Bronchopulmonary Dysplasia: Bronchopulmonary Dysplasia: Prevention and ManagementPrevention and Management

Namasivayam Ambalavanan M.D.Namasivayam Ambalavanan M.D.

Assistant Professor,Assistant Professor,Division of Neonatology,Division of Neonatology,

Department of Pediatrics, Department of Pediatrics,

University of Alabama at BirminghamUniversity of Alabama at Birmingham

Feb 2003Feb 2003

Overview of presentationOverview of presentation Bronchopulmonary dysplasia: a moving target?Bronchopulmonary dysplasia: a moving target? PathogenesisPathogenesis Strategies for prevention of BPDStrategies for prevention of BPD Strategies for management of BPDStrategies for management of BPD OutcomeOutcome AppendixAppendix

BPD vs. CLDBPD vs. CLD Initially labeled “bronchopulmonary dysplasia” Initially labeled “bronchopulmonary dysplasia”

[BPD][BPD] Later called “neonatal chronic lung disease” or Later called “neonatal chronic lung disease” or

“chronic lung disease of infancy” [CLD]“chronic lung disease of infancy” [CLD] Many experts now believe the term Many experts now believe the term

“bronchopulmonary dysplasia” is more accurate “bronchopulmonary dysplasia” is more accurate in describing the pathogenesis and that CLD is in describing the pathogenesis and that CLD is not a specific diagnosis or descriptionnot a specific diagnosis or description

IntroductionIntroduction Northway, Rosan, and Porter (1967) :BPD :premature Northway, Rosan, and Porter (1967) :BPD :premature

infants who developed RDS, required prolonged infants who developed RDS, required prolonged mechanical ventilation with high pressures and FiOmechanical ventilation with high pressures and FiO22. . Classic clinical and radiographic course had four stagesClassic clinical and radiographic course had four stages: :

II: RDS, : RDS,

II: dense parenchymal opacification,II: dense parenchymal opacification,

III: bubble-like pattern, III: bubble-like pattern,

IV: hyperlucency of bases with strands of radiodensity in IV: hyperlucency of bases with strands of radiodensity in upper lobes.upper lobes.

Currently, a milder form of BPD is more commonly seen Currently, a milder form of BPD is more commonly seen in tiny premies who have only mild pulmonary disease not in tiny premies who have only mild pulmonary disease not requiring high ventilatory supportrequiring high ventilatory support

IntroductionIntroduction Definitions: Definitions: 1.1. 1980’s: Oxygen dependence for 28 days or 1980’s: Oxygen dependence for 28 days or

more after birth more after birth (Tooley WH. J Pediatr 95: 851-8, 1979)(Tooley WH. J Pediatr 95: 851-8, 1979)

2.2. 1990’s: Oxygen dependence at 36 wks’ 1990’s: Oxygen dependence at 36 wks’ corrected age corrected age (Shennan et al. Pediatrics 82:527-32, 1988)(Shennan et al. Pediatrics 82:527-32, 1988)

More correlated with abnormal pulmonary outcome at 2 More correlated with abnormal pulmonary outcome at 2 years (63% PPV) vs. 28 d definition (38% PPV).years (63% PPV) vs. 28 d definition (38% PPV).

3.3. 2121stst century: New physiologic definition of century: New physiologic definition of BPDBPD

Physiologic definition of BPDPhysiologic definition of BPD Problem with previous definitions: The decision to Problem with previous definitions: The decision to

administer oxygen is not uniform and the definition administer oxygen is not uniform and the definition of acceptable saturation (85-98%) varies.of acceptable saturation (85-98%) varies.

Development of a “room air test” to document the Development of a “room air test” to document the need for oxygen by the NICHD Neonatal Research need for oxygen by the NICHD Neonatal Research NetworkNetwork

What is OWhat is O22 requirement (failure in test)? requirement (failure in test)? Saturation <88% for 5 continuous minutesSaturation <88% for 5 continuous minutes Any saturation <80% on an accurate pulse Any saturation <80% on an accurate pulse

oximeter readingoximeter reading

Study DesignStudy Design Baseline phase x 5 minBaseline phase x 5 min Oxygen reduction phase as per protocol every 10 Oxygen reduction phase as per protocol every 10

min with continuous monitoringmin with continuous monitoring

O2 reduction phase

Rapid Pass (15 min in RA>96%)

Rapid Fail (80-88% for 5 min (or) <80% immediate fail

Intermediate: 88-96% in first 15 min.Monitor for total 60 min.

No BPD

BPD

Some BPDSome No BPD

Incidence Varies by definition, selection bias, survival Varies by definition, selection bias, survival Developed countries: NICHD Neonatal Network Developed countries: NICHD Neonatal Network

for 2001for 2001

BPD-36BPD-36 UAB UAB All centersAll centers

401-1500g401-1500g 11%11% (n=297)(n=297) 23% (n=3589)23% (n=3589)

401-1000g401-1000g 19% (n=154)19% (n=154) 39% (n=1517)39% (n=1517) Developing countries: Developing countries:

PGI: PGI: BPD-28BPD-28: <1000g: 50% ; 1000-1249g: 8%; : <1000g: 50% ; 1000-1249g: 8%; 1250-1499g: 2.3% (Indian Pediatrics Feb 2002)1250-1499g: 2.3% (Indian Pediatrics Feb 2002)

Incidence • UAB statistics (1998-1999) of all live births <34 w(excluding 10 deaths before admission)

• 401-1000 g (2001; n=154): 82% IMV, 73% surf, 16% steroids for BPD

GA 23 24 25 26 27 28 29 30 31 32 33 34

n 34 52 50 62 63 82 87 85 100 168 158 160

Survival

(%)

35 48 82 85 95 89 97 94 99 98 99 99

BPD

(%)

26 19 32 34 14 4 2 0 0 1 0 0

PathogenesisPathogenesis

IncreasedAirwayCompliance

Pressure/ flowinhomogeneity

Immature cells surfactantdeficiency

DIFFUSE ALVEOLAR DAMAGE

BRONCHOPULMONARY DYSPLASIA

Barotrauma Infection / InflammationRECOVERY

BarotraumaInfection / InflammationPDAO2 Toxicity

Proteinleak

Retained fluid

PULMONARY IMMATURITYPULMONARY IMMATURITY

Respiratory DistressSyndrome

Prevention of BPDPrevention of BPD Ventilatory StrategiesVentilatory Strategies

Selective intubation / Avoid IMV (Prophylactic IMV Selective intubation / Avoid IMV (Prophylactic IMV bad)bad)

Early CPAPEarly CPAP Minimal (‘gentle”) ventilationMinimal (‘gentle”) ventilation Early extubationEarly extubation

Pharmacologic StrategiesPharmacologic Strategies Antenatal steroidsAntenatal steroids Vitamin A supplementationVitamin A supplementation OthersOthers

Other management:Other management: PDA, Infection PDA, Infection

Conservative Indication For CV and BPDConservative Indication For CV and BPD

0

25

50

75

100

Control Conservative

Intubation

0

10

20

30

40

Control Conservative

BPD

Adapted from Poets and Sens*, Gitterman et al., and Lindner et al, de Klerk and de Klerk*.*and/or mortality

Per

cen

t (%

)

Poets and SensGitterman, et alLindner, et alde Klerk and de Klerk

Ventilatory strategies for BPD preventionVentilatory strategies for BPD prevention

1.1. Conservative indications for assisted ventilationConservative indications for assisted ventilation

2.2. Smallest possible tidal volumeSmallest possible tidal volume

3.3. Sufficient inspiratory and expiratory timesSufficient inspiratory and expiratory times

4.4. Moderate PEEP to prevent end expiratory alveolar Moderate PEEP to prevent end expiratory alveolar collapse and maintain adequate lung volumecollapse and maintain adequate lung volume

5.5. Early/prophylactic use of surfactantEarly/prophylactic use of surfactant

6.6. Acceptance of hypercapnic acidosis Acceptance of hypercapnic acidosis

7.7. Aggressive weaning from assisted ventilation Aggressive weaning from assisted ventilation

8.8. Rescue with high frequency if air leak syndromesRescue with high frequency if air leak syndromes

Non-ventilatory strategies for BPD preventionNon-ventilatory strategies for BPD prevention

Antenatal steroidsAntenatal steroids Vitamin A supplementation Vitamin A supplementation (Tyson et al. NEJM (Tyson et al. NEJM 340:1962, 1999)

Avoidance of infectionsAvoidance of infections Closure of PDA Closure of PDA (but TIPP trial did not show a difference in BPD (but TIPP trial did not show a difference in BPD

despite a decrease in PDA from 50 to 24%. despite a decrease in PDA from 50 to 24%. Schmidt et al. NEJM Schmidt et al. NEJM 344:1966-72, 2001344:1966-72, 2001))

Optimal fluid and electrolyte management: moderate water Optimal fluid and electrolyte management: moderate water and sodium restriction in first week of life (and sodium restriction in first week of life (Tammela et al. Tammela et al. Acta Paediatr 81:207-12,1992; Costarino et al. J Pediatr 120: 99-Acta Paediatr 81:207-12,1992; Costarino et al. J Pediatr 120: 99-

106, 1992; Hartnoll et al 82: F19-23, 2000106, 1992; Hartnoll et al 82: F19-23, 2000))

BPD ManagementBPD Management Treatment is directed towards major pathophysiology:Treatment is directed towards major pathophysiology:

Pulmonary edema => Pulmonary edema => DiureticsDiuretics Bronchoconstriction and airway hyperreactivity => Bronchoconstriction and airway hyperreactivity =>

BronchodilatorsBronchodilators Airway inflammation => Airway inflammation => SteroidsSteroids Cor pulmonale =>Cor pulmonale => Vasodilators Vasodilators Chronic lung injury and repair =>Chronic lung injury and repair =>Antioxidants, Antioxidants,

nutrition, prevention of infectionsnutrition, prevention of infections

Management - DiureticsManagement - Diuretics DIURETICS:DIURETICS: Furosemide Furosemide ++ ThiazidesThiazides

When to consider :When to consider :1 Babies >1-2 wks w/ mod-severe lung disease on Babies >1-2 wks w/ mod-severe lung disease on

ventilatorventilator2 BPD w/ volume overloadBPD w/ volume overload3 “ “Stalled” BPDStalled” BPD4 BPD w/ inadequate nutrition due to fluid BPD w/ inadequate nutrition due to fluid

restrictionrestriction

Management - DiureticsManagement - Diuretics How?How?

