PPresentationsRespiratory Distress Management in Pediatric ...€¦ · Respiratory Distress...

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49th Annual Meeting

OWNING CHANGE: Taking Charge of Your Profession

Respiratory Distress Management in Pediatric Critically Ill Patients: A Focus on

the Use of ECMOLyn Tucker, PharmD

Clinical Pharmacist, Pediatric Emergency DepartmentWolfson Children’s Hospital

Jacksonville, Florida

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

Objectives

Describe the pathophysiology and risk factors of respiratory distress in pediatric ICU patients

Formulate clinical therapeutic recommendations for the management of respiratory distress in pediatric patients

Evaluate the role of extracorporeal membrane oxygenation (ECMO) in the management of pediatric patients with respiratory distress

Identify possible issues for pharmacists in dosing other medications while patients are on ECMO

Describe adverse effects and monitoring parameters used for pediatric patients on ECMO

Definition

Acute Respiratory failure Inability of lungs to maintain adequate oxygen and

carbon dioxide homeostasis Acute hypoxemia (SaO2 < 90%, PaO2 < 60 mmHg)

Acute hypercarbia, hypercapnia (PaCO2 > 55 mmHg)

pH < 7.35

Hammer J. Pediatr Respir Rev. 2013;14(2):64-69

Airway Differences


Anatomy Pediatric AdultTongue Large Normal

Epiglottis Shape Floppy, U-shaped Firm, Flatter

Epiglottis Level Level of C3 - C4 Level of C5 – C6

Trachea Smaller, shorter Wider, longer

Larynx Shape Funnel shaped Column

Larynx Position Angles posteriorly away from glottis Straight up and down

Narrowest Point Sub-glottic region At level of Vocal cords

Lung Volume 250 mL at birth 6000 mL as adult

Poor accessory muscle development

Less rigid thoracic cage

Horizontal ribs, primarily diaphragm breathers

Increased metabolic rate, increased O2

consumption

Pediatric Respiratory System


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Pediatric Respiratory System


respiratory reserve + O2 demand

= respiratory failure risk

Croup

Aspiration

Asthma

Bronchiolitis

Bronchopulmonary dysplasia (BPD)

Pneumonia

Sepsis

Near Drowning

Common Causes


Patient Case

TE is a 2 yo 15 kg F with previous history of 3 reactive airway exacerbations in the last 4 months who presents with worsening cough, increased work of breathing and wheezing. On PE – RR is 48 breaths/min with moderate retractions, SpO2 88%.

What is most likely cause of TE’s respiratory distress? Acute asthma exacerbation

Pneumonia

Croup

Asthma

Definitions Asthma Chronic, inflammatory disorder of airways mediated by

mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells

Asthma exacerbations Acute or subacute episodes of progressively worsening SOB,

cough, wheezing, and chest tightness

Status asthmaticus (SA) Life threatening form of asthma unresponsive to initial

standard therapy that leads to respiratory failure

NAEPP Asthma Guidelines 2007SOB: Shortness of breath

Asthma Pathophysiology

Inflammation

NAEPP Asthma Guidelines 2007

Airway HyperresponsivenessAirway Obstruction

Clinical Symptoms

Clinical Asthma Score


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Risk Factors: Asthma-Related Death

Previous severe exacerbation Intubation or ICU admission for asthma

>2 hospitalizations or >3 ED visits in past year

Use of >2 canisters of SABA per month

Difficulty perceiving airway obstruction or severity of worsening asthma

Low socioeconomic status or inner-city residence

Comorbidities Cardiovascular disease or other chronic lung disease

NAEPP Asthma Guidelines 2007SABA: Short-acting beta agonist

Patient Case

TE is a 2 yo 15 kg F with previous history of 3 reactive airway exacerbations in the last 4 months who presents to the ED with worsening cough, increased work of breathing and wheezing. On PE – RR is 48 breaths/min with moderate retractions, SpO2 88%

What medications are needed?

