Antithrombin III in Pediatric ECMO: Our Perfect Teenage Heart-“thromb”?

Luke Smedley, PharmD PGY-1 Pharmacy Practice Resident

Department of Pharmacotherapy and Pharmacy Services, University Hospital Division of Pharmacotherapy, University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, UT Health San Antonio San Antonio, Texas

November 29 and December 8, 2017

Learning Objectives 1. Describe the role of ECMO in critically ill pediatric patients.2. Identify mechanisms of coagulopathy in critically ill pediatric patients receiving ECMO.3. Appraise the clinical data surrounding the use of antithrombin III in pediatric ECMO.4. Evaluate the appropriateness of antithrombin III in pediatric ECMO.

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Assessment Questions

1. Venovenous ECMO is used primarily for which type of organ failure? a. Cardiac failure b. Renal failure c. Respiratory failure d. Liver failure

2. True or false: coagulopathy is induced in ECMO by the complex interactions of the

patient’s coagulation factors and the ECMO circuit tubing.

3. Which test is used most commonly to monitor anticoagulation on ECMO, due to its point-of-care availability?

a. Antifactor Xa level b. Activated clotting time (ACT) c. Thromboelastography (TEG) d. Serum heparin concentration

4. True or false: a patient’s response to heparin occurs entirely independently of their

antithrombin III activity. ***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to

an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***

Speaker Disclosure: Luke Smedley has indicated he has no relevant financial relationships to disclose

relative to the content of this presentation. Off-label uses of antithrombin III (Thrombate®, ATryn®) in pediatric patients are discussed in this presentation.

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Extracorporeal Membrane Oxygenation (ECMO)

1. Introduction1–3

a. Almost 60,000 pediatric ECMO cases reported to Extracorporeal Life Support Organization

(ELSO) registry since 1989

i. Approximately one third of cases (22,000) since January 2009

b. Survival-to-discharge rate in all pediatric ECMO patients estimated at around 60%

c. Overall mortality rate for patients on ECMO is 35-40%

i. Bleeding and thrombosis events increase associated mortality up to 55%

d. Coagulation abnormalities are common in ECMO

i. 70% of pediatric patients on ECMO experience bleeding events

ii. 38% experience thrombotic events (either patient or circuit-related)

e. Average healthcare cost for single course of pediatric ECMO is over $230,000

f. Prevention and management of bleeding and thrombotic events are extremely important to

improve mortality rates and optimize use of healthcare resources

2. Definitions4–6

a. Also known as extracorporeal life support (ECLS)

b. Form of cardiopulmonary bypass to provide gas exchange for patients with severe respiratory

failure, cardiac failure, or both

c. Blood is pumped from patient’s venous circulation to membrane lung that removes carbon

dioxide and adds oxygen, and then is returned to patient

i. Venovenous (VV) ECMO (see fig. 1)

1. Blood is returned through a large vein for circulation through the heart

2. Typically used for pulmonary failure/insufficiency with adequate cardiac

function

ii. Venoarterial (VA) ECMO (see fig. 1)

1. Blood is returned through an artery to bypass the heart

2. Typically used for pulmonary and cardiac failure/insufficiency

Figure 1: Venovenous and Venoarterial ECMO

https://thoracickey.com/wp-content/uploads/2016/06/C31-FF2.gif

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3. Basic ECMO Circuitry (see fig. 2)7–10

a. Mechanical blood pump

i. Centrifugal pumps are current standard

ii. Provide flow of approximately 75-150 mL/kg/min for infants and children

b. Bladder

i. Placed at lowest point on drainage side of circuit

ii. Ensures constant supply of blood for pump, and regulates stability of circuit

c. Membrane oxygenator

i. Adds oxygen and removes carbon dioxide from blood

ii. Surface area of membrane determines oxygenation capacity

d. Heat exchanger

i. Blood flow through tubing causes significant heat loss

ii. Warms blood to maintain normal body temperature

e. Tubing

i. Made from polyvinylchloride-based plastic compound

ii. Can be coated with biocompatible lining to reduce inflammatory and coagulation

response to non-biologic surface

f. Circuit bridge

i. Connects venous access limb of circuit to arterial access limb

ii. Allows for continuation of blood circulation through circuit if patient needs

temporary disconnection

iii. Facilitates weaning off VA ECMO as patient tolerates being off circuit without being

entirely disconnected

g. Priming requires 300-400 mL of exogenous blood products

i. Blood volume in children > 3 months is approximately 70 mL/kg

1. In 20-kg child, adds 20-30% to total blood volume

ii. Term neonates have blood volume of approximately 80-90 mL/kg

1. In 3-kg neonate, doubles total blood volume

Figure 2: ECMO Circuitry

Current Surgical Therapy. 12th ed., pg. 1389

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4. Outcomes and Complications2

Table 1. ECMO Cases and Survival to Discharge, 2009 - 20152

Number of Cases Survived ECLS Survival to discharge

Neonatal Respiratory Cardiac ECPR

6,586 3,285 1,045

5,330 (81%) 2,258 (69%) 716 (69%)

