Pulmonary Hypertension in Newborns with Meconium

Aspiration

New Therapeutic Aspects

Pekka Kääpä, MDResearch Centre of Applied and Preventive Cardiovascular Medicine,University of Turku

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN)

High pulmonary artery pressure

Right-to-left shunting

Hypoxemia

Low systemic arterial pressure

PULMONARY HYPERTENSION OF THE NEWBORN

Incidence > 1:1000 births

Mortality 30-50%

Neurological sequelae 10-30%

Chronic lung injury ca. 25%

DIAGNOSIS OF PULMONARY HYPERTENSION

Clinical signs (hypoxemia)

Clinical tests (pre-postductal pO2)

Doppler/ultrasound – examinations

Catheterization

PULMONARY HYPERTENSION OF THE NEWBORN

Obstruction of the pulmonary vessels: Idiopathic RDS Aspiration Infection

Pulmonary vascular hypoplasia

High blood viscosity: Infants of diabetic mothers

MECONIUM ASPIRATION SYNDROME

Meconium-stained amniotic fluid in 10-15% of deliveries

Respiratory failure in 5% of infants, often connected with pulmonary hypertension

Mortality up to 40%

PATHOPHYSIOLOGY OF MECONIUM ASPIRATION SYNDROME

Airway occlusion Direct tissue injury Pulmonary hypertension Inflammation Surfactant dysfunction

PULMONARY RESPONSES IN MECONIUM ASPIRATION

Immediate ventilation/perfusion mismatch - concentration dependent

Progressive pulmonary hypertension from 2 hours on - concentration dependent

Inflammatory changes and surfactant dysfunction in 4-6 hours

Tissue necrosis after 24-48 hours

TREATMENT STRATEGIES IN MECONIUM ASPIRATION

Ventilatory assistance / oxygenation

Vasodilatory treatment

Anti-inflammatory drugs

Surfactant administration / lavage

ECMO

TREATMENT STRATEGIES OF PULMONARY HYPERTENSION IN MECONIUM ASPIRATION

Ventilatory assistance / oxygenation

Vasodilatory treatment (-> NO)

Anti-inflammatory drugs (-> Dexa)

ECMO

PULMONARY VASODILATORY TREATMENT

Tolazoline (1 mg/kg/h) not selective, dilatory effect poor hemorrhagies, hypotension, renal

failures in 50-70%

Prostacyclin(PGI2)(10-60 ng/kg/min) systemic hypotension

Inhaled nitric oxide (INO)

INHALED NITRIC OXIDE (INO) IN MECONIUM ASPIRATION

Selective pulmonary vasodilation

Modulation of endothelial permeability

Attenuation of leucocyte function

Inhibition of platelet aggregation

Nitric oxidein MAS

Nitric oxidein MAS

INO IN EXPERIMENTAL MECONIUM ASPIRATION

Author Model INO Response ------------------------------------------------------Barrington

Piglet 5-80ppm SO2 ,PAP 1995

Rais-Bahrami Piglet 10-40ppm SO2, PAP 1997

Cuesta 1998 Lamb 20ppm PO2, PAP

Holopainen Piglet 1, 10 ppm PO2,PAP 1999

INO IN EXPERIMENTAL MECONIUM ASPIRATION

Transient or short-term improvement of oxygenation

Small or no reduction in pulmonary hypertension

Effects similar at different doses (5-80 ppm)

No clear effect on the ventilatory parameters or inflammatory lung tissue response

INO IN CLINICAL MECONIUM ASPIRATION SYNDROME

Variable improvement of oxygenation (in about 50%)

Decreased need for ECMO

No reduction in mortality

• Cochrane Database 2001• Weinberger et al., Pharmacol Ther 2001

INO IN MECONIUM ASPIRATION

Improves ventilation/perfusion matching

Effect on oxygenation and pulmonary vascular resistance variable

Severity of the parenchymal disease critical in the responsiveness to INO

--> Experimental mode of treatment

TREATMENT STRATEGIES OF PULMONARY HYPERTENSION IN MECONIUM ASPIRATION

Ventilatory assistance / oxygenation

Vasodilatory treatment (-> NO)

Anti-inflammatory drugs (-> Dexa)

ECMO

Steroids in MAS

Steroidsin MAS

STEROIDS IN EXPERIMENTAL MECONIUM ASPIRATION

Author Model Steroid Response ----------------------------------------------------- Franz 1975 Rabbit HC survival

Soukka 1997 Pig MP (pre) FiO2,PAP ,PVR

Khan 1999 Piglet Dexa FiO2,compliance

Wu 1999 Piglet Dexa PAP

Holopainen Piglet Dexa (pre) FiO2,PAP PVR

2000

STEROIDS IN CLINICAL MECONIUM ASPIRATION

No effect on oxygenation, ventilation or survival

• (Yeh et al., 1977)

Improvement of oxygenation• (da Costa et al., 2001)

STEROIDS IN MECONIUM ASPIRATION

Early steroid administration may improve the pulmonary function and oxygenation

Steroids may attenuate the inflammatory lung injury

Potential side-effects: hypertension, immunosuppression, poor neurological development (?)

--> Experimental treatment

THERAPEUTIC APPROACH TO MECONIUM ASPIRATION WITH PPHN

Therapeutic effect of INO or steroids variable and generally poor

Combination of therapies, or addition of exogenous surfactant may be more effective

Potential side-effects may limit the use

POOR THERAPEUTIC RESPONSE OF PULMONARY HYPERTENSION IN MECONIUM ASPIRATION

Selectivity of the vasodilators poor

Treatment of the lung disease insufficient

Continuous systemic hypotension

FUTURE THERAPEUTIC ASPECTS OF MECONIUM ASPIRATION SYNDROME

New modes of therapy: surfactant lavage liquid ventilation

Early start of the therapy: prophylactic at birth / first hours

Preventive measures

RESEARCH GROUP

Hanna Soukka, MD Kalle Korhonen, MD Minna Aaltonen, MD Jaakko Kytölä, MD Heikki Lukkarinen, BM Jani Lehtonen, BM Aida Steiner, BM