Treatment Goals

Correct hypoxemia

Reverse airflow obstruction

Decrease airway edema

Restore adequate pulmonary functions

Reduce likelihood of relapse


Medication Route Dose

Inhaled short-acting β2 agonistsAlbuterol

Levalbuterol

Intermittent nebulizationContinuous nebulizationMetered-dose inhaler

Nebulization

0.15 mg/kg (minimum 2.5 mg) Q20min 0.5 mg/kg/hr or 10-15 mg/hr4-8 puffs Q20 min x 3 doses, then Q1-4h as needed0.075 mg/kg (minimum dose 1.25 mg) Q20 minutes x 3 doses, then Q1-4h as needed

AnticholinergicIpratropium Nebulization 0.25–0.5 mg Q20 min x 3 doses, then

Q2-4h as needed

CorticosteroidsPrednisone, prednisoloneDexamethasoneMethylprednisolone

OralOralIntravenous

1-2 mg/kg/day divided Q12h0.6 mg/kg daily x 2 days (Max:16 mg)2 mg/kg initially or 1 mg/kg Q6h

Adjunctive medicationsMagnesium Sulfate Intravenous 25-75 mg/kg/dose over 20 min

SA Treatment in the PICU


SA Treatment in the PICU

Medication Route Dose

Systemic β2 agonistsTerbutaline Subcutaneous

Intravenous

0.01 mg/kg/dose every 20 minutes for 3 doses, then Q2-6h as needed (Max: 0.4 mg/dose)Loading dose: 2-10 mcg/kg/doseInfusion: 0.08-0.4 mcg/kg/min

MethylaxanthinesAminophylline Intravenous Loading dose: 5.7 mg/kg/dose

Infusion based on age: 1-<9 yo 1.01 mg/kg/hr 9-<12 yo 0.89 mg/kg/hr12-<16 yo 0.63 mg/kg/hr >16 yo 0.51 mg/kg/hr Therapeutic serum concentration: 5-15 mcg/mL

Ketamine Intravenous Loading dose: 1-2 mg/kg/doseInfusion: 0.5-2 mg/kg/hr

Streetman DD et al. Ann Pharmacother. 2002;36:1254

Patient Case

TE continued to have wheezing and increased work of breathing after receiving albuterol 2.5 mg and ipratropium 0.5 mg q20 min x 3 doses with methylprednisolone 30 mg (2 mg/kg). She was admitted to the general pediatrics floor for further management.

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Community-Acquired Pneumonia (CAP)

Definition Presence of signs and symptoms of pneumonia in a

previously healthy child due to an infection acquired outside of the hospital

IDSA guideline scope 3 months – 18 years of age

Exclusions Immunocompromised

Mechanical ventilation

Chronic lung disease (e.g. cystic fibrosis)

Bradley JS et al. Clin Inf Dis. 2011;53(7):617-630IDSA: Infectious Diseases Society of America

Risk Factors

Not fully immunized

Underlying medication conditions Sickle cell disease

Asthma

BPD

Cystic fibrosis

Immunodeficiency syndromes

Durbin WJ et al. Pediatr Rev. 2008;29:148

Common Pathogens

Age Pathogens3 weeks - 3 months Bacteria

Chlamydia trachomatis, Streptococcus pneumoniae, Bordetella pertussis

VirusesRespiratory syncytial virus (RSV), Parainfluenza, Influenza, Adenovirus

4 months - 4 years BacteriaStreptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae

VirusesRSV, Parainfluenza, Human metapneumonvirus, Influenza, Rhinovirus

5 years - Adolescence BacteriaStreptococcus pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumoniae

Durbin WJ et al. Pediatr Rev. 2008;29:148

Site-of-Care Management

Hospitalization Criteria

Moderate to Severe CAPRespiratory distressSpO2<90%

Infants <3-6 months with suspected bacterial CAP

Suspected or documented CAP caused by virulent pathogen (e.g. CA-MRSA)

Concern regarding monitoring or compliance at home

PICU Criteria

Invasive mechanical ventilation

Noninvasive positive pressure ventilation (e.g. CPAP or BiPAP)

Impending respiratory failure

Sustained tachycardia, hypotension, or need pharmacologic support for BP or perfusion