4,444 (67%) 1,487 (45%) 445 (43%)

Pediatric Respiratory Cardiac ECPR

3,903 4,581 2,507

2,732 (70%) 3,389 (74%) 1,471 (59%)

2,353 (60%) 2,600 (57%) 1,066 (43%)

Total 21,907 15,896 (73%) 12,394 (59%)

a. Most common patient and circuit complications are problems with cannula, intracranial

hemorrhage, surgical site bleeding, air in the circuit, and oxygenator failure

i. See appendices I and II

Table 2. Risk Factors for Complications and Death in Children Receiving ECMO Support1,11

Bleeding Complications Thrombotic Complications Death

Younger patients (i.e. neonates)

Placed directly on ECMO from cardiopulmonary bypass

Cardiac indication for ECMO

Higher level of organ failure at initiation

Cardiac surgery

Lack of home ventilator or tracheostomy

No chronic conditions

Venoarterial mode of ECMO

Cardiovascular or shock indication for ECMO

Baseline hepatic failure

Premature infants

Baseline feeding tubes

Bleeding event

5. Indications for ECMO12

a. Acute severe heart or lung failure with high mortality risk despite optimal conventional

therapy

i. Should be considered when mortality prediction is >50%

ii. Should be implemented when mortality prediction is >80%

iii. Should be considered after 7 days of mechanical ventilation at high levels of

support

b. For specific indications for respiratory and cardiac support, see appendix III

6. Contraindications to ECMO12

a. Conditions incompatible with normal life if patient recovers

b. Preexisting conditions which affect quality of life

i. Poor CNS status

ii. End stage malignancy

iii. Risk of systemic bleeding with anticoagulation

c. Futile intervention

d. For contraindications specific to respiratory or cardiac support, see appendix IV

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Table 3. Most Common Disease States ECMO in Neonatal/Pediatric Patients9,10

Respiratory Cardiac

Meconium aspiration syndrome

Congenital diaphragmatic hernia

Persistent pulmonary hypertension of the newborn

Respiratory distress syndrome

Infective pneumonia

Congenital cardiac defects o Hypoplastic left heart syndrome o Left or right ventricular outflow tract

obstruction o Septal defects

Coagulopathy in Extracorporeal Membrane Oxygenation

1. Normal Hemostatic Pathway (see figure 3)14–16

Figure 3: Hemostatic Pathway

Nelson’s Textbook of Pediatrics. 20th ed., pg. 2380

a. Coagulation involves interactions between the vascular endothelium and plasma proteins

i. When endothelium is damaged, subendothelium is exposed

1. Contains collagen, thromboxane, von Willebrand factor (vWF), and other

platelet attracting entities

ii. Exposure allows compounds to interact with procoagulant proteins and non-

activated platelets, causing platelet adhesion/activation and formation of platelet

plugs

iii. Activated platelets allow tissue factor in the endothelium to activate factor VII,

initiating extrinsic (tissue factor) pathway

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b. Contact with foreign or nonbiologic substances also induces hemostasis

i. When Factor XII comes in contact with these substances, it is activated and

activates Factor XI, initiating intrinsic (contact) pathway

c. During clot formation, endothelium is stimulated and releases tissue type plasminogen

activator (tPA) as part of negative feedback loop

i. tPA activates plasminogen to plasmin, causing fibrinolysis which aids clot

breakdown and limits extension

2. Mechanism of Coagulopathy in ECMO15,17

a. ECMO circuit acts as continuous thrombotic stimulus

i. Within seconds of blood contact with circuit, factor XII becomes activated, initiating

intrinsic pathway

ii. Fibrinogen and vWF adsorb to the circuit within seconds, allowing for platelet

activation and plugging

b. Patient’s endothelium releases tPA in attempt to balance hypercoagulable state

i. May lead to increased risk of bleeding

c. Activated clotting proteins circulate through circuit and patient’s vasculature, increasing risk

of in vivo thrombus formation

d. Multi-organ failure leads to further shifts in coagulation status

3. Coagulopathy in Neonates and Children18

a. Multiple studies have shown further coagulation abnormalities in neonates and children

receiving ECMO

b. Hundalani, et al, demonstrated all pediatric patients have extrinsic pathway activation on

ECMO day one

i. Neonates had continuous activation through ECMO day five

ii. Children ≥ 30 days old had lower levels of activation on ECMO day five18

Anticoagulation in ECMO

1. Unfractionated Heparin (UFH)19–21

a. Interacts with antithrombin (AT) and tissue factor pathway inhibitor (TFPI)

b. Binds to AT via a pentasaccharide sequence

i. Binding creates a conformational change that increases rate of serine protease

inhibition

c. UFH-AT complex inhibits factors Xa, IXa, XIa, XIIa, and IIa (thrombin)

i. Inhibition of thrombin requires both UFH and thrombin to bind to AT

ii. Inhibition of factor Xa only requires binding of AT to UFH

d. UFH increase antithrombotic effect of TFPI by two to four-fold by increasing its affinity for

factor Xa

2. Heparin Monitoring in ECMO19

a. Activated clotting time (ACT)