Therapeutic trial (Lasix): Give 1 mg/kg iv or 2 mg/kg Therapeutic trial (Lasix): Give 1 mg/kg iv or 2 mg/kg po/og x 4-5 doses. If no improvement, increase dose. If po/og x 4-5 doses. If no improvement, increase dose. If improvement, give long term. If no improvement, no improvement, give long term. If no improvement, no long term. Eval weekly.long term. Eval weekly.

Monitor for side effects: Fluid-electrolyte balance/ Monitor for side effects: Fluid-electrolyte balance/ alkalosis/ osteopenia / ototoxic / gall stones. alkalosis/ osteopenia / ototoxic / gall stones. Alternate Alternate day Rx may decrease side effects.day Rx may decrease side effects.

No evidence to support any long-term benefit No evidence to support any long-term benefit ((Brion et al. Brion et al. Cochrane Database Syst Rev (1):CD001817, 2002Cochrane Database Syst Rev (1):CD001817, 2002))

Management - Bronchodilators Types of Bronchodilators:Types of Bronchodilators:

Methylxanthines ( Theophylline, caffeine )Methylxanthines ( Theophylline, caffeine )Bronchodilator, diuretic, resp stimulantBronchodilator, diuretic, resp stimulantweak bronchodilator, increased side effectsweak bronchodilator, increased side effects

-adrenergic agonists ( mainly -adrenergic agonists ( mainly , less , less 1 )1 )mainly smooth muscle relaxation, also enhance mainly smooth muscle relaxation, also enhance

mucociliary transport, redistribute pulmonary mucociliary transport, redistribute pulmonary blood flowblood flow

Anticholinergics - Atropine, IpratropiumAnticholinergics - Atropine, Ipratropium

Management - Bronchodilators Results:Results:

Bronchodilators improve pulmonary function in the Bronchodilators improve pulmonary function in the short-term.short-term.

No studies on long-term efficacyNo studies on long-term efficacy Inhaled salbutamol did not prevent BPD in a RCT Inhaled salbutamol did not prevent BPD in a RCT

((Denjean et al. Denjean et al. Eur J Pediatr 157:926-31, Nov 1998Eur J Pediatr 157:926-31, Nov 1998)) Long term safety ? -Long term safety ? -receptors in the brain.receptors in the brain.

Is bronchoconstriction protective ?Is bronchoconstriction protective ? Focal bronchoconstriction may have protective action Focal bronchoconstriction may have protective action

by limiting lung injury to distal unitsby limiting lung injury to distal units May maintain airway wall rigidityMay maintain airway wall rigidity

Management - Vasodilators VASODILATORSVASODILATORS

WHY ?WHY ?Alveolar hypoxia leads to pulmonary vasoconstriction and Alveolar hypoxia leads to pulmonary vasoconstriction and

structural remodeling of the pulmonary vascular bed.structural remodeling of the pulmonary vascular bed. Oxygen a potent vasodilator, main vasodilator used in BPD. Oxygen a potent vasodilator, main vasodilator used in BPD.

Keep POKeep PO22 60-80, SpO 60-80, SpO2 2 92-95%.92-95%. Hydralazine, Diltiazem, Nifedipine used in very small trials Hydralazine, Diltiazem, Nifedipine used in very small trials

showed hemodynamic improvement.showed hemodynamic improvement. Nitric Oxide (NO) improves oxygenation in some infants Nitric Oxide (NO) improves oxygenation in some infants

((Pilot study by Banks et al. Pediatrics Pilot study by Banks et al. Pediatrics 103:610-8, Mar 1999103:610-8, Mar 1999))

Management - Steroids STEROIDS - Widespread use, different regimensSTEROIDS - Widespread use, different regimens

HIGH RISK: HIGH RISK: Use is not recommendedUse is not recommended WHY ?WHY ?

Anti-inflammatory properties (early)Anti-inflammatory properties (early)Modulate lung repair (late)Modulate lung repair (late)

HOW ?HOW ?Early vs Late useEarly vs Late useShort-term vs Long-term courseShort-term vs Long-term coursePO/IV vs Inhaled routePO/IV vs Inhaled route

AAP/CPS statement Pediatrics 109: 330-8 Feb 2002 ““The routine use of systemic dexamethasone for The routine use of systemic dexamethasone for

the prevention or treatment of chronic lung the prevention or treatment of chronic lung disease in infants with very low birth weight is disease in infants with very low birth weight is notnot recommended” recommended”

““Outside the context of a randomized, controlled Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen infant on maximal ventilatory and oxygen support).support).””

Summary of systemic dexamethasone for BPDSummary of systemic dexamethasone for BPD BPD and BPD/Death are decreased by steroidsBPD and BPD/Death are decreased by steroids However, short-term risks are significantHowever, short-term risks are significant No improvement in survivalNo improvement in survival Long-term neurodevelopment is worse in infants Long-term neurodevelopment is worse in infants

treated with steroids (about a 2-fold increase in CP)treated with steroids (about a 2-fold increase in CP) Alternatives:Alternatives:

Low doses of hydrocortisone ?Low doses of hydrocortisone ? Inhaled steroids ?Inhaled steroids ? Other steroids eg. Methylprednisolone ?Other steroids eg. Methylprednisolone ?

RCT OF VITAMIN A IN ELBW INFANTSRCT OF VITAMIN A IN ELBW INFANTS

CLD or Death

CLD in Survivors

Hospital-acquired sepsis

Grade 3/4 IVH

Death, 3/4 IVH, or PVL

Decreased Risk Increased Risk

0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3

RR with 95% ClTyson et al. NEJM 340:1962, 1999

Routine antisepsis and hand-washing precautionsRoutine antisepsis and hand-washing precautions Routine infection control measuresRoutine infection control measures Specific prophylaxis (when available, depending Specific prophylaxis (when available, depending

on country):on country): Palivizumab (Synagis): humanized monoclonal Palivizumab (Synagis): humanized monoclonal

antibody to RSVantibody to RSV Pneumococcal conjugate vaccine (7-valent, Pneumococcal conjugate vaccine (7-valent,

Prevnar)Prevnar) Influenza vaccineInfluenza vaccine

Prevention of infectionsPrevention of infections

Treatment of infectionsTreatment of infections Postnatal sepsis associated with more BPDPostnatal sepsis associated with more BPD((Van Marter et al. J Pediatr 140:171-6, Feb 2002Van Marter et al. J Pediatr 140:171-6, Feb 2002 ) ) Is Ureaplasma colonization associated with BPD?Is Ureaplasma colonization associated with BPD?

No (No (Heggie et al. PIDJ 20:854-9, Sept 2001Heggie et al. PIDJ 20:854-9, Sept 2001)) Only if persistently (+) (Only if persistently (+) (Castro-Alcaraz et al. Castro-Alcaraz et al.

Pediatrics 110:e45, Oct 2002Pediatrics 110:e45, Oct 2002)) Even if associated with BPD, erythromycin treatment Even if associated with BPD, erythromycin treatment

may not be effective (may not be effective (Buhrer et al. Drugs 61:1893-9, Buhrer et al. Drugs 61:1893-9, 20012001))

Summary of BPD management Prevention is better than treatmentPrevention is better than treatment Oxygen therapyOxygen therapy, avoidance of environmental and infectious hazards. , avoidance of environmental and infectious hazards.

Essential not to underutilize or discontinue OEssential not to underutilize or discontinue O22 too early (may lead to too early (may lead to feeding difficulty, slow growth, bronchoconstriction, Pulmonary feeding difficulty, slow growth, bronchoconstriction, Pulmonary hypertension )hypertension )

Optimize nutritionOptimize nutrition Bronchodilators and diuretics may lead to short-term improvements. Bronchodilators and diuretics may lead to short-term improvements.

