Lung Hypoplasia: Prediction of the severity - Onehealth.ca

Anatomical and FunctionalPredictors of Fetal & NeonatalLung HypoplasiaYuka Yamamoto, M.D.Fetal & Neonatal Cardiology ProgramUniversity of AlbertaDec. 15 th 2009

Outline• Fetal Lung Development andPhysiology• Criteria of Lung Hypoplasia (LH)• Incidence and Causes of LH• Parameters to Predict the Severity ofLH• Clinical case (R.T.)• Nitrofen-induced CDH Rat Study

Outline• Fetal Lung Development andPhysiology• Criteria of Lung Hypoplasia (LH)• Incidence and Causes of LH• Parameters to Predict the Severity ofLH• Clinical case (R.T.)• Nitrofen-induced CDH Rat Study

Development of the HumanLungType II pneumocytesInitial differentiationComplete matureCrests protrude into sacculesForm the acinus1986 Pringle KC

Factors for Fetal LungDevelopment‣Lung growth• Amniotic fluid volume• Intrathoracic space• Lung liquid volume• Pressure• Breathing movements‣Lung maturation• Glucocorticoids• Thyroid hormones

Outline• Fetal Lung Development andPhysiology• Criteria of Lung Hypoplasia (LH)• Incidence and Causes of LH• Parameters to Predict the Severity ofLH• Case Report• Nitrofen-induced CDH Rat Study

Lung Hypoplasia (LH):Clinical Features‣Immediate onset of severe respiratoryinsufficiency after birth‣Small lung capacity‣Required high ventilatory pressures in theabsence of airway obstruction oratelectasis

Pathological Criteria of LH< 28 weeksLung / Body weight 28 weeksLung / Body weight

Outline• Fetal Lung Development andPhysiology• Criteria of Lung Hypoplasia (LH)• Incidence and Causes of LH• Parameters to Predict the Severity ofLH• Clinical case (R.T.)• Nitrofen-induced CDH Rat Study

2.7 in 10,000 live birth; 2007 D. Gallot et al.LH: Incidence‣9-11/ 10,000 live births‣Perinatal mortality: 70% (55- 100%)• Preterm Premature Rupture of Membranes(pPROM) : 10% of all pregnancies (5-45% withworld-wide reports)90%in labour10%prolonged pPROMLH 12.9% in pPROM(15- 28w); 2000 HungWinn.• Congenital Diaphragmatic Hernia (CDH):

LH: Etiology•Oligohydraminos based•Renal: bilateral renal agenesis•Non- renal: pPROM•Intrathoracic masses (CDH, Congenital CysticAdenomatoid Malformation; CCAM)•Renal oligohydraminos•Skeletal malformation•Neuromuscular and central nervous system anomalies•Pleural effusions•Cardiac lesions•Abdominal wall defects•Primary LH syndromes associated with LH2000 J. Laudy and J. Wladimiroff

Preterm Premature Rupture ofMembranes (pPROM)Perinatal mortality in pregnancies with pPROMAFI1cm2cm5cm10cmPeriod 14 daysLatency period14 days7 days0 days28 days21 days•Gestational age at rupture of membranes•Latency period•Volume of amniotic fluid2000 H. Winn et al.Independent factorsto predict LH

Congenital Diaphragmatic Hernia(CDH)

Outline• Fetal Lung Development andPhysiology• Criteria of Lung Hypoplasia (LH)• Incidence and Causes of LH• Parameters to Predict the Severity ofLH• Clinical case (R.T.)• Nitrofen-induced CDH Rat Study

Parameters to Predict Severity ofLH• Lung Volume Estimation• Branch Pulmonary Artery (PA) Diameters• PA Doppler Flow:– Acceleration Time/ Ejection Time (AT/ET ratio)– Peak Early Diastolic Reverse Flow (PEDRF)– Pulsatility Index (PI)• 3D Lung Volume Measurement (echo)• MRI:– Lung-to-Liver Signal Intensity Ratio (LLSIR)– Lung volume

2D Lung Volume Estimation•TA/ HA (thoracic / heart area) ratio•TC/ AC (thoracic/abdominal circumference) ratio•CC/ TC (cardiac/ thoracic circumference) ratio•(TA- HA)/ TA ratioBoth the ellipse and diametermethods of measuringcardiothoracic ratio arereproducible.2006 A. Awadh et al.