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i. Measures clotting of whole blood (all components) by exposing sample to an

activator (either kaolin or celite)

ii. Advantages

1. Used for decades in ECMO patients

2. Only routine point-of-care (POC) test used standardly in ECMO

3. Measures time for blood to clot under existing clinical conditions (not just

based on heparin)

4. Allows for quick analysis of level of anticoagulation

iii. Disadvantages

1. Does not give specific information regarding clotting deficiencies

2. Inconsistent in measurements and reliability in neonatal population

3. Large variation between machines

4. Not a direct marker of heparin efficacy

b. Antifactor Xa activity (anti-Xa level)

i. Measures ability to catalyze inhibition of known amount of excess factor Xa by AT

1. Concentration of UFH in test plasma is inversely proportional to amount of

residual factor Xa

2. Reported in anti-Xa units

ii. Universal target heparin concentration is 0.3 – 0.7 units/mL

1. Some ECMO centers target higher levels (i.e. 0.7 – 1.1 units/mL)

iii. Advantages

1. Direct marker of heparin efficacy

2. Is not affected by other hemostatic deficiencies

iv. Disadvantages

1. Cannot measure until heparin is at steady state (4 – 6 hours after initiation or

dose change)

2. Does not give information about other aspects of anticoagulation

c. Activated partial thromboplastin time (aPTT)

i. Plasma test activated by phospholipids

ii. Advantages

1. Provides global measure of hemostasis in absence of cellular components

iii. Disadvantages

1. Therapeutic range varies between labs based on reagent sensitivities

2. May be affected by fluctuations in other clotting factors and inhibitors

3. Variable reliability in pediatric ECMO due to changes in developmental

hemostasis with age

d. Thromboelastography (TEG)

i. Whole-blood POC test that evaluates viscoelastic properties of blood clot

formation

ii. Advantages

1. Provides information on integrity of coagulation cascade, platelet function,

platelet-fibrin interactions, and fibrinolysis

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2. Describes multiple phases of coagulation, allowing practitioners to tailor

interventions based on where abnormality lies

iii. Disadvantages

1. Expensive test, and not widely used in ECMO centers currently22

2. Requires 2 mL of blood to run

3. Standard Practices for Anticoagulation and Monitoring22

a. Anticoagulation and monitor practices vary widely by ECMO center (see table 4)

Table 4. Responses to Survey by Bembea, et al., Regarding Anticoagulation Practices in ECMO22

Question Responses

What is the minimum UFH infusion rate allowed by your protocol? (n = 115 respondents)

0 units/kg/hr 1 – 10 units/kg/hr 11 – 25 units/kg/hr >25 units/kg/hr

35 (30%) 62 (54%) 18 (16%)

0

What is the maximum UFH infusion rate allowed by your protocol? (n = 115 respondents)

No upper limit 50 – 75 units/kg/hr 76 – 100 units/kg/hr 101 – 125 units/kg/hr

83 (72%) 21 (18%)

8 (7%) 3 (3%)

What non-UFH anticoagulation do/can you use in your ICU? (n = 107 respondents)

Argatroban Bivalirudin Lepirudin No other options

48 (45%) 10 (9%)

6 (6%) 50 (47%)

Do you ever use any of the listed products for management of anticoagulation/hemorrhage/thrombosis in ECMO patients? (n = 94 respondents)

Aminocaproic acid Recombinant human factor VIIa Tranexamic acid Aprotinin Other

a

63 (67%) 63 (67%) 21 (22%) 13 (14%) 10 (11%)

ACT goal (sec) (n = 116 respondents) Minimum ACT goal, mean (SD) Maximum ACT goal, mean (SD) Do not follow, n (%)

183 (13) 210 (15)

3 (2%)

PT/aPTT monitoring frequency (n = 116 respondents) Every 4 – 5 hours Every 6 – 8 hours Every 9 – 12 hours >12 hours apart Not monitored

12 (10%) 41 (35%) 20 (17%) 36 (31%)

7 (6%)

AT activity measurements (n = 117 respondents) Routinely Occasionally Never

60 (51%) 36 (31%) 21 (18%)

AT activity monitoring frequency (n= 89 respondents) Every 1 – 8 hours Every 9 – 12 hours Every 13 – 24 hours Only as needed

7 (8%) 17 (19%) 45 (51%) 20 (22%)

Anti-Xa level measurements (n = 115 respondents) Routinely Occasionally Never

46 (40%) 29 (25%) 40 (35%)

Anti-Xa level monitoring frequency (n = 66 respondents) Every 1 – 8 hours Every 9 – 12 hours Every 13 – 24 hours Only as needed

15 (23%) 12 (18%) 27 (41%) 12 (18%)