Long-term effects unknown.Long-term effects unknown. Avoid steroids as far as possibleAvoid steroids as far as possible Experimental management: Enzyme, Gene, Cytokine, Antioxidant, Experimental management: Enzyme, Gene, Cytokine, Antioxidant,

Antiprotease administration, Lung transplantAntiprotease administration, Lung transplant

Outcome Short-term outcomeShort-term outcome

Mortality in first year is high ( Respiratory failure, sepsis, or Mortality in first year is high ( Respiratory failure, sepsis, or intractable cor pulmonale) : 11-73% (23%)intractable cor pulmonale) : 11-73% (23%)

Respiratory infections not more frequent, but earlier and more Respiratory infections not more frequent, but earlier and more severe. 22% risk of hospitalization in first yr for resp illness, severe. 22% risk of hospitalization in first yr for resp illness, 40-50% for all causes.40-50% for all causes.

Higher risk of growth and developmental delay Higher risk of growth and developmental delay Gradual improvement in pulmonary function and cor pulmonale Gradual improvement in pulmonary function and cor pulmonale

usual, with adequate nutrition, growth and control of infection.usual, with adequate nutrition, growth and control of infection.

Outcome (contd.) Long-term outcomeLong-term outcome

Lung function - Lung function - Poor compliance,Poor compliance, increased resistance,increased resistance, expiratory airflow limitation (bronchospastic and expiratory airflow limitation (bronchospastic and

bronchomalacic),bronchomalacic), increased WOB, air trapping, reactive airway disease. increased WOB, air trapping, reactive airway disease. May persist into adulthood.May persist into adulthood.

Appendix

IntroductionIntroduction Indications for mechanical ventilationIndications for mechanical ventilation Ventilator variables for controlling Ventilator variables for controlling

mechanical ventilationmechanical ventilation BPD PathogenesisBPD Pathogenesis BPD ManagementBPD Management

IntroductionIntroduction Factors influencing incidence:Factors influencing incidence:

Definition usedDefinition used Nature of patient population (Race, Sex, Antenatal Nature of patient population (Race, Sex, Antenatal

steroid use, Infection incidence etc.)steroid use, Infection incidence etc.) Wide variation between different centers (Avg: Wide variation between different centers (Avg:

4% of the babies req vent, 15% of RDS req vent 4% of the babies req vent, 15% of RDS req vent >3 d & surviving 30 days.)>3 d & surviving 30 days.)

23-26% of VLBW survivors in USA/Canada23-26% of VLBW survivors in USA/Canada

IntroductionIntroduction Factors influencing incidence:Factors influencing incidence:

Survival statistics in patient population Survival statistics in patient population Developing nations have very low CLD Developing nations have very low CLD

since most ELBWs die within 28 dayssince most ELBWs die within 28 daysSurfactant improves survival of smaller Surfactant improves survival of smaller

babies, but overall incidence of BPD samebabies, but overall incidence of BPD same[“Shift of survival and BPD curves [“Shift of survival and BPD curves

downward”]downward”]

Introduction Introduction (contd.)(contd.) Clinical presentation:Clinical presentation:

Progression of XRay findings through 4 stages Progression of XRay findings through 4 stages (Northway) now rarely seen : (Northway) now rarely seen : I: RDS, I: RDS, II: dense parenchymal opacification,II: dense parenchymal opacification,III: bubble-like pattern, III: bubble-like pattern, IV: hyperlucency of bases with strands of IV: hyperlucency of bases with strands of

radiodensity in upper lobes.radiodensity in upper lobes.

IntroductionIntroduction (contd.) Clinical presentation (contd.)Clinical presentation (contd.)

Many premies have mild disease initially, but Many premies have mild disease initially, but after a few days or weeks, chronic lung disease after a few days or weeks, chronic lung disease appears - maybe triggered by infection, PDA or appears - maybe triggered by infection, PDA or barotrauma.barotrauma.

Survivors show slow but steady improvement in Survivors show slow but steady improvement in their lung function and XRay changes and can their lung function and XRay changes and can be weaned from the ventilator and oxygen be weaned from the ventilator and oxygen therapy after weeks to months.therapy after weeks to months.

Introduction Introduction (contd.)(contd.)

Clinical presentation (contd.)Clinical presentation (contd.)After extubation, retractions, tachypnea, and After extubation, retractions, tachypnea, and

crackles persist for variable periods. crackles persist for variable periods. Atelectasis occurs frequently.Atelectasis occurs frequently.

Infants with more severe lung damage may die Infants with more severe lung damage may die of progressive respiratory failure, cor of progressive respiratory failure, cor pulmonale, or infections.pulmonale, or infections.

Goals of mechanical ventilation

To achieve adequate gas exchange with To achieve adequate gas exchange with minimal lung injury and other adverse effectsminimal lung injury and other adverse effects

The definitions of “adequate gas exchange” The definitions of “adequate gas exchange” and “minimal lung injury” will depend on the and “minimal lung injury” will depend on the underlying pathophysiology and the clinical underlying pathophysiology and the clinical condition of the neonatecondition of the neonate

Adequate Gas Exchange

The definition of adequate gas exchange will The definition of adequate gas exchange will determine:determine: the indications for the initiation of mechanical the indications for the initiation of mechanical

ventilationventilation the desired blood gas valuesthe desired blood gas values the ventilator adjustments to maintain the the ventilator adjustments to maintain the

blood gas values within the desired rangesblood gas values within the desired ranges

Indications for mechanical ventilationI. Clinical criteria:I. Clinical criteria: Respiratory distress : retractions (intercostal, Respiratory distress : retractions (intercostal,

subcostal, suprasternal) and tachypnea (rate > 60-subcostal, suprasternal) and tachypnea (rate > 60-70/min) 70/min)

Central cyanosis (cyanosis of oral mucosa or an Central cyanosis (cyanosis of oral mucosa or an oxygen saturation of <85%) on oxygen by hood oxygen saturation of <85%) on oxygen by hood (head box) or continuous positive airway pressure (head box) or continuous positive airway pressure (CPAP) at FiO(CPAP) at FiO22 > 60-70% > 60-70%

persistent apnea unresponsive to medical persistent apnea unresponsive to medical management (e.g. theophylline, caffeine, or CPAP) management (e.g. theophylline, caffeine, or CPAP)

Indications for mechanical ventilation

II. Laboratory criteria:II. Laboratory criteria: Severe hypercapnia: arterial carbon dioxide Severe hypercapnia: arterial carbon dioxide

tension (PaCOtension (PaCO22) > 60 mm Hg in early RDS or > ) > 60 mm Hg in early RDS or > 70-80 mm Hg in resolving RDS, accompanied 70-80 mm Hg in resolving RDS, accompanied by a pH of less than 7.20 by a pH of less than 7.20

Severe hypoxemia: arterial oxygen tension Severe hypoxemia: arterial oxygen tension (PaO(PaO22) < 40-50 mm Hg on oxygen by hood ) < 40-50 mm Hg on oxygen by hood (head box) or CPAP at FiO(head box) or CPAP at FiO22 > 60-70% > 60-70%

Prophylactic mechanical ventilation is not beneficial

Prophylactic mechanical ventilation not beneficial, even Prophylactic mechanical ventilation not beneficial, even for extremely premature neonates for extremely premature neonates

A decrease in the rates of intubation and mechanical A decrease in the rates of intubation and mechanical ventilation for very low birth weight (VLBW) neonates ventilation for very low birth weight (VLBW) neonates reduced bronchopulmonary dysplasia (BPD)reduced bronchopulmonary dysplasia (BPD)((Poets CF, Sens B:Pediatrics 1996;98: 24-27)Poets CF, Sens B:Pediatrics 1996;98: 24-27)

An individualized intubation strategy that restricted An individualized intubation strategy that restricted intubation and mechanical ventilation did not increase intubation and mechanical ventilation did not increase mortality or morbidity mortality or morbidity (Lindner W et al. Pediatrics 1999; 103: 961-967 )(Lindner W et al. Pediatrics 1999; 103: 961-967 )

Prophylactic mechanical ventilation is not beneficial (contd.) A significant part of the variation in BPD A significant part of the variation in BPD

between two centers could be explained by an between two centers could be explained by an increased incidence of BPD in the center with increased incidence of BPD in the center with more frequent use of mechanical ventilation more frequent use of mechanical ventilation

((Van Marter LJ et al. Pediatrics 2000, 105:1194-Van Marter LJ et al. Pediatrics 2000, 105:1194-1201)1201)

Ventilator controls The ventilator controls on most pressure-controlled The ventilator controls on most pressure-controlled

time-cycled ventilators are:time-cycled ventilators are: Positive end expiratory pressure (PEEP)Positive end expiratory pressure (PEEP) Peak inspiratory pressure (PIP)Peak inspiratory pressure (PIP) Ventilator rate (VR)Ventilator rate (VR) Inspiratory time (TI), expiratory time (TE), or Inspiratory time (TI), expiratory time (TE), or

inspiratory-expiratory ratio (I:E)inspiratory-expiratory ratio (I:E) Inspired oxygen concentration (FiOInspired oxygen concentration (FiO

22)) Flow rate Flow rate

Positive end expiratory pressure (PEEP) PEEP maintains or improves lung volume PEEP maintains or improves lung volume

(functional residual capacity or FRC), prevents (functional residual capacity or FRC), prevents alveolar collapse, and improves V/Q matching alveolar collapse, and improves V/Q matching

PEEP, rather than PIP or TPEEP, rather than PIP or TII, is the main , is the main

determinant of FRC determinant of FRC Low PEEP: atelectasis, low FRC, and low PaOLow PEEP: atelectasis, low FRC, and low PaO22

High PEEP: low VHigh PEEP: low VTT, high FRC, and high PaCO, high FRC, and high PaCO22

Optimal PEEP: between 3 - 6 cm HOptimal PEEP: between 3 - 6 cm H22O pressureO pressure

Peak Inspiratory Pressure (PIP)

Changes in PIP affect PaOChanges in PIP affect PaO22 by affecting the by affecting the

mean airway pressure and thus influencing V/Q mean airway pressure and thus influencing V/Q matching. matching.

