1. No category

5/5/2015
Introduction
Anticoagulation Monitoring in Pediatric
Patients Undergoing Extracorporeal
Membrane Oxygenation (ECMO)
Julie Dang, Pharm.D.
PGY-1 Pharmacy Practice Resident
Detroit Medical Center, Children’s Hospital of Michigan
The speaker has no actual or potential conflicts of interest in relation to this presentation.
• ECMO is a form of prolonged cardiopulmonary
bypass to support patients with respiratory
and/or cardiac failure refractory to conventional
treatment
• Improvement in ECMO technology, research,
and outcomes continues to grow through
collaborative efforts of the Extracorporeal Life
Support Organization (ELSO)
Maslach-Hubbard A, Bratton SL. World J Crit Care Med. 2013;2(4):29-39.
ECMO Indications
Goals of ECMO
•
•
•
•
•
•
•
•
• Decrease respiratory and/or cardiac work load
• Increase healing time
• Minimize complications
Meconium aspiration syndrome
Persistent pulmonary hypertension
Congenital diaphragmatic hernia
Severe sepsis
Severe respiratory distress
Bridge to transplant
Post-surgical repair of congenital cardiac defects
Cardiopulmonary support for organ donation
Maslach-Hubbard A, Bratton SL. World J Crit Care Med. 2013;2(4):29-39.
Photo adapted from: http://s593.photobucket.com/user/stevs102/media/Rhys/Rhys_152.jpg.html
ECMO Statistics
Extracorporeal Life Support Organization. ECLS Registry Report International Summary. Published January 2015.
Buck ML. Clin Pharmacokinet. 2003;42(5):403-17.
1
5/5/2015
Complications of ECMO
Hemostatic Balance During ECMO
•
•
•
•
•
• Continuous contact between blood and ECMO
circuit leads to chronic hemostatic activation
Hemorrhage/hemolysis
Thrombosis
Neurologic deficits
Acute kidney injury
Infection
– Hypercoagulable state
• Anticoagulation is necessary to prevent
thrombotic complications
– Anticoagulant of choice: unfractionated heparin (UFH)
• Bleeding complications may occur due to
coagulation instability in critically ill patients
Maslach-Hubbard A, Bratton SL. World J Crit Care Med. 2013;2(4):29-39.
Anticoagulation and ECMO
• Anticoagulation management varies across each
ECMO centers
• No definitive guidelines or consensus for the
most appropriate management of
anticoagulation during ECMO available
Extracorporeal Life Support Organization. ELSO Anticoagulation Guideline. Published 2014.
Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37-S42.
Anticoagulation and ECMO
Activated Clotting
Time (ACT)
• Measures clotting time of whole blood
• Goal: 180-220 seconds
Activated Partial
Thromboplastin Time
(aPTT)
• Measures time to clot formation within
intrinsic pathway
• Goal: 48-78 seconds
Anti-Factor Xa
(anti-Xa) levels
• Measures heparin effect and factor Xa
inhibition
• Goal: 0.3-0.7 units/mL
Antithrombin III
(ATIII) Levels
• Binds to heparin to inhibit factor Xa and
thrombin formation
• Goal: 50-120%
Extracorporeal Life Support Organization. ELSO Anticoagulation Guideline. Published 2014.
Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37-S42.
Extracorporeal Life Support Organization. ELSO Anticoagulation Guideline. Published 2014.
Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37-S42.
Learning Question #1
Learning Question #2
• Which of the following is the anticoagulant of
choice for patients on ECMO?
• Which of the following is not an appropriate
laboratory test to utilize to ensure efficacy of
anticoagulation in ECMO patients?
A.
B.
C.
D.
Low molecular weight heparin
Vitamin K antagonists
Unfractionated heparin
Direct thrombin inhibitors
A.
B.
C.
D.