TEG measurements (n = 116 respondents) Routinely Occasionally Never

21 (18%) 29 (25%) 66 (57%)

aOther agents listed: acetylsalicylic acid (4), warfarin (2), prostacyclin (2), serine protease inhibitors (1), dipyridamole (1)

Abbreviations: ACT = activated clotting time, aPTT = activated partial thromboplastin time, AT = antithrombin, FFP = fresh frozen plasma, ICU = intensive care unit, PRBC = packed red blood cells, TEG = thromboelastography, UFH = unfractionated heparin

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Heparin Resistance and Antithrombin Use in ECMO

1. Heparin Resistance12,23,24

a. Defined as inability to reach target monitoring levels with heparin doses > 35-40 units/kg/hr

b. In ECMO, cause is multifactorial, but mainly attributed to antithrombin (AT) deficiency

i. Blood exposure to heparin and circuit causes consumption of endogenous AT

ii. Neonates and young infants have low levels of AT

1. Neonates have approximately 30% of adult levels

2. Adult values are not reached until 3 to 6 months of age

c. Heparin resistance can be problematic due to increased time to therapeutic anticoagulation

and increased risk of fluid overload

2. Antithrombin III (ATIII)20,25–28

a. Active form of antithrombin (AT)

i. Terms ATIII and AT are used interchangeably in practice

b. Alpha2-glycoprotein found in human plasma

c. Inhibitor of serine proteases produced by the liver

d. Inhibits thrombin and factor Xa by forming irreversible covalent bond

i. Also inactivates plasmin and factors IXa, IXa, and XIIa to lesser degree

e. Available commercially as human antithrombin (Thrombate III®) and recombinant

antithrombin (ATryn®)

f. Half-life of human antithrombin (Thrombate III®) is approx. 2.5 – 3.8 days and recombinant

antithrombin (ATryn®) is 11.6 – 17.7 hours

i. Half-life and clearance are affected by heparin infusion rate29

g. Can measure AT activity in patients on ECMO

i. Presented as units/mL or percent activity (1 unit/mL = 100% activity)

h. FDA-approved indications

i. Thrombate III®

1. Treatment of patients with hereditary AT deficiency in connection with

surgical or obstetrical procedures or with thromboembolism

ii. ATryn®

1. Prevention of perioperative and peripartum thromboembolic events in

hereditary AT-deficient patients

3. AT in ECMO24

a. Theoretically, AT supplementation may reduce heparin utilization and improve

anticoagulation status in ECMO patients

b. Studies in patient receiving cardiopulmonary bypass show that AT can lower heparin

requirement, but has no effect on clinical outcomes30–32

c. Use in ECMO is still controversial, and its place in therapy not well-defined

i. Approximately $2,200 - $4,500 per vial for Thrombate III® and $1,600 - $8,700 per

vial for ATryn®

ii. Cost and outcomes must be closely evaluated to prevent unnecessary healthcare

spending

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Clinical Question and Literature Review

Should antithrombin be used as a standard agent with heparin for anticoagulation in neonatal and pediatric extracorporeal membrane oxygenation?

Table 5. Studies evaluating AT administration in pediatric and/or neonatal ECMO.

Treatment Groups Outcome Take Home Points

Byrnes, et al. (2014)33

Group 1 (n = 21): received AT in day-based analysis

Group 2 (n = 19): did not receive AT in day-based analysis

AT given for AT activity <70% to correct to 100% using formula (100 – AT level)/1.4 + circuit factor (based on circuit volume)

Associated with 0.02 unit/mL increase in anti-Xa level

20% reduction in heparin rate at 3 – 6 hours: 29.3% in Group 1 vs 17.8% in Group 2 (p = 0.1061)

Increased risk of circuit change (OR 3.15, 95% CI 1.21 – 8.16)

Associated with slightly better anticoagulation control

Associated with numerical decrease in heparin rate

Increased risk of circuit change in patients requiring AT

Ryerson, et al. (2014)34

Analyzed before and after individual doses of AT (n = 36)

Continuous UFH infusion to achieve goal aPTT of 65 - 125 sec and anti-Xa level of 0.35 – 0.7 units/mL

AT given as bolus of whole vial

(~ 1000 units) for AT activity ≤

0.5 units/mL (50%)

Anti-Xa level increased 0.21 units/mL in patients ≤12 months and 0.09 units/mL in patients >12 months

aPTT increased by 9 sec in patients ≤12 months

UFH dose decreased 11.6 units/kg/hr in patients ≤12 months and 12.6 units/kg/hr in patients >12 months

No bleeding or clotting events

Associated with better numerical control of anti-Xa level and a numerical decrease in UFH dose

Results were not compared statistically, so difficult to make conclusions

Wong, et al. (2015)35

Group 1 (n = 30): At least one dose of AT during ECMO

Group 2 (n = 34): No AT during ECMO

AT activity corrected to 120% when less than 80% with 1) UFH dose >40 units/kg/hr or 2) presence of circuit thrombus

UFH dose decreased by 10.1 units/kg/hr at 3 hours and 10.2 units/kg/hr at 12 hours