The level of PIP also affects the pressure The level of PIP also affects the pressure gradient (gradient (P) which determines the tidal P) which determines the tidal volume volume

PIP increases normally increase PaOPIP increases normally increase PaO22 and and

decrease PaCOdecrease PaCO22

Peak Inspiratory Pressure (PIP) contd. Very high PIP may lead to hyperinflation and Very high PIP may lead to hyperinflation and

decreased lung perfusion and cardiac output, decreased lung perfusion and cardiac output, leading to a decrease in oxygen transport despite leading to a decrease in oxygen transport despite an adequate PaOan adequate PaO22

High levels of PIP also increase the risk of High levels of PIP also increase the risk of “volutrauma”, air leak syndromes, and lung injury“volutrauma”, air leak syndromes, and lung injury

PIP required depends mainly on the compliance PIP required depends mainly on the compliance of the respiratory system. of the respiratory system.

Peak Inspiratory Pressure (PIP) contd. Clinical indicator of adequate PIP is gentle chest rise Clinical indicator of adequate PIP is gentle chest rise

with every ventilator-delivered breath, similar to with every ventilator-delivered breath, similar to spontaneous breathing. spontaneous breathing.

The degree of observed chest wall movement during The degree of observed chest wall movement during the ventilator-delivered breaths indicates the the ventilator-delivered breaths indicates the compliance with fair accuracy compliance with fair accuracy

(Aufricht et al. Am J Perinatol 10:139-142, 1993)(Aufricht et al. Am J Perinatol 10:139-142, 1993) Minimal effective PIP: start low (e.g. 15-20 cm HMinimal effective PIP: start low (e.g. 15-20 cm H

22O) O)

and increase slowly (in steps of 1-2 cm Hand increase slowly (in steps of 1-2 cm H22O) O)

Factors to be considered in selecting PIP

YesYes No No

Lung complianceLung compliance WeightWeight

Blood gas derangementBlood gas derangement ResistanceResistance

Chest rise Chest rise Time constantTime constant

Breath soundsBreath sounds PEEPPEEP

OthersOthers OthersOthers

Ventilator rate The ventilator rate (frequency) determines The ventilator rate (frequency) determines

alveolar minute ventilation and thereby PaCOalveolar minute ventilation and thereby PaCO22 alveolar minute ventilation = frequency x [tidal alveolar minute ventilation = frequency x [tidal

volume – dead space] volume – dead space] Relationship not linear: As ventilator rate Relationship not linear: As ventilator rate

increases and Tincreases and TI I decreases below 3 time constants, decreases below 3 time constants, VVT T decreases and minute ventilation falls decreases and minute ventilation falls (Boros et al. Pediatrics 74: 487-492, 1984)(Boros et al. Pediatrics 74: 487-492, 1984)

As time constant is low in RDS, rates As time constant is low in RDS, rates >> 60/min 60/min can be usedcan be used

TI , TE , and I:E The TThe TI I and Tand TEE are normally adjusted based on the are normally adjusted based on the

time constant time constant Changes in I:E change MAP, and thus PaOChanges in I:E change MAP, and thus PaO22

When corrected for MAP, changes in I:E are not When corrected for MAP, changes in I:E are not as effective in improving PaOas effective in improving PaO2 2 as changes in PIP as changes in PIP or PEEP or PEEP (Stewart et al. Pediatrics 67:474-81, 1981)(Stewart et al. Pediatrics 67:474-81, 1981)

Higher ventilatory rates combined with a short THigher ventilatory rates combined with a short T II decrease air leaksdecrease air leaks (Octave. Arch Dis Child 66:770-775, 1991;

Pohlandt et al. Eur J Pediatr 151:904-909, 1992)

Gas exchangeGas exchange MAP increases with increasing PIP, PEEP, MAP increases with increasing PIP, PEEP,

TTII to T to TEE ratio, rate, and flow ratio, rate, and flow

PEEP

PIP

TI

RateFlow

Pressure

TimeTI TE

PEEP

PIP

Inspired oxygen concentration (FiO2)

Changes in FiOChanges in FiO22 alter PaO alter PaO2 2 directly by changing directly by changing

the A-a DOthe A-a DO22

Insufficient data to compare the roles of OInsufficient data to compare the roles of O22--

induced versus pressure-associated (or volume-induced versus pressure-associated (or volume-associated) lung injury in the neonateassociated) lung injury in the neonate

Generally believed that risk of OGenerally believed that risk of O2 2 toxicity is less toxicity is less

than that of volutrauma with FiOthan that of volutrauma with FiO22 < 0.6 - 0.7 < 0.6 - 0.7

Frequent FiOFrequent FiO22 changes are required, based on changes are required, based on

pulse oximetry rather than occasional blood gasespulse oximetry rather than occasional blood gases

Inspired oxygen concentration (FiO2)

During early RDS, FiO2 first increased to 0.6 to 0.7 before additional increases in MAP

During weaning, first decrease PIP to relatively safe levels, then decrease FiO2 below 0.4 to 0.5

Maintenance of an adequate MAP and V/Q matching may permit a reduction in FiO2

Reduce MAP before a very low FiO2 (<0.3) is reached, to reduce the risk of air leaks.

Flow rate As long as a sufficient flow is used, there is As long as a sufficient flow is used, there is

minimal effect on the pressure waveform or on minimal effect on the pressure waveform or on gas exchangegas exchange

Higher flow leads to a more “square wave” Higher flow leads to a more “square wave” pressure waveform, which increases MAP, pressure waveform, which increases MAP, turbulence, and risk of air leaksturbulence, and risk of air leaks

A minimum flow rate of about 3 times the A minimum flow rate of about 3 times the infant’s minute ventilation is usually required, infant’s minute ventilation is usually required, and 6-10 L/min is usually sufficient and 6-10 L/min is usually sufficient

Ventilator settings In view of the low compliance, short time

constant, low FRC, and risk for air leaks, it is usually preferred to use rapid rates (>60/min) moderate PEEP (4-5 cm H2O)

low PIP (10-20 cm H2O)

TI of 0.3-0.4 s

VT is generally 3 - 6 mL/kg body weight

Ventilator settings Randomized controlled trials have shown that a

rapid rates and short TI (versus slow rates and long TI) decrease air leaks (Octave. Arch Dis Child 66:770-775, 1991;

Pohlandt et al. Eur J Pediatr 151:904-909, 1992) Animal models also show that rapid, shallow

ventilation produce less lung injury than slow, deep breaths (Albertine et al. Am J Respir Crit Care Med 159: 945-958, 1999)

Clinical estimation of optimal TClinical estimation of optimal TI I and Tand TEE

Short TI Optimal TI Long TI

Inadeq VT Short insp. plateau Long plateau

Short TE Optimal TE Long TEAir trapping Short exp. plateau Long exp. plateau

ChestWallMotion

Time

ChestWallMotion

Weaning off ventilator When good spontaneous ventilatory attempts are

present and mechanical ventilation contributes only minimally to total ventilation

Normally done when ventilator rates are 15/min or less, at a PIP <15 cm H2O and a FiO2 < 40%.

Extubation from low rates is more successful as compared to extubation from endotracheal CPAP(Davis and Henderson-Smart. Cochrane Rev. CD 001078, 2000)

BPD PathogenesisBPD Pathogenesis Features of the immature lung increasing susceptibility:Features of the immature lung increasing susceptibility:

Barotrauma Barotrauma : Poorly compliant airspaces, but highly : Poorly compliant airspaces, but highly compliant airwayscompliant airways

HyperoxiaHyperoxia : Poorly developed antioxidant defenses : Poorly developed antioxidant defenses InfectionInfection : Altered airway clearance, immature macrophages & : Altered airway clearance, immature macrophages &

WBCWBC InflammationInflammation : : Poorly developed anti-oxidant, antiproteolytic Poorly developed anti-oxidant, antiproteolytic

and antielastolytic systemsand antielastolytic systems Increased permeabilityIncreased permeability of the alveolo-capillary membrane of the alveolo-capillary membrane

with decreasing gestational age.with decreasing gestational age.