Anti-Factor Xa Level (Anti-Xa)
Activated Clotting Time (ACT)
Activated Partial Thromboplastin Time (aPTT)
Mean Corpuscular Volume (MCV)
2
5/5/2015
Anticoagulation Monitoring in Pediatric
Patients Undergoing ECMO
Goal
Anticoagulation Monitoring in Pediatric
Patients Undergoing Extracorporeal
Membrane Oxygenation (ECMO)
• To evaluate heparin infusion rate
changes based on various
laboratory coagulation parameters
• To assess efficacy in preventing
thrombotic and bleeding
complications
Julie Dang, Pharm.D.1
Preceptor: Joanna Ditouras, Pharm.D.1
Co-Investigators: Michelle Veenstra, M.D.2, Paul
Stockmann, M.D.2, and Kelly Holzhausen, Pharm.D.1
1Department of
Pharmacy Services, Children’s Hospital of Michigan, Detroit, Michigan
Pediatric Surgery, Children’s Hospital of Michigan, Detroit, Michigan
2Department of
Study Design
Retrospective Chart Review
• January 1, 2013 to February 28, 2015
• 220-bed tertiary pediatric hospital in Detroit, MI
Inclusion Criteria
• Level I pediatric trauma center
• Patients <18 years of age on ECMO at Children’s Hospital of
Michigan (CHM)
– 38-bed pediatric intensive care unit (PICU)
• Level IV neonatal center
Exclusion Criteria
• Patients >18 years of age
– 43-bed neonatal intensive care unit (NICU)
• ECMO Center of Excellence
Statistical Analysis
• Descriptive statistics
http://www.childrensdmc.org/
Data Collection
Therapeutic Monitoring Parameters
• Patient demographics
• Hospital service
•
•
•
•
•
– PICU
– Cardiovascular (CV) Surgery
– NICU
• Type of ECMO
• Number of hours on ECMO
ACT
Anti-Xa levels
APTT
ATIII levels
Number of fresh frozen plasma (FFP)
administrations
• Number of platelet administrations
3
5/5/2015
Complications
Survival Outcomes
Hemorrhagic
• Incidences of bleeding
defined as:
• Symptomatic bleeding in
a critical area or organ
• Bleeding requiring
surgical intervention
• Bleeding resulting in
death
• Number of packed red
blood cell (PRBC)
administrations
Thrombotic
• Systemic thrombosis
• Number of oxygenator
changes
• Number of ECMO circuit
changes
CHM ECMO Anticoagulation Protocol
Before Protocol
After Protocol
• Bolus: 100 units/kg
• Bolus: 100 units/kg
• Continuous infusion
• All patients:
• 20 units/kg/hr
• Continuous infusion
• Patients ≤5 kg:
• 20 units/kg/hr
• Patients >5 kg:
• 10 units/kg/hr
CHM ECMO Anticoagulation Protocol
•
•
•
•
Survival to decannulation
30 day survival post decannulation
Surgical procedures while on ECMO
Culture positive infections
CHM ECMO Anticoagulation Protocol
Heparin Titration
Before Protocol
• Managed by ECMO
Respiratory Therapists
• Doses adjusted based
on ACTs alone
• Target Coagulation
• Managed by primary
service
• Doses adjusted by antiXa levels and other
clinical factors
• Target Coagulation
• ACT: 180-220 sec
• Anti-Xa: 0.3-0.7 units/mL
• ATIII Activity: ≥70%
• ACT: 200-300 sec
Results
46 Total Patients
• No standard
• Transfusions given as needed
Transfusions • ATIII levels were not tested or corrected
Before
Protocol
• Platelets <100,000/mm3: 10 mL/kg
• PRBC (Hgb <10 gm/dL): 10 mL/kg
• ATIII Activity
Transfusions • >70%: No correction
• 50-70%: administer FFP 10 mL/kg
After
• <50%: Correct to 100-120%
Protocol
Heparin Titration
After Protocol
7 patients excluded due to no
ECMO information from EMR
39 Patients
Included
24 Patients
Before Protocol
NICU:
10 Patients
PICU:
5 Patients
15 Patients After
Protocol
CV Surgery:
9 Patients
NICU:
6 Patients
PICU:
3 Patients
CV Surgery:
6 Patients
4
5/5/2015
Patient Demographics
Before Protocol (n=24)
Median [Range]
After Protocol (n=15)
Median [Range]
7.1 mos [17 hrs-5 yrs]
1.8 yrs [1 day-15 yrs]
Average ACT: 204.7 sec
(Range: 135-712 sec)
70
60
Weight
5.29 kg [2.2-16.3 kg]
8.54 kg [2.8-36 kg]
Height
58.56 cm [45-117 cm]
69.2 cm [49-152 cm]
ECMO Hours
120 hrs [11 hrs-12.4 days]
211 hrs [32 hrs– 44.6 days]
Gender
Male: 13 (54%)
Female: 11 (46%)
Male: 10 (67%)
Female: 5 (33%)
VV: 4 (17%)
VA: 19 (79%)
VV  VA: 1 (4%)
VV: 0 (0%)
VA: 14 (93%)
VV  VA: 1 (7%)
Type of ECMO
80
Percentage
Age
Therapeutic Monitoring Before Protocol
50
ACT
aPTT
40
30
20
10
0
Within Range