No difference in circuit changes, ECMO duration, hospital LOS, ICU LOS, in vivo thrombus or hemorrhage, need for blood products, or hospital mortality

Associated with reduced UFH dose three hours post-dose with continued reduction through hour 12

No difference in clinical outcomes

Tzanetos, et al. (2017)36

Analyzed subjects before and after administration of AT (n = 77)

AT given to maintain AT activity >80%

Suggested dose was bolus of 50 units/kg, but sometimes continuous infusion was used based on physician preference

AT activity < 80% not associated with risk of thrombotic event (OR 1.02, 95% CI 0.97 – 1.06)

AT activity > 80% not associated with risk of bleeding event (OR 1.06, 95% CI 1.01 – 1.11, p = 0.44)

AT activity correlated with anti-Xa level (r = 0.367, p = 0.021) but not ACT (p > 0.05) or heparin dose (p > 0.05)

AT activity positively correlated with anti-Xa level

AT activity does not correlate to ACT or heparin dose

Lower AT activity not associated with thrombotic event, and higher AT activity not associated with bleeding event

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Table 6

Niebler RA, et al. Antithrombin replacement during extracorporeal membrane oxygenation.37

Design and Methods

Single-center before and after retrospective chart review (n = 31)

Population: Inclusion Exclusion

Received AT while supported on ECMO Second administration of AT in same period of ECMO support

Intervention AT was administered as a single bolus dose when activity was < 80%

Dosing was at the discretion of the treating physician

Dose was rounded to full vial at times to prevent waste

Endpoints: Change in ACT and heparin dose at 4, 8, and 24 hours

Change in AT activity at 8 and 24 hours

Chest tube and/or measured dressing output and PRBC transfusion volume at 24 hours

Survival to discharge and incidence of ICH

Baseline Characteristics:

Median age: 0.3 years (range 1 day – 19.5 years)

Median weight: 5.9 kg (range 1.95 – 90 kg)

Median AT dose: 82.8 units/kg (range 6.5 – 295.4 units/kg) o Mean dose in patients < 1 year: 138 ± 72 units/kg o Mean dose in patients > 1 year: 36 ± 23 units/kg

Results

ACT level did not change significantly from baseline at 4, 8, or 24 hours

Heparin dose did not change significantly from baseline at 4, 8, or 24 hours

AT activity increased from 61.5 ± 13 to 96.8 ± 25.6 at 8 hours and 92 ± 18.2 at 24 hours (p < 0.001)

Chest tube output/measured dressing output was not significantly different 24 hours before to 24 hours after AT administration

o This remained insignificant in patients with doses >100 units/kg and in patients supported after CPB

Rates of intracranial hemorrhage and survival to discharge were not significantly different in patients who received AT compared to a historical control

Authors’ Conclusions:

AT administration resulted in higher AT activity for 24 hours without a significant effect on heparin requirement or ACT

Measures of bleeding did not increase after administration of AT

Reviewer’s Critique

Limitations Strengths

Retrospective study with small sample size

Dosing regimen not well-defined

Supplemented fresh frozen plasma

No matching between study cohort and historical control

Did not evaluate thrombotic complications

Evaluated effects of AT in individual patients

Evaluated subgroups of those receiving large doses of AT and those on CPB

Evaluated both cardiac and respiratory indications for ECMO

Abbreviations: ACT = activated clotting time, AT = antithrombin, CPB = cardiopulmonary bypass

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Table 7

Wong TE, et al. Antithrombin concentrate use in pediatric extracorporeal membrane oxygenation: a multicenter cohort study.

38

Design

Retrospective multi-institutional cohort study

Obtained data from PHIS, a system that contains data from 43 free-standing children’s hospitals

Population: Inclusion Exclusion

18 years old or younger

Had an ICD-9 procedural code of 39.65 (ECMO) or a charge mapped to a CTC code starting with 521181 (ECMO)

Had discharge disposition

Dates of service not available for ECMO or AT concentrate doses

Received all AT concentrate doses outside of their ECMO course

Second admission for ECMO

Study Groups: AT- (n = 6,670) = did not receive AT while on ECMO

AT+ (n = 1,931) = received at least one dose of AT while on ECMO

Endpoints: Thrombotic or hemorrhagic events, mortality, and hospital length of stay

Baseline Characteristics:

Age: 63.3% were ≤ 30 days, 12.8% were 31 – 364 days, and 24.8% were ≥ 1 year old o More were ≤ 30 days in AT+ group (64.9% vs 61.6%, p = 0.02)

Female: 44.6%

Median duration of ECMO: 5 days o Median duration longer in AT+ group (7 days vs 4 days, p < 0.001)

≥ 3 CCC flags: 10.6% o Higher in AT+ group (13.6% vs 9.7%, p < 0.001)

More cardiovascular CCC in AT+ group (66.2% vs 72.6%, p < 0.001)

More metabolic CCC in AT+ group (7.7% vs 5.1%, p < 0.001)