BPD PathogenesisBPD Pathogenesis Complications of Hyperoxia:Complications of Hyperoxia:

CytotoxicityCytotoxicity epithelium & endothelium epithelium & endothelium Pulmonary edema and Pulmonary edema and hemorrhagehemorrhage

Cytotoxicity Cytotoxicity on airway lining & macrophages Poor airway clearance on airway lining & macrophages Poor airway clearance and increased infectionand increased infection

Pulmonary edema Pulmonary edema + + inhibition of surfactant synthesis inhibition of surfactant synthesis leads to worsening leads to worsening compliancecompliance

Inhibition of pulmonary vascular response to hypoxia leads to Inhibition of pulmonary vascular response to hypoxia leads to shuntingshunting , , V/Q mismatchV/Q mismatch

Inhibition of normal Inhibition of normal lung repairlung repair, healing by fibroblast proliferation, healing by fibroblast proliferation Inhibition of normal Inhibition of normal lung developmentlung development, decreased alveolarization, decreased alveolarization Loss of pulmonary endothelial functionsLoss of pulmonary endothelial functions

Lung Injury During Mechanical Ventilation

1. Chest wall restriction limits pressure-induced lung 1. Chest wall restriction limits pressure-induced lung injury injury (Hernandez, et al., 1988)(Hernandez, et al., 1988)

2.2. Overexpansion of the thorax with negative Overexpansion of the thorax with negative pressures causes lung injury pressures causes lung injury (Dreyfus, et al. 1988)(Dreyfus, et al. 1988)

Changes in intubation rates in relation to Changes in intubation rates in relation to outcome in VLBW infantsoutcome in VLBW infants

19199292 19931993 19941994 pp value value

n=665n=665 n=664n=664 n=672n=672

Intubated (%)Intubated (%) 7878 7878 6666 <0.05<0.05

OO22 at 28d (%) at 28d (%) 2121 2020 1717 <0.05<0.05

Death or ODeath or O22 at 28d (%) at 28d (%) 3232 2929 2727 NSNS

Death or ODeath or O22 in < 1.0 kg (%) in < 1.0 kg (%) 6262 5454 5252 <0.05<0.05

Death or ODeath or O22 in 1-1.5 kg (%) in 1-1.5 kg (%) 1414 1212 99 <0.05<0.05

CPAP (%)CPAP (%) 44 55 66 NSNS

Poets and Sens. Pediatrics 98:24, 1996

Ventilator-Associated Lung Injury Ventilator-Associated Lung Injury (VALI)(VALI)

Likely mechanisms• Volume rather than pressures

• End expiratory volume rather than VT or FRC

• Transalveolar pressure and reopening of alveoli• Repeated collapse and reopening of alveoli• Very low positive end expiratory pressure• Oxidant injury

A BTime A High VT

B Normal VT, high PEEP

Volutrauma ZoneV

olu

me

Which Volumes Cause Lung Injury?Which Volumes Cause Lung Injury?

EFFECT OF TIDAL VOLUMEEFFECT OF TIDAL VOLUMEON LUNG COMPLIANCEON LUNG COMPLIANCE

0

1

2

3

0 60 120 180 240Age (min)

32 cc/kg

16 cc/kg

8 cc/kg

Com

pli

ance

(c

c/cm

H2O

•kg)

Bjorklund et al. Pediatr Res 39:326A, 1996

Early CPAP: prophylactic or rescue?Early CPAP: prophylactic or rescue? Prophylactic CPAP (before onset of respiratory distress) Prophylactic CPAP (before onset of respiratory distress)

practiced at some centers. practiced at some centers. Rescue CPAP (after onset of distress):Rescue CPAP (after onset of distress):

Often combined with an dose of surfactant given by a Often combined with an dose of surfactant given by a brief intubationbrief intubation

May decrease the need for mechanical ventilation and May decrease the need for mechanical ventilation and improve respiratory failure and reduce mortalityimprove respiratory failure and reduce mortality

May increase risk of pneumothorax May increase risk of pneumothorax (Ho et al. Cochrane Rev 2000 ;(4): CD002271 (Ho et al. Cochrane Rev 2000 ;(4): CD002271 ))

(Verder et al. Pediatrics 1999;103: E24 )(Verder et al. Pediatrics 1999;103: E24 )

1.1. Maintenance of normocapnia in some patients Maintenance of normocapnia in some patients with severe respiratory failure necessitates high with severe respiratory failure necessitates high ventilatory support.ventilatory support.

2.2. Compensated respiratory acidosis is generally Compensated respiratory acidosis is generally well tolerated and may reduce lung injury.well tolerated and may reduce lung injury.

Permissive Hypercapnia: BackgroundPermissive Hypercapnia: Background

Relative Risk for BPDRelative Risk for BPD

Variable N Relative risk (95% CI)

Highest PaCO2 at 48 or 96 hr

> 50 mm Hg 21 Reference group

40-49 mm Hg 52 1.35 (0.95, 1.90)

< 40 mm Hg 46 1.45 (1.04, 2.01)Kraybill et al., J Pediatr 115:115-120, 1989

Risk for BPD in Neonates with RDS: Risk for BPD in Neonates with RDS: Variables in Logistic RegressionVariables in Logistic Regression

OddsConfidence

Ratio IntervalVE Index < 0.15 3.1 1.4 - 6.8a/A Ratio < 0.15 2.2 1.01 - 4.6Low PaCO2 (< 29 vs 40) 5.6 2.0 - 15.6

(30-39 vs >40) 3.3 1.3 - 8.4Birthweight < 1000 grams 5.1 2.4 - 10.7C/S Due to Fetal Distress 4.4 1.7 - 11.4

Garland et al. Arch Pediatr Adolesc Med 149-617, 1995

Volume vs. Pressure in Lung InjuryPulm.Pulm. Epith.Epith. HyalineHyaline LymphLymph Filtr.Filtr.

VolumeVolume PressurePressure EdemaEdema InjuryInjury Memb. Flow Coef.Memb. Flow Coef.

IPPVIPPV HighHigh HighHigh YesYes YesYes Yes Yes YesYes Yes Yes

Iron LungIron Lung HighHigh LowLow YesYes YesYes Yes N/A N/AYes N/A N/A

StrappingStrapping LowLow HighHigh NoNo NoNo No No NoNo No No

Dreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge Dreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge

et al, 1990; Carlton et al 1990et al, 1990; Carlton et al 1990

CPAP at Birth in VLBW Infants

CCPAPPAP ControlControl

n=70n=70 n=57n=57 p valuep value

Intubated (%)Intubated (%) 3030 5353 <0.05<0.05

Dur. intubation (d)Dur. intubation (d) 6(3-9)6(3-9) 4.5(3-7)4.5(3-7) NSNS

OO22 at 28 days (%) at 28 days (%) 3030 3232 NSNS

Nosocomial infection (%)Nosocomial infection (%) 2121 3737 <0.05<0.05

Gitterman et al. Eur J Pediatrics. 156:384, 1997

CPAP at Birth in VLBW Infants

0

25

50

75

100

Control CPAP

IntubationO at 28d

2

Gitterman et al. Eur J Pediatrics. 156:384, 1997

Per

cen

t (%

)

CV vs CPAP at Birth in ELBW Infants

CPAPCPAP RRoutineoutine IntubationIntubation p valuep value

N=67N=67 N=56N=56

DR intubation (%)DR intubation (%) 4040 8484 <0.01<0.01

Intubated (%)Intubated (%) 6565 9393 <0.01<0.01

Mortality (%)Mortality (%) 2222 2727 NSNS

OO22 at 36 weeks (%) at 36 weeks (%) 1212 3232 <0.05<0.05

IVH > 2 (%)IVH > 2 (%) 1616 3838 <0.01<0.01

Lindner et al. Pediatrics 103:961, 1999

0

25

50

75

100

Control CPAP

IntubationO at 36 weeks

2

CV VS CPAP at Birth in ELBW Infants

Lindner et al. Pediatrics 103:961, 1999

Per

cen

t (%

)

CPAP in Infants 1-1.5 KgCPAPCPAP ControlControl p valuep value

n=59n=59 n=57n=57

Intubated (%)Intubated (%) 1414 65 65 <0.001<0.001

Surfactant (%)Surfactant (%) 1212 4040 <0.001<0.001

Ventilation (d)Ventilation (d) 22 66 <0.05<0.05

Oxygen suppl (d)Oxygen suppl (d) 22 44 <0.01<0.01

OO22 at 28d (%) at 28d (%) 00 1111 <0.05<0.05

OO22 at 28d or death (%) at 28d or death (%) 33 1616 <0.05<0.05

OO22 at 36w or death (%) at 36w or death (%) 33 1111 0.250.25de Klerk and de Klerk. J Paedr Child Health 37:161:201

CPAP in Infants 1-1.5 Kg

0

25

50

75

100

Control CPAP

Intubation

O at 28d or death

de Klerk and de Klerk. J Paedr Child Health 37:161:201

2

Per

cen

t (%

)

Demographic Characteristics of ELBW and Demographic Characteristics of ELBW and BPDBPD

Without BPD With BPDCharacteristic (n=50) (n=97)Gestational age (wk) 28 + 2 27 + 2*Birth weight (gm) 902 + 74 883 + 73Sex (% male) 34 60*Race (% white) 32 43Roentgenographic score 1.98 + 1.25 2.77 + 1.16*

