HiFi NO and ECMO

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					HiFi, NO, and ECMO

   Eric Demers, MD
        11/7/02
  Fellow’s Conference
    High Frequency Ventilation
• Based on the premise that patients could be
  effectively ventilated at very high rates with
  tidal volumes less than dead space volume.
• First mention in 1915 by Yandell
  Henderson (panting dogs).
• Development of technique during 1970’s
  for clinical application.
             How does it work?
• At least five proposed mechanisms of gas
  transport in HiFi ventilation:
  1. Direct Alveolar Ventilation by Bulk Convection
  2. Pendelluft
  3. Convective Dispersion due to Asymmetric
  Velocity Profiles
  4. Taylor-type Dispersion
  5. Molecular Diffusion
      (Chang, H.K. J. Appl. Physiol. 1984; 56(3):553-563.)
Slutsky, A.S., Drazen, J.M. NEJM 2002; 347(9):630-1.
  Direct Alveolar Ventilation by
         Bulk Convection
• Fresh Inspired gas directly ventilates alveoli
  closest to mouth/ETT
• Tidal Volume needs to exceed a certain
  lower limit to achieve this (critical closing
  pressure/volume)
• ? Most Efficient gas exchange mechanism
              Pendelluft
• Occurs in areas of lung with non-
  homogeneous time constants
• Time constant = dynamic compliance x
  resistance
• Exaggerated during HiFi ventilation
A. Expiration
B. Inspiration
    Convective Dispersion due to
    Asymmetric Velocity Profiles
•   Large and medium airways
•   Velocity profile changes with time
•   Phase variations
•   Complex branching system
      Taylor-Type Dispersion
• “Augmented Diffusion”
• Axial velocity (convection) and radial
  concentration gradient (diffusion) involved
• Laminar vs. turbulent flow
• Difference in inspiratory and expiratory
  flow
• Large airways
• Probably plays role in CO2 removal
         Molecular Diffusion
• Random thermal oscillations of molecules
• Occurs at alveolar-capillary interface
• Dominant gas transport at this surface (as it
  is in conventional mechanical ventilation)
Cordingley, JJ, Keogh, BF. Thorax 2002;57: 729-34
             Bunnell LifePulse
•   High Frequency Jet Ventilator
•   Requires special adaptor to accelerate gas flow
•   Used in tandem with CMV (IMV 2-10), same PIP
•   PIP: 8-50 cm H2O
•   PEEP: 5-8 cm H2O
•   I:E = 1:6
•   Frequency: 4-11 Hz
•   Ti: 0.02-0.034 sec
•   Passive expiration
        SensorMedics 3100 A
• High Frequency Oscillator
• Frequency: depends on pt size, resp mechanics (3-
  15 Hz)
• Amplitude (Δ Pressure): “Tidal Volume”
• Mean Airway Pressure (alter by bias gas flow
  adjustment or outlet resistance): + 2 cm H20 over
  CMV
• I:E = 1:2
• Active expiration
        SensorMedics 3100 A
• Frequency
  Preterm: 12-15
  Older premies/early chronic lung dz: 10-12
  Term: 8-10
• Lungs have natural resonant frequency.
• At this frequency, gas momentum supplies energy
  to overcome compliance. Only external force
  required is to overcome resistance.
• As complicance increases, frequency decreases.
• As resistance decreases, frequency increases.
        Infrasonics Infant Star
•   HFOV meets HFJV (Hybrid)
•   No acceleration of gas
•   Can be used with CMV
•   I:E = 1:5
•   Active expiration
               Reminder
In most neonatal lung disease with
  hypoxemia, the primary problem is diffuse
  atelectasis leading to V/Q mismatch and
  shunt
               Ventilation
• Ventilation = f x Vt2
• As you increase frequency, less and less
  time for airway/alveoli to equilibrate,
  decreased amplitude of pressure wave at
  alveoli and decreased CO2 removal.
 Theoretical indications for HiFi
• Air Leak (PIE, Bronchopleural fistula)
• Severe uniform non-RDS (Pneumonia,
  PPHN)
• Aspiration syndromes
• Pulmonary Hypoplasia
• Severe respiratory failure
           Rationale for Use
• Animal studies, both preterm and older,
  indicate better lung inflation, less alveolar
  and airway damage vs. CMV.
• Has not translated well to human studies
              Human Studies
•   Term vs. Preterm
•   Rescue vs. Primary therapy
•   Ventilation strategy
•   Airway recruitment vs. stabiliazation
•   Outcomes
•   Safety
     Cochrane reviews of HiFi
• HFJV vs. CMV for RDS in Premies 2002.
• HFOV vs. CMV for Pulm Dysfunction in
  Premies 2002.
• Rescue HiFi vs. CMV for Pulm.
  Dysfunction in Premies 2002.
• Rescue HiFi vs. CMV for severe Pulm.
  Dysfunction in infants at or near term 2002.
           Summary of Trials
• “Positive trials marked by recruitment strategy in
  HFV arm and/or CMV with slow rates, large Vt
  and/or low PEEP. Negative trials marked by
  absence of recruitment strategy in HFV arm or use
  of nonconventional higher rates and small Vt in
  CMV arm and/or delayed randomization using
  HFV as a rescue.”
-Rimensberger, Curr. Opin. Pediatr. 2002;14: 315-
  21.
      Recent Trials in Premies
• Courtney, et. al. and Johnson, et. al. in
  NEJM 2002 347(9):633-42, 643-52.
• Courtney study (US) showed decreased
  CLD with no difference in adverse
  outcomes.
• Johnson study (UK) showed no difference
  in outcomes.
          Burning questions
• Is HiFi safe?
• Is Hifi useful? (and what population?)
• In what instances is it useful?
• Should you wean to CMV? (How do you
  wean?)
• Do we really understand how this works?
          Nitric Oxide (NO)
• Selective Pulmonary Vasodilator
• Previously known as EDRF
• Inhaled rapidly bound/inactivated by
  hemoglobin (~3000 times greater affinity
  for hemoglobin vs. O2)
• Acts via cGMP to cause myosin
  phosphorylation, activation of K+ channels,
  etc.
             NO History
• 1980: EDRF described
• 1987: EDRF = NO
• 1992: NO named Science magazine’s
  “Molecule of the year”
• 1997: NINOS trial
• 1999: FDA approved
               NO Functions
•   Vasodilation
•   Neurotransmitter
•   Inhibits platelet aggregation and adhesion
•   Bronchodilation
•   Immune/Inflammatory modulation
   NOS (Nitric Oxide Synthase)
• At least three isoforms (All three found in
  lung)
  1. Endothelial NOS (eNOS)
  2. Neuronal NOS (nNOS)
  3. Inducible NOS (iNOS)