Observed/ Expected Lung area toHead circumference (O/E LHR)survivalsdied1996 A. Metkus, et al.Sensitivity 46%, False positive rate 10%2007 J. Jani et al.

3D Lung Volume Measurements*Without LHWith LH*Without LHWith LHSensitivity: 83%, Specificity: 100%PPV 100% NPV 92%2007 F. Gerards et al.

Pulmonary ArteryHEARTLUNG

Pulmonary Artery

Pulmonary ArteryGood correlationwith lung weight!2002 J. Sokol et al.

PA Diameters in CDHRt. CDH2001 J. Sokol et al.Ipsilateral branch PA diameter results inprogressive hypoplasia advanced gestation.

Duration onoxygenDuration ofventilationLength ofstayr p r p r pLPA(ga) - 0.69 0.009* -0.68 0.007* -0.77 0.002*RPA(ga) -0.43 0.139 -0.41 0.143 -0.41 0.1602006 Sokol et al.Ipsilateral PA Diameter predictive ofrespiratory morbidity

Branch PA Doppler FlowPeak Systolic Velocity(PSV)Peak Diastolic Velocity(PDV)Peak Early Diastolic Reverse Flow(PEDRF)Pulsatility Index (PI) = (PSV- PDV)/ Mean Velocity

Branch PA Doppler FlowProximalDistalMiddle2000 & 2002 J. Laudy

PA Doppler Depending on theMiddle branchPartDistal branch2000 J. LaudyThere are Inter-pulmonary (proximal, middle, distal)differences in arterial blood flow velocity parameters

Acceleration time / Ejection time (AT/ET) ratioATETIn pulmonary hypertension•Rapid acceleration•Short acceleration timeAT in adults highly correlates with mean pulmonaryartery pressure.1983 Circulation, A. Kitabatake et al.

AT/ET ratio by Fuku et al. 2003 Am J OnstetGynecol.Normal range of LPA (n= 75)Outcome of suspected LH (n=17)Dead casesSurvived casesAT/ ET ratio correlates with survival in fetusesat risk for lung hypoplasia

Peak Early Diastolic Reverse Flow (PEDRF)PEDRFHigher PEDRF is seen with higher pulmonary vascular resistance.

Peak early diastolic reverse flow (PEDRF)By O. Moreno- Alvarez et al. 2008 Ultrasound Obstet GynecolPEDRFContralateralIpsilateralcontrolscontralateralipsilateralPEDRF has significantrelationship with O/E LHR

Maternal Hyperoxygenation TestBeforeReactive: Decrease in Pulsatility Index (PI) > 20%AfterNon reactive: Decrease in PI < 20%BeforeAfter2002 R. Broth et al.

Maternal Hyperoxygenation Testn= 29Non- Reactiven= 15Reactiven= 14Lethal LH (+)n= 12Lethal LH (-)n= 3Lethal LH (+)n= 1Lethal LH (-)n= 13Sensitivity: 92%, Specificity: 82%2002 R. Broth et al.

Maternal Hyperoxygenation Test1998 Circulation, J. Rasanen20- 26 weeksRoom air60% oxygenBefore During AfterBefore During After31- 36 weeksRoom air60% oxygenBefore During AfterBefore During After

Fetal Lung-to- Liver Signal IntensityRatio (LLSIR) at MRILungLiver2005 L. Brewerton et al.