*p<0.005 Kraybill et al., J. Pediatr 115:115-120, 1989

Treatment Variables of ELBW infants Treatment Variables of ELBW infants and BPDand BPD

Without BPD With BPDCharacteristic (n=29) (n=90)Pressure management

PIP (cm H2O)At 48 hr 21 + 6 22 + 7At 96 hr 18 + 5 19 + 5

Paw (cm H2O)At 48 hr 12 + 6 12 + 5At 96 hr 6 + 2 8 + 3

Kraybill et al., J. Pediatr 115:115-120, 1989

Treatment Variables of ELBW infants Treatment Variables of ELBW infants and BPDand BPD

Without BPD With BPDCharacteristic (n=29) (n=90)Oxygen management

FiO2 (%)At 48 hr 49 + 24 54 + 25At 96 hr 33 + 18 38 + 20

PaO2 (mmHg)At 48 hr 85 + 30 79 + 36At 96 hr 72 + 17 74 + 19

PA-aO2 (mmHg)At 48 hr 221 + 175 268 + 175At 96 hr 127 + 128 158 + 137

Kraybill et al., J. Pediatr 115:115-120, 1989

Relative Risk for BPDRelative Risk for BPD

Variable N Relative risk (95% CI)

Highest PaO2 at 48 or 96 hr< 70 mm Hg 30 Reference group 70-80 mm Hg 23 0.80 (0.60, 1.07)81-100 mm Hg 37 0.90 (0.72, 1.13)> 100 mg Hg 29 0.76 (0.57, 1.01)

Kraybill et al., J Pediatr 115:115-120, 1989

Logistic Regression Model to Logistic Regression Model to Predict BPDPredict BPD

Independent Variable p rSex (male) <0.01 0.20PaCO2 at 48 hr <0.05 -0.14Roentgenographic score 0.10 0.07Gestational age 0.13 -0.04Race 0.79 0.00Kraybill et al., J. Pediatr 115:115-120, 1989

RANDOMIZED TRIAL OF PERMISSIVE RANDOMIZED TRIAL OF PERMISSIVE HYPERCAPNIA IN PRETERM INFANTSHYPERCAPNIA IN PRETERM INFANTS

G Mariani, J Cifuentes, WA CarloG Mariani, J Cifuentes, WA Carlo

Department of Pediatrics, University of Alabama Department of Pediatrics, University of Alabama at Birminghamat Birmingham

Pediatrics 104: 1082-8, 1999Pediatrics 104: 1082-8, 1999

p = 0.002 Log rank test

Duration of MV (hours)

0 12 24 36 48 60 72 84 96

Infa

nts

on

MV

(%

)

0

20

40

60

80

100 NormocapniaPermissive hypercapnia

EFFECTS OF MINIMAL VENTILATION IN A MULTICENTER RANDOMIZED CONTROLLED TRIAL

OF VENTILATOR SUPPORT AND EARLY CORTICOSTEROID THERAPY IN EXTREMELY LOW

BIRTH WEIGHT INFANTS

The Steroid And VEntilation (SAVE) TrialThe Steroid And VEntilation (SAVE) Trial

NICHD Neonatal Research NetworkNICHD Neonatal Research Network

Carlo et al. J Pediatr Carlo et al. J Pediatr 141: 370-4141: 370-4, Sept 2002, Sept 2002

SAVE Trial

Centers and Principal InvestigatorsUniv of Alabama at BirminghamUniv of Alabama at Birmingham Wally Carlo, MDWally Carlo, MDHarvard UniversityHarvard University Ann Stark, MDAnn Stark, MDEmory UniversityEmory University Barbara Stoll, MDBarbara Stoll, MDCase Western Reserve UniversityCase Western Reserve University Avroy Fanaroff, MB, BChAvroy Fanaroff, MB, BChYale UniversityYale University Richard Ehrenkranz, MDRichard Ehrenkranz, MDUniversity of Tennessee-MemphisUniversity of Tennessee-Memphis Sheldon Korones, MDSheldon Korones, MDUT Southwestern Medical Center-DallasUT Southwestern Medical Center-Dallas Jon Tyson, MDJon Tyson, MDWayne State UniversityWayne State University Seetha Shankaran, MDSeetha Shankaran, MDBrown UniversityBrown University William Oh, MDWilliam Oh, MDUniversity of MiamiUniversity of Miami Charles Bauer, MDCharles Bauer, MDUniversity of CincinnatiUniversity of Cincinnati Ed Donovan, MDEd Donovan, MDStanford UniversityStanford University David Stevenson, MDDavid Stevenson, MDUniversity of New MexicoUniversity of New Mexico Lu-Ann Papile, MDLu-Ann Papile, MDResearch Triangle InstituteResearch Triangle Institute Ken Poole, PhDKen Poole, PhDNICHDNICHD Linda Wright, MDLinda Wright, MD

SAVE Trial

Hypothesis

A strategy of minimal ventilation support A strategy of minimal ventilation support (defined as a PCO(defined as a PCO22 goal > 52 mmHg) in infants goal > 52 mmHg) in infants

501 to 1000 grams, initiated within 12 hours of 501 to 1000 grams, initiated within 12 hours of birth and maintained as long as mechanical birth and maintained as long as mechanical ventilation is needed during the first 10 days, ventilation is needed during the first 10 days, reduces by at least 20% the incidence of death or reduces by at least 20% the incidence of death or chronic lung disease at 36 weeks postmenstrual chronic lung disease at 36 weeks postmenstrual age.age.

Sample Size

1200 infants1200 infants

Ventilator strategyVentilator strategy

MinimalMinimal RoutineRoutine

SStress Dosetress Dose 300300 300300

PlaceboPlacebo 300300 300300

Steroid strategy

SAVE Trial

Study Design MulticenterMulticenter Randomized-stratified by center and birth Randomized-stratified by center and birth

weight groupweight group 2 x 2 Factorial design2 x 2 Factorial design InterventionsInterventions

Corticosteroid/PlaceboCorticosteroid/PlaceboMinimal/Routine ventilationMinimal/Routine ventilation

SAVE Trial

Ventilatory Intervention (Continued) Pressure-limited, time-cycled ventilation with or Pressure-limited, time-cycled ventilation with or

without SIMV is preferred; HFV is discouraged.without SIMV is preferred; HFV is discouraged. The preferred ventilator strategy for infants in the The preferred ventilator strategy for infants in the

minimal ventilator support group is to use the minimal ventilator support group is to use the smallest possible tidal volume with the smallest possible tidal volume with the conventional ventilator.conventional ventilator.

Ventilator strategy is maintained for ten days Ventilator strategy is maintained for ten days unless extubation occurs sooner.unless extubation occurs sooner.

SAVE Trial

Methods - Ventilatory Management

Goals: Minimal ventilation groupGoals: Minimal ventilation group -- PCOPCO22 > 52 mmHg > 52 mmHg

Routine ventilation group Routine ventilation group -- PCO2 PCO2 << 48 mmHg 48 mmHg In both groups:In both groups:

Priority was given to decrease tidal volume by Priority was given to decrease tidal volume by decreasing peak inspiratory pressure (PIP) or increasing decreasing peak inspiratory pressure (PIP) or increasing raterate

Tidal volume was measured dailyTidal volume was measured daily The same extubation criteria (rate < 10/min, FiOThe same extubation criteria (rate < 10/min, FiO22 < 0.50, < 0.50,

and pH > 7.25) were used and pH > 7.25) were used

SAVE Trial

Ventilatory InterventionVentilatory Intervention

Routine ventilator supportRoutine ventilator support

(Normocapnia)(Normocapnia)

PCOPCO22 goal: < 48 mmHg goal: < 48 mmHg

PaOPaO22 goal: 50-80 mmHg goal: 50-80 mmHg

OO22 sat goal: 88-95% sat goal: 88-95%

pH goal: pH goal: 7.20 7.20

Minimal ventilator supportMinimal ventilator support

(Permissive hypercapnia)(Permissive hypercapnia)

PCOPCO22 goal: > 52 mmHg goal: > 52 mmHg

PaOPaO22 goal: 50-80 mmHg goal: 50-80 mmHg

OO22 sat goal: 88-95% sat goal: 88-95%

pH goal: pH goal: 7.20 7.20

SAVE Trial

Results - Primary Outcome MeasureResults - Primary Outcome Measure

MinimalMinimal RoutineRoutine

VentilationVentilation VentilationVentilation RRRR CICI

(N=109)(N=109) (N=111)(N=111)

Mortality or CLD (%)Mortality or CLD (%) 6363 6868 0.920.92 (0.76-1.12)(0.76-1.12)

Mortality (%)Mortality (%) 2323 2222 1.061.06 (0.65-1.74)(0.65-1.74)

CLD (%)CLD (%) 5252 6060 0.880.88 (0.67-1.14)(0.67-1.14)

SAVE Trial

Results - Secondary AnalysesResults - Secondary Analyses Minimal Minimal RoutineRoutine

VentilationVentilation Ventilation RRVentilation RR CI NNT CI NNT

CLD or death in CLD or death in

501-750 gm (%)501-750 gm (%) 6868 8686 0.790.79 (0.65-0.96)* 6(0.65-0.96)* 6

Ventilation at Ventilation at

36 wk (%)36 wk (%) 11 1818 0.090.09 (0.01-0.67)* 7(0.01-0.67)* 7

OO22/CPAP/Vent/CPAP/Vent

at 36 wk (%) at 36 wk (%) 4747 5757 0.830.83 (0.60-1.13) —(0.60-1.13) —

*p<0.05*p<0.05

SAVE Trial

PCO2 While on a Ventilator

30

40

50

60

0 2 4 6 8 10

Routine Ventilation

Minimal Ventilation

Study Day

Wei

ghte

d P

CO

2 (m

mH

g)

Com

pli

ance

(c

c/cm

H2O

•kg)

0

2

4

6

0 60 120 180 240

Age (min)

TIMING OF SURFACTANT AND LUNG VOLUTRAUMA

Ingirmarsson et al. Pediatr Res 41:255A, 1997.