More neuromuscular CCC in AT+ group (8.2% vs 6.5%, p = 0.01)

More respiratory CCC in AT+ group (19.3% vs 14.6%, p < 0.001)

Results

AT- (n = 6,670) AT+ (n = 1,931) p-value

Any thrombosis or hemorrhage 3,109 (46.6) 1,108 (57.4) <0.001

Any thrombosis 1,043 (15.6) 460 (23.8) <0.001

Venous thrombosis 554 (8.3) 250 (13.0) <0.001

Arterial thrombosis 574 (8.6) 261 (13.5) <0.001

Hemorrhage 2,542 (38.1) 904 (46.8) <0.001

Hospital LOS, median (range) 27 (1 – 611) 34 (0 – 736) <0.001

In-hospital mortality 2,749 (41.2) 839 (43.5) 0.08

AT administration was associated with 55% increase in risk of thrombosis (p < 0.001), 27% increase in risk of hemorrhage (p < 0.001), and 37% increase in risk of either thrombosis or hemorrhage (p < 0.001)

There was no significant difference in risk of mortality

Authors’ Conclusions:

Subjects who received AT were more likely to experience thrombotic and bleeding complications and have slightly longer hospital admissions with no difference in mortality

Reviewer’s Critique

Limitations Strengths

Retrospective database study

Did not control for AT dose or dosing strategy

Used diagnosis and outcome codes for results

Did not evaluate timing of event in relation to AT administration

Extremely large sample size

Controlled for many different confounding factors using propensity score matching

90% powered to find 20% difference in thrombotic events

Abbreviations: CCC = complex chronic conditions, CTC = Clinical Transaction Classification, ICD-9 = International Classification of Diseases, Ninth Revision, LOS = length of stay, PHIS = Pediatric Health Information System

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Table 8

Stansfield BK, et al. Outcomes following routine antithrombin III replacement during neonatal extracorporeal membrane oxygenation.

39

Design

Single-center retrospective cohort study

Patient Population

Inclusion Exclusion

Neonates receiving ECMO support for primary respiratory failure

Supported on ECMO for less than 24 hours

ECMO for primary cardiac support

Intervention: 125 units/kg of human AT not to exceed one 10 mL vial (approximately 500 units) at ECMO initiation and again 12 hours later

Serum AT activity measured daily and additional 125 units/kg dose given if activity <100% (1 unit/mL)

Heparin started at 10 units/kg/hr, and titrated by 10 units/kg/hr to maintain ACT within pre-specified range

Study Groups: Control (n = 90) = received ECMO before initiation of AT protocol

AT (n = 72) = received ECMO after initiation of AT protocol

Endpoints: Circuit lifespan, thrombotic/hemorrhagic complications, and blood product/heparin use

Baseline Characteristics:

Gestational age, in weeks: 38.7 ± 1.6 in control group, 38.5 ± 1.7 in AT group (p = 0.46)

Birth weight: 3.4 ± 0.6 kg in control group, 3.3 ± 0.6 kg in AT group (p = 0.177)

Venovenous ECMO: 46% in control group, 92% in AT group (p = < 0.001)

Results

Total circuit lifespan was not different between groups

Patients in AT group required less blood products than control (54.7 ± 20.1 mL/kg/day vs 67.4 ± 34.9 mL/kg/day, p = 0.001)

Patients in AT group had higher heparin dose than control (30.4 ± 7.1 units/kg/hr vs 27.5 ± 10.8 units/kg/hr, p = 0.032)

Anti-Xa level lower in control group (0.3 ± 0.14 units/mL vs 0.48 ± 0.16 units/mL, p < 0.001) o Level at 0 – 24 hours: 0.05 ± 0.16 units/mL vs 0.2 ± 0.19 units/mL (p < 0.001) o Level at 25 – 48 hours: 0.2 ± 0.2 units/mL vs 0.43 ± 0.21 units/mL (p < 0.001) o Level at 49 – 72 hours: 0.36 ± 0.19 units/mL vs 0.52 ± 0.25 units/mL (p < 0.001) o Level at 73 – 96 hours: 0.38 ± 0.2 units/mL vs 0.58 ± 0.25 units/mL (p < 0.001)

Mean ACT higher in control group than AT group o At 0 – 24 hours: 204.5 ± 12 sec vs 199.5 ± 7.2 sec (p = 0.001) o At 25 – 48 hours: 201.3 ± 12.7 sec vs 197.6 ± 6.9 sec (p = 0.019) o At 49 – 72 hours: 201.7 ± 13.5 sec vs 197.3 ± 8.4 sec (p = 0.006) o No significant difference after 72 hours

Patients in AT group had lower rate of clots in oxygenator (6.9% vs 41.7%, p < 0.001), clots in bladder (17.3% vs 55%, p < 0.001), and clots in another location (44.8% vs 71.7%, p = 0.014)

No significant difference in rates of hemorrhagic complications or CNS infarcts

Patients in AT group had lower rate of all-around complications (40.3% vs 66.7%, p < 0.001)