SpO2<92% or inspired O2 >0.50

Altered mental status

Bradley JS et al. Clin Inf Dis. 2011;53(7):617-630

Inpatient Empiric TherapyBacterial Atypical Viral

Fully Immunized

Ampicillin IV 200-400 mg/kg/day divided Q6h

Penicillin G IV 200,000-250,000 units/kg/day divided q4-6h

Alternatives:Ceftriaxone IV 50-100 mg/kg/day divided Q12-24h

Cefotaxime IV 150 mg/kg/day divided Q8h

Azithromycin IV 10 mg/kg/day once daily on day 15 mg/kg/day once daily on days 2-5

Alternatives:>7 yo: Doxycycline IV 2-4 mg/kg/day divided Q12h

Erythromycin IV 20 mg/kg/day divided Q6h

Levofloxacin IV<5yo: 20 mg/kg/day divided Q12h>5yo: 10 mg/kg/day once daily

Oseltamivir PO<1yo: 6 mg/kg/day divided Q12h

>1yo: Weight based divided BID<15 kg- 60 mg/day>15-23 kg: 90 mg/day>23-40 kg: 120 mg/day>40 kg: 150 mg/day

NOT Fully Immunized

Ceftriaxone IV 50-100 mg/kg/day divided Q12-24h

Cefotaxime IV 150 mg/kg/day divided Q8h

Alternatives:Levofloxacin IV <5yo: 20 mg/kg/day divided Q12h>5yo: 10 mg/kg/day once daily

Azithromycin IV10 mg/kg/day once daily on day 15 mg/kg/day once daily on days 2-5

Alternatives:>7 yo: Doxycycline IV 2-4 mg/kg/day divided Q12h

Erythromycin IV 20 mg/kg/day divided Q6h

Levofloxacin IV<5yo: 20 mg/kg/day divided Q12h>5yo: 10 mg/kg/day once daily

Oseltamivir PO<1yo: 6 mg/kg/day divided Q12h

>1yo: Weight based divided BID<15 kg- 60 mg/day>15-23 kg: 90 mg/day>23-40 kg: 120 mg/day>40 kg: 150 mg/day

Clin Inf Dis. 2011;53(7):617-630

Community-Acquired Pneumonia

Length of therapy Typical duration is 10 days

Follow up for improvement in 48-72h

Minimizing resistance Limit exposure to antibiotics

Limit spectrum

Proper dose

Shortest effective duration


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CAP Prevention

Immunizations Streptococcus Pneumoniae

Haemophilus influenzae

Pertussis

Influenza annually (>6 months)

Parents and caregivers of infants <6 months should be immunized for influenza and pertussis


Patient Case

On evening of admission TE found in respiratory distress. Mom yelled for help and Pediatric Code Blue was called. BVM ventilation initiated. On PE - Severe retractions, spontaneous respirations, minimal air entry

Continuous albuterol 10 mg/hr and magnesium sulfate 750 mg IV over 20 min

Upon arrival to PICU

BiPAP, continuous albuterol 20mg/hr, ipratropium 0.5 mg Q4h, methylprednisolone 15 mg IV Q6h, magnesium sulfate infusion 50mg/kg/hr x 5 hrs

BVM: Bag valve mask

Patient Case

TE had acute oxygen desaturation into 20's with placement of NG tube, required BVM ventilation. Continuous albuterol 20 mg/hr, terbutaline load 2

mcg/kg and infusion 0.08 mcg/kg/min, magnesium sulfate infusion 50 mg/kg/hr x 5 hours

Episode of acute oxygen desaturation into 60’s with minimal air movement. Intubated and placed on mechanical ventilation

Terbutaline titrated

NG: Nasogastric

Patient Case

Continued episodes of acute desaturation with optimal ventilation settings Aminophylline load 5.7 mg/kg, infusion 1.01 mg/kg/hr

TE placed on ECMO for continued support

Extracorporeal membrane oxygenation (ECMO)

Modified cardiopulmonary bypass circuit

Provides cardiac support, blood oxygenation and carbon dioxide removal

Allows for support for a prolonged period of time (days to weeks)