“Rescue” SurfactantProphylactic Surfactant

Surfactant: which one to use? Natural surfactants reduce ventilatory Natural surfactants reduce ventilatory

requirements faster, decrease pneumothorax and requirements faster, decrease pneumothorax and mortality risk mortality risk (Soll & Blanco. Cochrane Rev 4, 2001)(Soll & Blanco. Cochrane Rev 4, 2001)

Natural surfactants: Bovine origin (e.g. Survanta, Natural surfactants: Bovine origin (e.g. Survanta, Infasurf) or Porcine origin (e.g. Curosurf)Infasurf) or Porcine origin (e.g. Curosurf)

Infasurf and Curosurf have a longer duration of Infasurf and Curosurf have a longer duration of action and may slightly decrease ventilator action and may slightly decrease ventilator requirements compared to Survanta requirements compared to Survanta (Bloom et al. (Bloom et al. Pediatrics 100; 31-38, 1997; Speer et al. Arch Dis Child Fetal Pediatrics 100; 31-38, 1997; Speer et al. Arch Dis Child Fetal Neonatal Ed;72:F8-13, 1995)Neonatal Ed;72:F8-13, 1995)

Surfactant use: repeat doses Repeat doses are given depending on the clinical

status and the ventilatory settings Higher threshold (>40% FiO2 with a MAP > 7 cm

H2O) for uncomplicated RDS

Lower threshold (>30% FiO2) may reduce mortality in infants with RDS complicated by perinatal compromise or sepsis

(Kattwinkel et al. Pediatrics 106:282-288, 2000)

Surfactant use: how many doses?Multiple doses of surfactant are normally required Multiple doses of surfactant are normally required for moderate to severe RDS. Multiple doses of for moderate to severe RDS. Multiple doses of natural surfactant (e.g. Survanta):natural surfactant (e.g. Survanta):

improve oxygenation improve oxygenation reduce ventilator requirementsreduce ventilator requirements reduce pneumothorax (RR 0.51)reduce pneumothorax (RR 0.51) tend to reduce mortality (RR 0.63)tend to reduce mortality (RR 0.63)

((Dunn et al. Pediatrics;86:564-571, 1990;Dunn et al. Pediatrics;86:564-571, 1990; Speer et al Speer et al Pediatrics. 89:13-20, 1992; Soll. Cochrane Rev. (2): Pediatrics. 89:13-20, 1992; Soll. Cochrane Rev. (2):

CD000141, 2000CD000141, 2000))

Surfactant use: how many doses? Synthetic surfactant (e.g. Exosurf):Synthetic surfactant (e.g. Exosurf):

Two doses as good as 3-4 doses Two doses as good as 3-4 doses

((OSIRIS. Lancet 340:1363-9,1992)OSIRIS. Lancet 340:1363-9,1992)

Three doses better than one dose (lower Three doses better than one dose (lower mortality, ventilator requirement, need for mortality, ventilator requirement, need for HFV)HFV)

((American Exosurf Neonatal Study. J Pediatr;126:969-78, 1995)American Exosurf Neonatal Study. J Pediatr;126:969-78, 1995)

BPD Management - difficulties in studyBPD Management - difficulties in study

Definition ; objective assessment of severity ; variable statusDefinition ; objective assessment of severity ; variable status confounding effect of multiple risk factorsconfounding effect of multiple risk factors limited number of patients per center ; difference between limited number of patients per center ; difference between

centers in patient populationcenters in patient population historical controls / retrospective studies of little use since rapid historical controls / retrospective studies of little use since rapid

changes in management techniqueschanges in management techniques Technical limitation of PFTs ; data dropout due to death, Technical limitation of PFTs ; data dropout due to death,

discharge or extubationdischarge or extubation

Elective HFOV: Elective HFOV: Meta-analysis of 8 Meta-analysis of 8 studiesstudies (Henderson-Smart: Cochrane Rev 4, 2001)

No difference in mortality Trends toward decreases in BPD in survivors at 36-37 weeks (RR 0.73

(0.57, 0.93) and death or CLD at 28-30 weeks Significant increase in severe (grades 3 & 4) IVH and in any air leak

[RR 1.19 (1.03, 1.38)] in the HFOV group 2 trials with neurodevelopmental F/U : more survivors in the HFOV

group are abnormal [RR 1.26 (1.01, 1.58)] (Ogawa 93, HiFi 89) Sub-group with high volume strategy did not have increased IVH or

PVL Not currently recommended

Elective HFJV: Elective HFJV: Meta-analysis of 3 Meta-analysis of 3 studiesstudies Carlo 90, Wiswell 96, Keszler 97Carlo 90, Wiswell 96, Keszler 97 HFJV is associated with a reduction in BPD at 36 HFJV is associated with a reduction in BPD at 36

weeks PMA in survivors [RR 0.58 (0.34, 0.98), weeks PMA in survivors [RR 0.58 (0.34, 0.98), NNT 7 ]NNT 7 ]

Increase in PVL in the trial by Wiswell [RR 5.0 Increase in PVL in the trial by Wiswell [RR 5.0 (1.19, 21.04), NNH 4.0 (2.3,14.5)] where a ‘high (1.19, 21.04), NNH 4.0 (2.3,14.5)] where a ‘high volume strategy' was not the standard protocolvolume strategy' was not the standard protocol

Requires more investigationRequires more investigation

((Bhuta and Henderson-Smart. Cochrane Rev 4, 2001Bhuta and Henderson-Smart. Cochrane Rev 4, 2001))

Rescue HFOVRescue HFOV Only one good trial (HIFO Study Group. J Pediatr 1993;122:609-619)

Reduction in new air leak [RR 0.73 (0.55,0.96; NNT 6] Mortality and the use of IPPV at 30 days was similar in

the HFOV and CV groups. The rate of IVH of any grade increased with HFOV [RR

1.77 (1.06,2.96), NNH 6] Insufficient evidence for conclusions at present

(HIFO Study Group. J Pediatr 1993;122:609-619; Bhuta and Henderson-Smart. Cochrane Rev 4, 2001)

Newer modes of ventilationNewer modes of ventilation Patient-triggered ventilation (PTV) / Synchronized Patient-triggered ventilation (PTV) / Synchronized

IMV (SIMV)IMV (SIMV) May shorten duration of IMV and weaningMay shorten duration of IMV and weaning(Greenough et al. Cochrane Rev 4, 2001)(Greenough et al. Cochrane Rev 4, 2001)

Proportional Assist Ventilation (PAV)Proportional Assist Ventilation (PAV)(Schulze et al. (Schulze et al. J Pediatr 135:339-344,1999J Pediatr 135:339-344,1999))

Continuous tracheal gas insufflation (CTGI)Continuous tracheal gas insufflation (CTGI)(Dassieu et al. Intensive Care Med 24:1076-1082,1998)(Dassieu et al. Intensive Care Med 24:1076-1082,1998)

Perflurocarbon assisted gas exchange (PAGE)Perflurocarbon assisted gas exchange (PAGE)(Wolfson et al. Pediatr Pulmonol 26:42-63,1998) (Wolfson et al. Pediatr Pulmonol 26:42-63,1998)

Surfactant use: prophylactic vs. Surfactant use: prophylactic vs. selective useselective use Multiple clinical trials and meta-analyses performedMultiple clinical trials and meta-analyses performed

((Dunn 1991, Kendig 1991, Merritt 1991, Egberts 1993, Kattwinkel Dunn 1991, Kendig 1991, Merritt 1991, Egberts 1993, Kattwinkel 1993, Walti 1995, Bevilacqua 1996 and 1997; Soll and Morley. 1993, Walti 1995, Bevilacqua 1996 and 1997; Soll and Morley. Cochrane Rev 4, 2001)Cochrane Rev 4, 2001)

Prophylaxis decreases the risk of pneumothorax, PIE, Prophylaxis decreases the risk of pneumothorax, PIE, mortality, and BPD or death associated with prophylactic mortality, and BPD or death associated with prophylactic surfactant administration. surfactant administration.

Meta-analysis : For every 100 infants treated Meta-analysis : For every 100 infants treated prophylactically, there will be 2 fewer pneumothoraces, prophylactically, there will be 2 fewer pneumothoraces,

and 5 fewer deaths.and 5 fewer deaths.