Authors’ Conclusions:

Routine administration of AT during neonatal ECMO is associated with modest improvement in control of anticoagulation management

Study suggests AT is safe and does not lead to unwanted bleeding

Reviewer’s Critique

Limitations Strengths

Retrospective study

Required patients to have respiratory indication

Lack of matching between groups

More patients on VV ECMO in AT group

Many changes in circuit technology

Looked specifically at neonatal population

Relatively large sample size

Well-defined anticoagulation/AT administration protocol

Abbreviations: ACT = activated clotting time, NICU = neonatal intensive care unit

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Conclusions

1. Antithrombin not associated with better clinical outcomes or improvement in anticoagulation status 2. Although some studies have shown higher rates of adverse events, they were not controlled for dose,

making it difficult to ascertain whether patients received adequate doses of the agent 3. Prospective randomized clinical trials should be done to assess the cost-effectiveness of antithrombin

administration, and its association with clinical outcomes

Recommendation

1. Should not be considered as standard therapy a. Can be considered in patients with heparin resistance of high risk of thrombotic complication b. Should be considered on case-by-case basis

i. This could include neonatal patients with history of thrombotic event, patients with concomitant multi-organ failure, or cardiac patients with absolute indication for anticoagulation

ii. Should be considered in patients with heparin doses > 55-60 mg/kg/hr with AT activity <40% and at least 2-3 clots in circuit

c. Should be understood that administration may improve numbers, but is not associated with any improvement in clinical outcomes

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http://online.lexi.com. Accessed November 3, 2017. 26. ATryn® [package insert]. Framingham, MA: rEVO Biologics, Inc; 2013. 27. Thrombate III® [package insert]. Research Triangle Park, NC: Grifols Therapeutics, Inc; 2016. 28. Salas CM, Miyares MA. Antithrombin III utilization in a large teaching hospital. P T 2013;38:764-79. 29. Moffett BS, Diaz R, Galati M, Mahoney D, Teruya J, Yee DL. Population pharmacokinetics of human

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31. Niebler RA, Woods KJ, Murkowski K, et al. A pilot study of antithrombin replacement prior to cardiopulmonary bypass in neonates. Artif Organs 2016;40:80-5. doi:10.1111/aor.12642.

32. Manlhiot C, Gruenwald CE, Holtby HM, et al. Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children: impact of low antithrombin activity. J Thorac Cardiovasc Surg 2016;151:444-50. doi:10.1016/j.jtcvs.2015.10.003.

33. Byrnes JW, Swearingen CJ, Prodhan P, Fiser R, Dyamenahalli U. Antithrombin III supplementation on extracorporeal membrane oxygenation. ASAIO J 2014;60:57-62. doi:10.1097/MAT.0000000000000010.

34. Ryerson LM, Bruce AK, Lequier L, Kuhle S, Massicotte MP, Bauman ME. Administration of antithrombin concentrate in infants and children on extracorporeal life support improves anticoagulation efficacy. ASAIO J 60:559-63. doi:10.1097/MAT.0000000000000099.

35. Wong TE, Delaney M, Gernsheimer T, et al. Antithrombin concentrates use in children on extracorporeal membrane oxygenation: a retrospective cohort study. Pediatr Crit Care Med 2015;16:264-9. doi:10.1097/PCC.0000000000000322.

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37. Niebler RA, Christensen M, Berens R, Wellner H, Mikhailov T, Tweddell JS. Antithrombin replacement during extracorporeal membrane oxygenation. Artif Organs 2011;35:1024-8. doi:10.1111/j.1525-1594.2011.01384.x.

38. Wong TE, Nguyen T, Shah SS, Brogan T V, Witmer CM. Antithrombin concentrate use in pediatric extracorporeal membrane oxygenation: a multicenter cohort study. Pediatr Crit Care Med 2016;17:1170-8. doi:10.1097/PCC.0000000000000955.

39. Stansfield BK, Wise L, Ham PB, et al. Outcomes following routine antithrombin III replacement during neonatal extracorporeal membrane oxygenation. J Pediatr Surg 2017;52:609-13. doi:10.1016/j.jpedsurg.2016.10.047.

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Appendices

Appendix I: Mechanical and Patient Related Complications with Neonatal ECMO2 Cardiac Respiratory

Complications Survival after complication

Difference from average

Complications Survival after complication

Difference from average

Mechanical Oxygenator failure Pump malfunction Cannula problem Air in circuit

123 (4%) 37 (1%)

156 (5%) 101 (3%)

36 (29%) 12 (32%) 52 (33%) 33 (33%)

16 13 12 12

280 (5%) 84 (1%)

696 (12%) 209 (4%)

147 (53%) 46 (55%)

400 (57%) 119 (57%)

16 13 11 11

Patient Seizure by EEG Cerebral infarct ICH Brain death Cardiac tamponade Surgical site bleeding GI hemorrhage Amputation

100 (4%) 93 (3%)

326 (11%) 21 (1%)

148 (5%) 739 (26%)

