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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
Hammer J. Pediatr Respir Rev. 2013;14(2):64-69
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
Hammer J. Pediatr Respir Rev. 2013;14(2):64-69
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Pediatric Respiratory System
Hammer J. Pediatr Respir Rev. 2013;14(2):64-69
respiratory reserve + O2 demand
= respiratory failure risk
Croup
Aspiration
Asthma
Bronchiolitis
Bronchopulmonary dysplasia (BPD)
Pneumonia
Sepsis
Near Drowning
Common Causes
Hammer J. Pediatr Respir Rev. 2013;14(2):64-69
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
NAEPP Asthma Guidelines 2007
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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
NAEPP Asthma Guidelines 2007
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
NAEPP Asthma Guidelines 2007
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
Bradley JS et al. Clin Inf Dis. 2011;53(7):617-630
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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
Bradley JS et al. Clin Inf Dis. 2011;53(7):617-630
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
Is ECMO of Proven Benefit for Respiratory Failure?
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
Is ECMO of Proven Benefit for Respiratory Failure?
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
Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-417
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
Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-417
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
Buck ML. Clin Pharmacokinet 2003; 42 (5): 403-417
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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
Increased volume of distribution
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
Increased volume of distribution
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
https://www.elso.org/Resources/Guidelines.aspx -Accessed 5/10/2015
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
Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S42
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)
Annich G, Adachi I. Pediatr Crit Care Med 2013; 14:S37–S42
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
https://www.elso.org/Resources/Guidelines.aspx -Accessed 5/10/2015
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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