ACT Trends Before Protocol
Above Range
Therapeutic Monitoring After Protocol
400
90
Average Heparin Dose:
31.4 units/kg/hr
(Range: 0-79.5 units/kg/hr)
350
Average Anti-Xa Level:
0.45 units/mL
(Range: 0-1.68 units/mL)
Average ACT: 231.7 sec
(Range: 100-575 sec)
80
70
300
Percentage
ACT Level (seconds)
Below Range
250
200
60
50
40
Anti-Xa
30
ACT
20
150
10
100
15
20
25
30
35
40
45
0
50
Heparin Dose (units/kg/hr)
Within Range
Anti-Xa Level Trends After Protocol
400
350
0.8
ACT Level (seconds)
Anti-Xa Level (units/mL)
Below Range
ACT Trends After Protocol
Average Heparin Dose:
33 units/kg/hr
(Range: 0-58.1 units/kg/hr)
1
0.9
Above Range
0.7
0.6
0.5
0.4
0.3
300
250
200
150
100
0.2
50
0.1
0
0
0
10
20
30
Heparin Dose (units/kg/hr)
40
50
0
10
20
30
40
50
Heparin Dose (units/kg/hr)
5
5/5/2015
Platelet and FFP Transfusions
Hemorrhagic Complications
Before Protocol
8/24 Patients (33%)
Before Protocol
After Protocol
Platelets
•No. of transfusions
•Average [range]
135
112/mm3 [23-490/mm3]
138
115.3/mm3 [27.4-200/mm3]
FFP
•No. of transfusions
36
79
ATIII
•No. of transfusions
•Average [range]
0
N/A
22
59.9% [18-101%]
PRBC Transfusions
After Protocol
6/15 Patients (40%)
CV Surgery
2 (25%)
CV Surgery
2 (33%)
NICU
4 (50%)
NICU
3 (50%)
PICU
2 (25%)
PICU
1 (17%)
Systemic Thrombotic Complications
Before Protocol
4/24 Patients (17%)
Before Protocol
After Protocol
No. of
transfusions
94
73
Average Hgb
[range]
12.39 gm/dL [6.3-21.8 gm/dL]
11.06 gm/dL [7.2-18.6 gm/dL]
Average Hct
[range]
36.2% [18.5-61.4%]
33% [22.4-48%]
ECMO Circuit Thrombotic Complications
After Protocol
5/15 Patients (33%)
NICU
1 (25%)
CV Surgery
2 (40%)
PICU
3 (75%)
NICU
1 (20%)
PICU
2 (40%)
Survival Outcomes
90
80
• Before Protocol: 4
• After Protocol: 9
70
n=19
n=12
n=17
60
Percentage
Oxygenator
Changes
50
n=7
40
Before Protocol
After Protocol
30
ECMO Circuit
Changes
• Before Protocol: 11
• After Protocol: 4
20
10
0
Survival To Decannulation
30 Day Survival After
Decannulation
6
5/5/2015
Survival Outcomes – Surgical Procedures
Before Protocol
After Protocol
11 Total Surgical Procedures
12 Total Surgical Procedures
Survival Outcomes – Infection Risk
Before Protocol
9/24 Patients (37.5%)
NICU
1 (8%)
PICU
4 (36%)
CV Surgery
7 (64%)
CV Surgery
7 (58%)
PICU
4 (33%)
• 11 Infections
• Average ECMO Hours: 118
After Protocol
5/15 Patients (33%)
• 10 Infections
• Average ECMO Hours: 383
Study Limitations
Future Directions
• Statistical testing for significance was not
performed
• Older pediatric patients underrepresented
• Continual reassessment of protocol
• Utilizing fibrinogen levels and cryoprecipitate
transfusions to optimize anticoagulation efficacy
• Expanding multidisciplinary care to utilize
hematology/oncology services
• Creating separate anticoagulation protocols for
different populations or age groups
Acknowledgements
References
•
•
•
•
•
Dr. Joanna Ditouras, Pharm.D.
Dr. Michelle Veenstra, M.D.
Dr. Kelly Holzhausen, Pharm.D.
Dr. Paul T. Stockmann, M.D.
•
•
•
•
Maslach-Hubbard A, Bratton SL. Extracorporeal membrane oxygenation for
pediatric respiratory failure: History, development and current status. World
J Crit Care Med. 2013;2(4):29-39.
Extracorporeal Life Support Organization. ECLS Registry Report
International Summary.
http://www.elso.org/Registry/Statistics/InternationalSummary.aspx.
Published January 2015. Accessed March 22, 2015.
Buck ML. Pharmacokinetic changes during extracorporeal membrane
oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet.
2003;42(5):403-17.
Extracorporeal Life Support Organization. ELSO Anticoagulation Guideline.
http://www.elso.org. Published 2014. Accessed March 22, 2015.
Annich G, Adachi I. Anticoagulation for pediatric mechanical circulatory
support. Pediatr Crit Care Med 2013; 14:S37-S42.
7
5/5/2015
Anticoagulation Monitoring in Pediatric
Patients Undergoing Extracorporeal
Membrane Oxygenation (ECMO)
Julie Dang, Pharm.D.
PGY-1 Pharmacy Practice Resident
Detroit Medical Center, Children’s Hospital of Michigan
The speaker has no actual or potential conflicts of interest in relation to this presentation.
8