Lequier L. J Intensive Care Med. 2004;19(5):243-258

History of ECMO

First report of ECMO use in adult with post-traumatic

respiratory failure1

Randomized clinical trial compared ECMO to conventional

ventilator therapy for ARDS failed to show improved outcomes2

Bartlet et al and O’Rourke et al showed improved outcomes in newborns and children with

respiratory failure3,4

ECMO Life Support Organization (ELSO) established

1Hill JD et al. NEJM. 1972;286(12):629-6342Zapol WM et al. NEJM. 1979;242(20):2193-2196

3Bartlett RH et al. Surgery. 1982; 9(2):425-4334O’Rourke PP et al. Pediatrics. 1989;84(6): 957-963

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Number of neonatal and pediatric ECMO treatments on an annual basis reported to ELSO registry

Extracorporeal Life Support Organization Registry Report 2012

ECMO Indications

Lung or cardiac disease that is: Acute

Life-threatening

Reversible

Unresponsive to conventional therapy

Chronic respiratory failure as bridge to transplant

Cardiopulmonary support for organ donation after circulatory determination of death

Extracorporeal Life Support Organization

ECMO Contraindications

Irreversible respiratory or cardiac failure

Mechanical ventilation >10 days?

Contraindication to anticoagulation

Malignancy

Incurable disease

<2 kg and <34 weeks post-menstrual age

Multi-organ failure

Severe or irreversible brain injury

Extracorporeal Life Support Organization

Is ECMO of Proven Benefit for Respiratory Failure?

Neonatal respiratory failure Persistent pulmonary hypertension, meconium aspiration,

congenital diaphragmatic hernia

UK randomized trial of neonatal ECMO (Lancet, 1996) ECMO: 32% (30/93) neonatal deaths

Conventional Therapy: 59% (54/92) neonatal deaths

Relative risk 0.55 (95% CI 0.39-0.77; p = 0.0005)

Proven benefit in regionalized setting

UK Collaborative ECMO Trial Group. Lancet. 1996;348(9020):75-82


Pediatric respiratory failure No good prospective study

Retrospective data: benefit in higher risk (not moribund) patients with respiratory failure

Green et alMulti-center, retrospective cohort analysis

331 patients, 2 weeks to 18 years of age

ECMO decreased mortality from 47.2% to 26.4% (p<0.01)

Green TP et al. Crit Care Med. 1996;24(2):323-329 Green TP et al. Crit Care Med. 1996;24(2):323-329


P < 0.05

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Survival After ECMO

ECMO Indication Number of ECMO Uses

Survival to Hospital Discharge

Neonatal (<30 days)RespiratoryCardiacECPR

27,7285,8101,112

74%41%40%

Pediatric (30 days-16 yo)RespiratoryCardiacECPR

6,5697,3142,370

57%50%41%

Adults (>16 yo)RespiratoryCardiacECPR

7,0085,6031,657

57%41%28%

Extracorporeal Life Support Organization, January 2015

Predictors of Survival

Younger age (<10 yo)1

Ventilator days pre-ECMO (<14 days)2

Lower PIP, lower A-a gradient3

No difference in survival if >2 weeks on ECMO4

1Domico MB et al. Pediatr Crit Care Med. 2012;13(1):16-212Zabrocki LA et al. Pediatr Crit Care Med. 2011;39(2):364-370

3Moler FW et al. Crit Care Med. 1992;20(8):1112-11184Green TP et al. Crit Care Med. 1996;24(2):323-329

49th Annual Meeting

OWNING CHANGE: Taking Charge of Your Profession

Respiratory Distress Management in Pediatric Critically Ill Patients: A Focus on

the Use of ECMO

Brian Kelly, PharmD, BCPSClinical Pharmacy Specialist – Pediatric Critical Care

UF Health Shands HospitalGainesville, FL

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

Objectives

Describe the pathophysiology and risk factors of respiratory distress in pediatric ICU patients

Formulate clinical therapeutic recommendations for the management of respiratory distress in pediatric patients

Evaluate the role of extracorporeal membrane oxygenation (ECMO) in the management of pediatric patients with respiratory distress

Identify possible issues for pharmacists in dosing other medications while patients are on ECMO

Describe adverse effects and monitoring parameters used for pediatric patients on ECMO