1 and 2 are Calcium dependent
Moncada S, Higgs A. NEJM 1993; 329(27): 2002-2012.
Moncada S, Higgs A. NEJM 1993; 329(27): 2002-2012.
  Neonatal Inhaled Nitric Oxide
     Study Group (NINOS)
• > 34 wks, hypoxic resp failure
• 20 ppm iNO vs O2
• Complete response: increase PaO2 > 20 mm Hg
  w/i 30 min. iNO initiation. If not, increased to 80
  ppm.
• No difference in death, but decreased ECMO
  (39% vs. 54 %)
• Only 3/53 infants (6%) responded to increase of
  iNO to 80 ppm.
• Cost of iNO was $36, 613/life saved
           NINOS, NEJM 1997;336(9)
             NO and PPHN
• Term infants (> 37 wks, > 2500 gms)
• OI > 25, PaO2 < 55 x 2
• iNO doubled systemic oxygenation in 16/30
  (53%) vs. 2/28(7%) controls.
• Decreased ECMO (40% vs. 71%)
• Mortality similar between groups

     Roberts, et. Al. NEJM 1997; 336(9).
          Cochrane Reviews
• Inhaled NO for respiratory failure in
  preterm infants 2002.
• Inhaled NO for respiratory failure in infants
  born at or near term 2002.
             Reminder