Management - DiureticsManagement - Diuretics DIURETICSDIURETICS

WHY ?WHY ?Clinical, XRay & Histologic evidence of interstitial Clinical, XRay & Histologic evidence of interstitial

& peribronchiolar pulmonary edema& peribronchiolar pulmonary edemaAbnormal regulation of water balance ; Abnormal regulation of water balance ;

hypervolemiahypervolemiaAcute and short term diuretics improve pulmonary Acute and short term diuretics improve pulmonary

function and occasionally gas exchangefunction and occasionally gas exchangeBenefit unrelated to urine outputBenefit unrelated to urine output

Management - DiureticsManagement - Diuretics DIURETICS:DIURETICS:

Types: Loop diuretics: FurosemideTypes: Loop diuretics: Furosemide

Thiazides : Chloro/HydrochlorothiazideThiazides : Chloro/Hydrochlorothiazide

SpironolactoneSpironolactone Results with Thiazides and Spironolactone conflicting, though Results with Thiazides and Spironolactone conflicting, though

blinded studies did show some improvementblinded studies did show some improvement Furosemide also increases vasodilator PG synthesis, causes Furosemide also increases vasodilator PG synthesis, causes

systemic and pulmonary vasodilation, increases surfactant systemic and pulmonary vasodilation, increases surfactant synthesis and decreases Clsynthesis and decreases Cl-- transport in the airway epithelium transport in the airway epithelium

Management - BronchodilatorsManagement - Bronchodilators BRONCHODILATORSBRONCHODILATORSPathways controlling airway smooth muscle tone :Pathways controlling airway smooth muscle tone :1 . Parasympathetic cholinergic : contraction, increase . Parasympathetic cholinergic : contraction, increase

mucusmucus2 . Beta-adrenergic : relaxation. Beta-adrenergic : relaxation3 . Nonadrenergic, noncholinergic (NANC) or . Nonadrenergic, noncholinergic (NANC) or

Peptidergic : Peptidergic : Bronchoconstrictor : Substance PBronchoconstrictor : Substance P Bronchodilator : VIP (possibly deficient in Asthma)Bronchodilator : VIP (possibly deficient in Asthma)

Management - BronchodilatorsManagement - Bronchodilators

WHY ?WHY ?Sufficient bronchial smooth muscle, even Sufficient bronchial smooth muscle, even

in tiny premiesin tiny premiesHyperplastic smooth muscle and Hyperplastic smooth muscle and

metaplastic epithelium in BPDmetaplastic epithelium in BPDCorrelation with family history of AsthmaCorrelation with family history of Asthma

Management - BronchodilatorsManagement - Bronchodilators Bronchodilators - How ?Bronchodilators - How ?

Albuterol 50 Albuterol 50 g q 4-6 hrs for 2-3 days. If g q 4-6 hrs for 2-3 days. If improvement noted, continue, and reassess improvement noted, continue, and reassess weekly.weekly.

Early steroids (<96 Hours of Age)Early steroids (<96 Hours of Age) BPD or BPD/Death at 28 d and 36 w were decreased by BPD or BPD/Death at 28 d and 36 w were decreased by

steroids (NNT =10), and weaning from ventilator was steroids (NNT =10), and weaning from ventilator was faster.faster.

Increase in short-term complications (hypertension, Increase in short-term complications (hypertension, hyperglycemia, GI bleeds, perforation). No change in NEC, hyperglycemia, GI bleeds, perforation). No change in NEC, IVH, severe ROP, or infection. Borderline increase in PVL IVH, severe ROP, or infection. Borderline increase in PVL (1.41 [0.93-2.13])(1.41 [0.93-2.13])

Long-term outcome worse with steroids, with increased Long-term outcome worse with steroids, with increased risk of CP in larger studies (Shinwell et al 2000: risk of CP in larger studies (Shinwell et al 2000: RR 3.2RR 3.2; ; Yeh et al 1998: Yeh et al 1998: RR 2.32RR 2.32))

Moderately early steroids (7-14 days)Moderately early steroids (7-14 days) BPD or BPD/Death at 28 d and 36 w were decreased BPD or BPD/Death at 28 d and 36 w were decreased

by steroids (NNT =7 for BPDby steroids (NNT =7 for BPD2828 and 4 for BPD and 4 for BPD3636), and ), and weaning from ventilator was faster.weaning from ventilator was faster.

Duration of hospital stay same. No difference in Duration of hospital stay same. No difference in severe ROP, IVH, or NEC. Increase in hypertension.severe ROP, IVH, or NEC. Increase in hypertension.

Increase in CP in steroid group in one study (O’Shea Increase in CP in steroid group in one study (O’Shea et al 1999: 12 of 48 in steroid vs. 3 of 45 in placebo; et al 1999: 12 of 48 in steroid vs. 3 of 45 in placebo; RR 3.75, CI 1.13-12.43)RR 3.75, CI 1.13-12.43)

Delayed Steroids (>3 weeks)Delayed Steroids (>3 weeks)

BPD and BPD/Death at 36 w were decreased by BPD and BPD/Death at 36 w were decreased by steroids, but not survival or duration of hospital stay.steroids, but not survival or duration of hospital stay.

No difference in NEC, GI bleeding, or infection.No difference in NEC, GI bleeding, or infection. Steroids led to poor weight gain or weight loss.Steroids led to poor weight gain or weight loss. Long-term outcome similar in one large study (Jones Long-term outcome similar in one large study (Jones

et al 1995: RR for CP 1.21, CI 0.68-2.16 ), but full et al 1995: RR for CP 1.21, CI 0.68-2.16 ), but full neurodevelopmental evaluation was not done in this neurodevelopmental evaluation was not done in this trial.trial.

Inhaled steroidsInhaled steroids Beclomethasone and Flunisolide have been tried by Beclomethasone and Flunisolide have been tried by

nebulization. May decrease nebulization. May decrease need for systemic steroidsneed for systemic steroidsside effectsside effects

Beclomethasone did not decrease BPD in RCTs Beclomethasone did not decrease BPD in RCTs ((Denjean et al. Denjean et al. Eur J Pediatr 157:926-31, Nov 1998; Eur J Pediatr 157:926-31, Nov 1998; Cole et al. Cole et al. 340(13):1005-10, Apr 1999340(13):1005-10, Apr 1999))

Type, dosage, and delivery methods still need to be Type, dosage, and delivery methods still need to be optimizedoptimized

Other medications: Vitamin AOther medications: Vitamin AVitamin AVitamin A ControlControl

(N=405)(N=405) (N=402)(N=402)

Birth weight (grams)Birth weight (grams) 770 770 35 35 769 769 138 138

Gestational age (weeks)Gestational age (weeks) 27 27 2 2 27 27 22

Mean airway pressure (cm HMean airway pressure (cm H22O)O) 7 7 3 3 7 7 2 2

FiOFiO22 0.41 0.41 0.19 0.19 0.41 0.41 0.20 0.20

Baseline retinol (µg/dL)Baseline retinol (µg/dL) 16 16 6 6 16 16 6 6

Tyson et al. NEJM 340:1962, 1999Tyson et al. NEJM 340:1962, 1999

Other antioxidantsOther antioxidants

No benefit demonstrated with Vit E supplementation No benefit demonstrated with Vit E supplementation ((Watts et al. Eur Respir J 4: 188-90, 1991Watts et al. Eur Respir J 4: 188-90, 1991))

No benefit shown with Superoxide Dismutase (SOD) No benefit shown with Superoxide Dismutase (SOD) ((Suresh et al. Cochrane Database Syst Rev (1): CD Suresh et al. Cochrane Database Syst Rev (1): CD 001968, 2001001968, 2001))

Catalase, Glutathione peroxidase etc are under Catalase, Glutathione peroxidase etc are under investigation.investigation.

Outcome (contd.) Long-term outcome (contd)Long-term outcome (contd)

Cor pulmonale - usually resolvesCor pulmonale - usually resolves Reactive Airway disease - 50% will have Reactive Airway disease - 50% will have

exercise induced bronchospasmexercise induced bronchospasm SIDS ? - BPD spells ?- acute obstructive SIDS ? - BPD spells ?- acute obstructive

episodes. Some reports of increased SIDS episodes. Some reports of increased SIDS incidence.incidence.

Outcome (contd.)Outcome (contd.) Long-term outcome (contd)Long-term outcome (contd)

Growth failure common. Growth failure common. – 50% < 10th centile at 6 mo. 50% < 10th centile at 6 mo. – Only 7% > 50th at 2 yrs. Only 7% > 50th at 2 yrs. • Resistance to oral stimulation,Resistance to oral stimulation,• forcing food, forcing food,

• increased caloric consumptionincreased caloric consumption

Outcome (contd.)Outcome (contd.)

Long-term outcome (contd)Long-term outcome (contd)– Studies on developmental outcome Studies on developmental outcome

inconclusive. Most show no relation to inconclusive. Most show no relation to BPD but to prematurity and other risk BPD but to prematurity and other risk factors. Relationship to time hospitalized, factors. Relationship to time hospitalized, but not with time ventilated.but not with time ventilated.

– Short stature and airflow obstruction Short stature and airflow obstruction persist into adulthood ( Northway’s 23 yr persist into adulthood ( Northway’s 23 yr follow-up )follow-up )