Types of ECMO

Based upon site of cannula insertion

Venoarterial (VA)

Most commonly used form

Removal of venous blood from the right internal jugular vein

Returned to body through cannula in right common carotid artery

Required for cardiac support

Appropriate for respiratory support

Venovenous (VV)

Blood is withdrawn from and returned to the right atrium via the right internal jugular vein

No hemodynamic support

Preferred for respiratory Uses only one major artery

Avoids potential systemic embolism

Maintains normal pulsatile blood flow

Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-417https://www.elso.org/Resources/Guidelines.aspx - Accessed 5/14/2015

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ECMO Circuit

http://www.mitchellmask.com/websites/Intro_ECMO_Site/images/diagrams/ecmo_diagram.jpg - Accessed 5/14/2015

Medication Use During ECMO

Standard medications used during ECMO Heparin – Prevention of clots in the circuit

Antibiotics – Prophylaxis & treatment of infection

Electrolyte supplementation

Sedatives & Analgesics

Anticonvulsants

Clinical studies of medication PK/PD in ECMO

Limitations: Small sample sizes

Differences in ECMO techniques & equipment

Complexity of patient population with widely divergent medical conditions

PK = PharmacokineticsPD = Pharmacodynamics

Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-417

Changes During ECMO

Factors affecting medication dosing in ECMO Physiologic Increased extracellular fluid (ECF)

Change in renal function

Pharmacokinetic Increased volume of distribution (Vd)

Prolonged elimination

Alterations in drug delivery Administration into the circuit


Physiologic Alterations

Increased ECF Patient’s blood volume + exogenous blood for priming

the ECMO circuit Priming the circuit

Requires 300-400 mL of exogenous blood products

Decrease in renal function More of a function of severe illness

Renal damage due to circulating vasoactive substances caused by ECMO

Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-417ECF = Extracellular fluid

Pharmacokinetic Alterations

Increased volume of distribution Priming the circuit

Slower drug clearance More of a function of severe illness, not ECMO itself

Concomitant renal dysfunction Hemofiltration or hemodialysis

Pharmacokinetic alterations return to baseline after decannulation


Alterations in Drug Delivery

Medication interactions with ECMO circuit

Inactivation Half-life of medication in relation to site of administration

E.g. Adenosine

Adsorption - Binding of some medications to membrane oxygenator Time since last circuit change

E.g. Fentanyl, insulin

Sequestration Shorter administration time acceptable for some medications

Dilution during passage through circuit E.g. Vancomycin


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Drug Factors

Hydrophilicity

Increased volume of distribution

Decreased peak concentrations

Clearance neutral

Dependent on renal function

Dosage adjustment

Increased loading dose

Lipophilicity

Volume of distribution is unchanged

Increased circuit sequestration

Clearance neutral

Dependent on hepatic function

Dosage adjustment

Increased loading dose

Increased frequency

Shekar K, et al. Journal of Critical Care (2012) 27, 741.e9–741.e18

Inactivation

Medications with short half-lives Administered into the circuit Activity can be lost before it reaches the patient

Examples:

Adenosine

Vasopressors – Epinephrine, norepinephrine

Should not be administered to the circuit

Administer as close to patient as possible

Effects on pharmacokinetics Increased clearance

Decreased bioavailability

Shekar K, et al. Journal of Critical Care (2012) 27, 741.e9–741.e18

Adsorption

Actual loss of drug in the circuit1

Pre- and post-oxygenator concentrations

Significant binding by medications

Lipophilic medications

Factors affecting adsorption2

Type of circuit

Polypropylene hollow fiber membrane oxygenators

Silicone membrane with hollow fiber oxygenators

Age of circuit

“Old” circuits Less medication binding

Saturated binding sites

Pharmacokinetic effects


Decreased peak concentration

1. Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-4172. Shekar K, et al. Journal of Critical Care (2012) 27, 741.e9–741.e18

Sequestration

Injection sites1

Pre-reservoir & reservoir injections Incomplete mixing

Delayed drug delivery to patient

Post-reservoir injection is preferred

Flow rates1

Less than 250 mL/min Results in pooling of the drug

Pharmacokinetic effects:2


Decreased peak concentration

1. Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-4172. Shekar K, et al. Journal of Critical Care (2012) 27, 741.e9–741.e18