• Most common cause of lack of
  responsiveness to inhaled nitric
  oxide is due to inadequate lung
  inflation (recruitment)
    Recommendations for Use
• Gestational Age
  – > 34 weeks gestation
  – Within the first 4 weeks of life
     • Most infants enrolled in INO studies by 1.7 days
  – No specific guidelines as to postnatal age when
    therapy initiated
  – Use before ECLS (CDH may be exception)
    Recommendations for Use
• Illness Severity
  – Oxygenation Index most commonly used
     • (MAP x FiO2 x 100)/PaO2
  – Study enrollment usually > 25, but most
    infants entered at > 40
  – Unclear whether enrollment of infants
    with less severe hypoxic respiratory
    failure would benefit from INO therapy
    Recommendations for Use

• Clinical multicenter studies suggest
  that indications for treatment with
  iNO may include an OI greater
  than 25 with echocardiographic
  evidence of extrapulmonary right-
  to-left shunting
      Duration of Therapy
– In multicenter studies, typical duration of
  exposure was less than 5 days
– Longer duration in infants with
  pulmonary hypoplasia
– Longer treatment requirements suggest
  further investigations into other causes of
  pulmonary hypertension
           Toxicity
• METHEMOGLOBINEMIA
• LUNG TOXICITY
 – EPITHELIAL CELL INJURY
 – LIPID PEROXIDATION
 – SURFACTANT PROTEIN ALTERATION
• TOXIC OXYGEN METABOLITES
• NITROGEN OXIDE DERIVATIVES
             Toxicity
• NO
    . - FREE RADICAL
• NO2 - NITROGEN DIOXIDE
   • AIR POLLUTANT, IRRITANT
• N2O - NITROUS OXIDE
   • ANESTHETIC AGENT, VASOCONTRICTOR
• ONOO - PEROXYNITRATE ION
        -
                 .
   • FORMED BY NO REACTION WITH O2- ION
              Monitoring
• Methemoglobin – Management
  Recommendations
  – < 5% Acceptable level
  – 5-10% Decrease NO by 50% until < 5%
  – > 10% Discontinue NO
                 Monitoring
• NO2, NOx
  – Management recommendations
    • < 3 PPM    Acceptable level
    • 3 -5 PPM   Decrease NO by 50% until < 3 PPM
    • > 5 PPM    Discontinue NO
                Weaning
• Weaning vs. discontinuing
• Abrupt withdrawal leads to decrease
  oxygenation, increased PVR
  -may respond to increased FiO2
  -restarting iNO leads to rapid improvement
However:
               Weaning
• Rebound effect: increased PVR, profound
  hypoxia, systemic hypotension
  -downregulate endogenous NO production
  -decreased cGMP or enhanced PDE-5
  activity
  -Pulmonary vascular disease more severe
  than you thought
                ECMO
• 1930-1950’s: John Gibbon, Clarence
  Dennis and others initial work.
• 1960’s: Callaghn, Rashkind, Dorson use
  prolonged cardiopulmonary bypass for RDS
  (all died of hemorrhagic complications).
• 1972: Hill and O’Brien report first
  successful case.
• 1975-6: First successful newborn case.
                    ECMO
• Bartlett, et. al. Pediatrics 1985; 76(4):479-87.
  -Newborns with respiratory failure. 10-140 days
  old, wt > 2 kg.
  -Adaptive allocation: “Randomized Play the
  Winner”: Urn with one convential, one ECMO
  ball at start.
  -Stopped when 10 balls of same type were added.
  - 1 control pt (RDS, PPHN): died
  - 11 ECMO(RDS, MAS, CDH, PPHN): all
  survived
                    ECMO
• O’Rourke, et. al. Pediatrics 1989; 84(6)957-63.
  -PPHN and respiratory failure, wt > 2.5 kg.
  -85% likelihood of dying (PaO2/PAO2 < 0.15)
  - Max of 4 deaths allowed in either arm.
  -4/10 died in conventional group.
  -9/9 survived in ECMO.
  -19/20 survived in ECMO.
           ECMO Principles
• Take over function of lungs and +/- heart
  for patient for diseases that are “reversible”
  and have high mortality without.
• Allows lungs to be “rested”.
             Neonatal ECMO
1. > 33 wks gestation (wt > 2 kg.)
2. Reversible pulmonary disease
   -Meconium aspiration
   -Idiopathic RDS
   -Sepsis with pneumonia
   -PPHN
   -CDH
3. Predicted Mortality of at least 80% (based on OI >
   40 for minimum of 2-4 hrs)
            Neonatal ECMO
4. Exclusions
   - Major chromosomal anomalies incompatible
   with reasonable outcome.
   - Major cardiac or CNS malformations.
   - Intracranial hemorrhage > Grade 1.
   - Ventilator support > 10 days.
   - Uncontrolled bleeding
   - Unreversible disease process
         V-A vs V-V ECMO
• V-A ECMO                • V-V ECMO
• Cardiac Support         • Indirect Cardiac
                            Support
• Requires cannulation    • Venous access only
  of internal carotid
  artery
• Complete lung support   • May require some
                            lung function
        Veno-arterial ECMO
• Blood is drained from a vein (usually the
  right atrium) and returned to the aorta.
• Provides both cardiac and pulmonary
  support as needed.
• Currently the support of choice for patients
  with cardiac failure (e.g., post-operative
  congenital cardiac disease.
        Veno-venous ECMO
• Blood is drained from a vein and returned to
  a venous.
• Drainage sites are dependent upon patient
  size and upon metabolic requirements.
• Double lumen cannula vs. multiple single
  lumen cannula.
              Starting ECMO
• Confirm Catheter placement (CXR and Echo):
  venous cannula w/i R. atrium, arterial cannula w/i
  ascending aorta.
• Prime Pump: circulate with CO2 followed by
  crystalloid and 5% albumin then 2 units PRBC’s.
• O2 delivery dependent on RPM of roller pump
• Oxygenator: both O2 and CO2 exchanged. Can
  form thrombus over time
         ECMO management
• Fluid management: pts often gain wt first 1-
  3 days, then diuresis
• “Rest Settings” on ventilator: 20-25/5 x 12,
  0.40, Ti=0.5
• Other Critical Care issues: Blood pressure,
  nutrition, seizures, etc.
           Anticoagulation
• Heparin continuous infusion:
  - 50-100 mg/kg bolus
  - 30-60 mg/kg/hr continuous infusion
• Monitored by Activated Clotting Time
  (ACT)
• Goal is 180-220 sec.
             ECMO Diseases
•   MAS
•   PPHN
•   CDH
•   Sepsis
•   Cardiac support/cardiac arrest
•   Acute Deterioration/other
    Neonatal ECMO cases