LLSIR by L. Brewerton et al. 2005Hypoplastic lungsAt more than 25weeks, all LLSIRs forthe LH are outside thelower bound.LLSIR is high potential predictorof severe LHafter 25 weeks of gestation.

Outline• Fetal lung development andphysiology• Criteria of Lung Hypoplasia (LH)•LH causes• Parameters to predict the severity ofLH• Clinical case• Nitrofen-induced CDH rat study

Clinical case• 37 y.o. G3 P1• Medical history: asthma• Obstetrics history: ectopic pregnancy• Family history: N/A• Natural pregnancy• 21 weeks: pPROM with no sign ofchorioamnionitis• Antenatal steroids at 24 weeks• Antibiotics: amoxicillin, erythromycin

pPROM at 31 weeks

pPROM at 33 weeksBranch PA DiametersRPA= 0.43 cmLPA= 0.44 cm

Room AirRPALPAHyperoxygenantionAT/ET= 0.18PEDRF= 14cm/sAT/ET= 0.15PEDRF= 18cm/sPI= 3.7RPALPAAT/ET= 0.13PEDRF= 11cm/sPI= 2.17AT/ET= 0.15PEDRF= 14cm/sPI= 2.5PI= 34% reduction

Clinical Report: Outcome• 34w2d• C/S due to the risk of chorioamnionitis• 2010g, 44.5cm boy• Apgar scores 3/6, UA pH= 7.28• Brief ventilatory support with CPAP• No positive results from infection screening• Discharge: 4 days later.Good lung maturity !

Outline• Fetal Lung Development andPhysiology• Criteria of Lung Hypoplasia (LH)• Incidence and Causes of LH• Parameters to Predict the Severity ofLH• Clinical case (R.T.)• Nitrofen-induced CDH Rat Study

Nitrofen –induced CDH Animal ModelSprague- Dawley ratE 9.5 day Control 100mg NitrofenE 11.5- 20.5 day ControlSildenafil(100mg/kg/d)ControlSildenafil(100mg/kg/d)20.5 day:Echo examination (fetal PAs) & Hyperoxygenation testC/SEvaluation of lung morphologyUp to 50%

ControlRoom airHyperoxia

Upcoming Research in• Prospective study• 130 patientsEdmonton– 60 lung hypoplasia (CDH, pPROM, CCAM,renal agenesis)– 70 control• Investigate the best predictor of lunghypoplasia severity using echo imaging,maternal hyperoxia testing and fetal MRIassessment

Thank you very much!For great supportDr. Lisa HornbergerDr. Lisa HowleyDr. Bernard ThebaudDr. Venu JainDr. Chari RadhaDr. Ravi BhargavaResearch Nurse: WinnieSavardFounding: Juntendo University

2002 J. Laudy et al. 2005 S. Yoshimura et al.Lung volume estimationTA/HA ratio(TA-HA)/TA ratiopPROMLHpPROMLHCC/TC ratioTC/AC ratiopPROMLHpPROMLH

1996 A. Metkus et al.55 fetuses with CDHdiagnosedLung area to Headcircumference (LHR)

Lung area to Headcircumference (LHR)2006 J. Jani et al.

Lung area to Headcircumference (LHR)184 CDH cases between 22 to 28 weeks2006 J. Jani et al.Poor prognosis= LHR< 1.0 with liver herniation

Observed LHR/ ExpectedNormal fetusLHR (O/E LHR)2005 C. F. A. Peralta et al., 2007 J. Jani et al.

LHR & O/E LHR in CDHSensitivity 46%, False positive rate 10%2007 J. Jani et al

PA Diameters in Normal FetusLPARPA2007 S. Katayama

PA diameters in CDH2008 R. Ruano et al.PA diameter may be useful topredict perinatal death but not LH itself.

NonreactiveeactiveSensitivity: 92%Specificity: 82%PPV: 79%NPV 93%2002 R. Broth et al.

MRI (LLSIR) at 29 weeksRtCoronalLungLiverLtLungHeartLLSIR=