Summary

Medication dosing in ECMO is affected by the following factors: Physiologic alterations

Increased extracellular fluid

Change in renal function

Pharmacokinetic alterations Larger volume of distribution

Slower clearance

Administration issues Delay in medication delivery

Loss of medication in circuit

Increased medication doses

Adverse Effects

Thrombosis

Bleeding Cannulation site

Intracranial hemorrhage

Gastrointestinal

Mucous membranes

Uterine

Thrombocytopenia

Heparin Induced Thrombocytopenia (HIT)https://www.elso.org/Resources/Guidelines.aspx - Accessed 5/10/2015

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Thrombosis

Thrombosis in the ECMO circuit

Every circuit will have some small clots

Located: site of connectors, infusion lines, pre-pump bladder or membrane lung Size: 1-5 mm – observation

Size: > 5 mm – require removing section or circuit change

Require careful examination with flashlight

Seen as very dark non-moving areas on the surfaces

Platelet/fibrin thrombi Appear as white areas on the circuit at connectors or stagnant areas

Etiology:

Periods of low flow

Inadequate anticoagulation

20% result in circuit change

https://www.elso.org/Resources/Guidelines.aspx - Accessed 5/10/2015

Bleeding

Major Bleeding

Hemoglobin (Hgb) fall of at least 2 g/dL in 24 hours

Greater than 20 mL/kg of blood loss over 24 hours

Transfusion requirement of 1 or more 10 mL/kg of PRBC transfusions over 24 hour period

Retroperitoneal, pulmonary or CNS bleeding

Bleeding requiring surgical intervention

Minor Bleeding

Less than 20 mL/kg of blood loss over 24 hours

Transfusion of one 10 mL/kg PRBC transfusion or less

Increased mortality in both cardiac & non-cardiac ECMO

Hemorrhagic complications

Requirement greater red blood cell transfusion volumes

https://www.elso.org/Resources/Guidelines.aspx - Accessed 5/10/2015PRBC = Packed Red Blood CellsCNS = Central Nervous System

Management of Bleeding

Packed Red Blood Cell (PRBC) transfusion

Fresh Frozen Plasma

Aliquots of 10 mL/kg for INR > 1.5-2 and/or significant bleeding

Cryoprecipitate

Fibrinogen levels <100-150 mg/dL

Platelet transfusion

10 mL/kg to maintain platelets > 100,000/ mcg/L

Antifibrinolytic Therapy

Aminocaproic acid or Tranexamic acid

Recombinant Activated Factor VII (rVIIa)

Dose: 40-90 mcg/kg

Prothrombin Complex Concentrates

Dose: 25-50 international units/kg

https://www.elso.org/Resources/Guidelines.aspx -Accessed 5/10/2015

Thrombocytopenia

Definition: Platelet count less than 150,000 mcg/L

Common in patients on ECMO

Causes: Underlying disease

Medications

Blood surface exposure

Platelet count less than 20,000 mcg/L Risk of spontaneous bleeding

Platelet transfusions Maintain platelet count greater than 80,000 mcg/L


Heparin-Induced Thrombocytopenia (HIT) Immune-mediated disorder1

IgG antibodies bind to complex of platelet factor-4 before binding to platelet Fc receptors, causing platelet activation and destruction

Immune reaction results in risk of:

Bleeding due to severe thrombocytopenia

Thrombosis in moderate-sized vessels including cerebral vessels

Platelet count will be consistently less than 10,000 mcg/L

Must stop heparin and switch to different anticoagulant2

Direct thrombin inhibitors

Argatroban – Usual 1st line

Bivalirudin

1. Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S422. https://www.elso.org/Resources/Guidelines.aspx - Accessed 5/10/2015

Anticoagulation in ECMO

Continuous contact between circulating blood and its cellular components with the nonbiologic surface of ECMO circuit1

Massive inflammatory & clotting response1

Results in hypercoagulant state2

Increased risk of thromboses

Antithrombotic therapy2

Prevention of thromboses

Unfractionated heparin (UFH)