 Diagnosis Cases % Survival
 MAS        3771         94
 RDS        1116         84
 PFC/PPHN 1391           83
 CDH        2081         58
 Sepsis      161         76
 Other       379         74
 Total     10349         80


ELSO registry 7/95, 116 centers
     Neonatal Complications
• Mechanical: Catheter diameter, length,
  kinks, positioning, etc.
• Neurologic: learning d/o, motor
  dysfunction, CP, ICH, SENSORINEURAL
  HEARING Deficit(25%)
• Renal: ATN
      Neonatal Complications
• Respiratory: pneumonia, continued support
• Blood: BLEEDING (~50% deaths due to
  bleeding complications)
  THROMBOCYTOPENIA
• Nutrition: poor growth/feeding problems
• Infection
   Neonatal ECMO complications

Complication % Incidence % Survived
ICH                   15         55
Seizure               13         65
Other Bleed            7         66
Hemolysis             12         72
Hemofilter            14         59
Oxygenator             5         62
Blood Leak             1         74
Air                    6         72
Clots                 25         75

   ELSO registry 7/95, 116 centers
              Monitoring
• ACT
• Cranial Ultrasounds
• CXR
                 Weaning
• Wean circuit flow (150 ml/kg/min – 30
  ml/kg/min)
• Level of respiratory support
• Clamp cannulas
• If patient tolerates, may be decannulated

				
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