridge to recovery

SF (%) versus time (months)

0

10

20

30

40

50

0m 3m 6m 12m 24m 30m

25

35

45

55

0m 3m 6m 12m 24m 30m

LVEDD (mm) versus time (mos)

• 3 parvovirus myocarditis patients with full recovery

• All needed both IV inotropes and levosimendan initially

• One agent discontinued after months, but remodeling and recovery

required treatment for 1 year

=Stop inotropes

=Stop levosimendan

SF (%)LVEDD


AI and/or LS as mainstay therapy

• 4 deaths after 0.8-2.1 years of AI

• 11 pts stable WHO class II: 7 pts AI+LS for 0.3-3.7 yrs / 4 pts only LS for 0.5-4.2yrs

• 3 discontinuations (1 LVAD, 2 CM still on LS)

0 5 10 15 20 25 30 35 40 45 50

15

14

13

12

11

10

9

8

7

6

5

4

3

2

1

AI LS

Mainstay therapy

: deaths

Pat

ien

ts

Months


AI and/or LS as mainstay therapy

2 yrs home inotropes

LVEDD 45mm, SF 21%, 2+ MR

3.4 yrs on HI, monthly Simdax

LVEDD 47mm, SF 21%, 2+ MR

Attempt at weaning

Start inotropes in hospital, home

after 1 month

LVEDD 48mm, SF 18%, 3-4+MR

AI and/or LS until Transplant

• 6 patients, dilated CM, AI 3-27 mos, levosimendan 7-24 mos

• Pts 1,2: heart transplant on AI (F/U 21 years post transplant)

• Pt 3: abrupt stop inotropes→shock→LVAD→Heart Tx (F/U 2 yrs)

• Pt 4, 5, 6: abrupt stop inotropes→shock→ECMO→Death

0 5 10 15 20 25 30

6

5

4

3

2

1

AI LS

Bridge to transplant

*

*

*

: deaths

Months

Pat

ien

ts


AI in PH due to LV dysfunction

44

62

28 28

1.6 1.7

9.8

19.8

32

26

20

14

3.6 3 2.84

0

10

20

30

40

50

60

Pt 1 Pt 2 Pt 1 Pt 2 Pt 1 Pt 2 Pt 1 Pt 2

Mean PAP(mmHg) PCWP(mmHg) CI (L/min/m2) PVRI (Wood U)

Baseline

After AI

Pulmonary hypertension in HF

Hem

od

ynam

icva

riab

les

bef

ore

an

d a

fter

AI

Both patients underwent successful heart transplantation at our

institution and remain stable over 21 years follow up


Ambulatory inotropes - Quality of life

• Diagnosis DCM 2.9yo

• Stabilization only on IV

Dob/Mil at 3.1 yo

• AI for 3.7 yrs

• Monthly LS 3.9 yrs

• Now 8yo

• 3rd grade at school

• Happy, playful with 4yo

brother

• Successful weaning of AI last

year, remained on LS, she

went swimming last summer!

Complications - Safety

• 4 line infections, in 3 patients:- 3 → IV antibiotics for 2 weeks with subsequent negative

cultures for weeks- 1 → 2nd infection 6 mos after the 1st → inadequate response to

IV antibiotics → catheter removal and reinsertion later

• 4 catheter dislodgements in infants → reinsertion

• No reports of pump malfunction or emergent hospital admissions apart from the line infections

• No neurologic, bleeding or thromboembolic events

• No sudden deaths, no defibrillator discharge


Heart or Heart-Lung Transplantation

• No pediatric heart transplant program in Greece

• Adult heart transplant program in Greece considers patients > 12 yo or small adult size

• Donor shortage (6-10 per year for Greece)

• No heart-lung or lung transplant program in Greece (for pulmonary hypertension pts)

• Difficult acceptance of candidates in foreign programs

• CHD issues: prior operations, guarded results, difficult acceptance of candidates in foreign transplant programs


Conclusions-Long-term AI and/or LS

• Feasible, safe, with few complications in pediatric pts with intractable CHF, even in infants

• Good QoL considering severity of disease

• Mainstay therapy in absence of transplant option

• No sudden deaths or significant arrhythmias (nonischemicetiology)

• Allows remodeling and possible recovery in myocarditis, which may take up to 1 year

• Improves PH to allow possible heart transplant

• Provides time to allow transfer in foreign Pediatric Transplant Program or allow growth to permit transplant in local Adult Transplant Program


There is no conflict of interest

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