Most widely used agent

1. Oliver WC. Semin Cardiothorac Vasc Anesth 2009; 13; 1542. Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S42

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Coagulation System in Children

Adults vs. children

Coagulation system for neonates, infants, & children

Contains all components for clotting but different concentrations Factors: VII, IX, X, XI, XII, prothrombin, prekallikrein, and high

molecular weight kininogen

Newborns: 50% of adult levels

Factors: VIII, XIII, V, fibrinogen, and vWF

Newborns: Approach or exceed adult levels

Platelets

Newborns: Hyporeactive compared to adults

Inhibitors of clotting: Protein C & S, Antithrombin III

Newborns: 50% of adult levels

Newborn coagulation system overall matures over 6 months to adult levels and function

Oliver WC. Semin Cardiothorac Vasc Anesth 2009; 13; 154

Anticoagulation Monitoring

Heparin Monitoring Several whole blood & plasma based test to assess

coagulation in vitro Activated Clotting Time (ACT)

Activated Partial Thromboplastin Time (APTT)

Antifactor Xa Assay

Thromboelastography (TEG)

All of the tests are not standardized

Antithrombin III (ATIII)

Platelets

Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S42

Activated Clotting Time (ACT)

Basic test measuring clotting of whole blood Performed at bedside by exposing sample to one of 2 activators

Used for decades

Advantages Point-of-care test that can be performed at bedside

The only routine point-of-care test for anticoagulation

Disadvantages Inconsistency in measurements

Reliability in neonate population

Variation between machines


Antifactor Xa Assay

Measure of UFH effect

Based on the ability of UFH to catalyze the inhibition of factor Xa by antithrombin

Outside of ECMO, gold standard for monitoring

UFH

Low molecular weight heparin

Becoming gold standard for management of UFH therapy in ECMO at many centers Measurements are performed daily

Usual goal: 0.3-0.7 IU/mL Some centers use higher goal of 0.7-1.1 IU/mL

Poor correlation between ACT ranges and antifactor Xa levels

Children and adults undergoing cardiopulmonary bypass for cardiac surgery

Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S42UFH = Unfractionated heparin

Thromboelastography (TEG)

Whole blood point of care test of the viscoelastic properties of clot formation Measures integrity of coagulation cascade From time of fibrin formation to clot lysis

Includes contribution of platelets

Provides information relating to multiple phases of coagulation in whole blood Very relevant to ECMO patients as they often have more than

one reason for coagulation abnormalities (e.g., fibrinolysis and

platelet dysfunction)


Anticoagulation Management

Anticoagulation at initiation of ECMO1

UFH bolus 50-100 units/kg IV to the patient

Administered 3 minutes prior to cannulation

UFH drip initiated at 7.5-20 units/kg/hr2

Initiated once ACT < 300 seconds

Adults: Lower dose range

Neonates & pediatrics: Higher dose range

Routine anticoagulation during ECMO1

Standard goal ACT:

180-220 seconds

Varies from center to center & type of monitoring equipment being used

Usual UFH infusion rates: 20-50 units/kg/hr

1) Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S422) https://www.elso.org/Resources/Guidelines.aspx - Accessed 5/10/2015

UFH = Unfractionated heparinACT = Activated Clotting Time

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Antithrombin III (ATIII)

Neonates and infants

Developmentally low AT activity & antigen levels

Optimal AT activity for patients receiving UFH for anticoagulation in ECMO

Unknown

Acquired AT deficiency

Escalating UFH requirements

UFH doses >35-40 units/kg/hr

Low AT concentration in plasma Clotting can still occur despite high doses of heparin

Subtherapeutic anticoagulation

AT replacement

AT activity < 30 to 80%

Evidence of reduced UFH effect clinically

Low ACT or anti-Xa levels

Most centers target levels >50% to >100%AT = AntithrombinUFH = Unfractionated HeparinACT = Activated Clotting Time


Summary

Thrombosis and bleeding are adverse effects that need to be monitored and addressed during ECMO therapy

There are several different tests available to monitor anticoagulation in ECMO All have advantages and disadvantages

Multiple tests will be used concomitantly

Monitoring and replacement of antithrombin when anticoagulation is not adequate

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