35 (1%) 3 (0.1%)

41 (41%) 31 (33%) 91 (28%)

0 62 (42%)

257 (35%) 7 (20%) 2 (67%)

4

12 17 45 3

10 25 -22

158 (3%) 180 (3%)

643 (11%) 23 (0.4%) 13 (0.2%) 386 (7%) 89 (2%)

0 (0)

77 (49%) 79 (44%)

255 (40%) 0

5 (38%) 134 (35%) 29 (33%)

-

19 24 28 68 30 33 35 -

Appendix II: Mechanical and Patient Related Complications with Pediatric ECMO2 Cardiac Respiratory

Complications

Survival after complication

Difference from average

Complications Survival after complication

Difference from average

Mechanical Oxygenator failure Pump malfunction Cannula problem Air in circuit

205 (5%) 49 (1%)

194 (5%) 105 (3%)

94 (46%) 22 (45%) 92 (47%) 49 (47%)

11 12 10 10

251 (8%) 47 (1%)

515 (15%) 181 (5%)

106 (42%) 24 (51%)

305 (59%) 90 (50%)

18 9 1

10

Patient Seizure by EEG Cerebral infarct ICH Brain death Cardiac tamponade Surgical site bleeding GI hemorrhage Amputation

101 (3%) 231 (6%) 251 (6%) 107 (3%) 171 (4%)

974 (25%) 79 (2%) 4 (0.1%)

42 (42%) 83 (36%) 65 (26%)

0 66 (39%)

496 (51%) 18 (23%) 3 (75%)

15 21 31 57 18 6

34 -18

111 (3%) 158 (7%) 243 (5%) 117 (4%) 84 (3%)

332 (10%) 135 (4%) 5 (0.1%)

39 (35%) 54 (34%) 52 (21%)

0 38 (45%)

168 (51%) 53 (39%) 4 (80%)

25 26 39 60 15 9

21 -21

Appendix III: Specific Indications for Cardiac and Respiratory ECMO12

2. Neonatal respiratory indications

a. Severe respiratory failure, refractory to maximal medical management, with a potentially

reversible etiology

i. Oxygenation Index (OI) > 40 for >4 hours

1. OI =Mean Airway Pressure x FiO2

Post-ductal PaO2x 100

ii. OI>20 with lack of improvement despite prolonged (>24h) maximal medical

therapy or persistent episodes of decompensation

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iii. Severe hypoxic respiratory failure with acute decompensation (PaO2 <40)

unresponsive to intervention

iv. Progressive respiratory failure and/or pulmonary hypertension with evidence of

right ventricular dysfunction or continued high inotropic requirement

3. Pediatric respiratory indications

a. Marginal or inadequate gas exchange at risk of ventilator-induced lung injury and who are

failing less invasive therapy

i. Severe respiratory failure as evidenced by sustained PaO2/FiO2 ratios <60-80 or

OI>40

1. OI =Mean Airway Pressure x FiO2

PaO2x 100

ii. Lack of response to conventional mechanical ventilation ± other forms of rescue

therapy (e.g. high frequency oscillatory ventilation (HFOV), inhaled nitric oxide,

prone positioning)

iii. Elevated ventilator pressures (e.g. mean airway pressure > 20-25 mm Hg on

conventional ventilation or > 30 mm Hg on HFOV or evidence of iatrogenic

barotrauma)

iv. Severe, sustained respiratory acidosis (e.g. pH < 7.1) despite appropriate ventilator

and patient management

4. Pediatric cardiac indications

a. Early postoperative cardiac failure in the operating room (unable to come off bypass)

b. High vasoactive agent requirements, metabolic acidosis, and decreased urine output for 6

hours

c. Cardiac arrest from any cause with response to CPR but still unstable

d. Myocardial failure unrelated to operation

i. Myocarditis

ii. Cardiomyopathy

iii. Toxic drug overdose

Appendix IV: Specific Contraindications to Cardiac and Respiratory ECMO12

5. Neonatal respiratory contraindications

a. Absolute contraindicatons

i. Lethal chromosomal disorder or other lethal anomaly

1. Trisomy 13 or 18

ii. Irreversible brain damage

iii. Uncontrolled bleeding

iv. Grade III or greater intraventricular hemorrhage

b. Relative contraindications

i. Irreversible organ damage (unless considered for organ transplant)

ii. Body weight < 2 kilograms

iii. Post-menstrual age < 34 weeks

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iv. Mechanical ventilation greater than 10-14 days

6. Pediatric respiratory contraindications

a. Absolute contraindications

i. Recent neurosurgical procedures or intracranial bleeding (within 10 days)

ii. Grade II or III intracranial hemorrhage

iii. Recent surgery or trauma

iv. Patients with severe neurologic compromise or genetic abnormalities (not

including trisomy 21)

b. Relative contraindications

i. End-stage hepatic failure

ii. Renal failure

iii. Primary pulmonary hypertension

7. Pediatric cardiac contraindications

a. Futile intervention