Teaching on Pulmonary Hypertension for Fellows

Objectives:

• Understand the fetal and immediate post-natal cardiovascular physiology, and the normal transition to extra-uterine life;

• Recognize prenatal, peri-partum and postnatal insults that can disturb this transition, and the mechanisms by which they do;

• Define "Pulmonary Hypertension", how it is diagnosed and its impact in the long-term. 

• Understand the particularities of bronchopulmonary dysplasia associated pulmonary hypertension, its screening, pathophysiology, diagnosis, management and natural history;

• Describe the management strategies for newborns with persistent pulmonary hypertension of the newborn;

• Optional: Recognize the particularities of congenital diaphragmatic hernia and post-capillary pulmonary hypertension and the strategies for management of these patients in the immediate post-natal life.

• Optional: Recognize the particularities of pulmonary hypertension associated with Down syndrome. 

• Optional: Establish a complete differential diagnosis of pulmonary hypertension and understand each subtype. 

Case 1

Michael was born at 23 weeks and 4 days after a pregnancy complicated by early gestational hypertension and premature rupture of membranes at 18 weeks. The mother of Michael is known for rheumatoid arthritis on a TNFalpha biologic and chronic NSAIDs use for severe arthritic changes. Mother was treated pre-natally with Adalat, labetalol, magnesium sulfate and betamethasone. She was hospitalized at 18 weeks of PPROM and covered with antibiotics. Serial ultrasound demonstrated severe oligohydramnios, with severe intra-uterine growth restriction (at <1st percentile). Doppler were worsening starting 20 weeks of gestation and it was decided to undergo a c-section at 23+4 weeks because arrest of fetal growth, maternal fever and reverse end-diastolic flow in the umbilical artery Dopplers. 

Michael was born at 382 grams and intubated in the delivery room. Surfactant was administered and he was put on HFOV (M14) immediately after birth due to severe hypoxic respiratory failure. His pre-ductal saturation at 3 hours of life was 90% and post-ductul was 76%, despite 100% FiO2. He was initially quite unstable and required iNO for 3 days, broad-spectrum antibiotics were initiated but were stopped at 48 hours after cultures were negative. A UVL central is placed, as well as a UAL, confirmed by X-Ray. Chest radiography indicates a bell appearance of the chest with bilateral air-bronchograms and small lung volume. Areas of the lung that are aerated are black with absent vascular markings.

Echocardiography options, which one corresponds most to the clinical scenario:

a)     Normal anatomical heart (SDS), large unrestrictive ductus left to right, dilated LV, dilated LA, LA/Ao 2.3, No VSD, normal LV and RV function. PFO Left to right. UVL seen at the entrance of the right atrium. Septum round in systole and in diastole. UAL seen in the descending abdominal aorta. How do we call this scenario? What are the risk factors? Treatment?

b)    Normal anatomical heart (SDS), ductus has spontaneously closed, PFO is right to left strict, no VSD, markedly decreased RV function (TAPSE 2mm), TR of 65 for sBP of 45/22. Septum bowing in systole. UVL seen at the entrance of the right atrium. UAL seen in the descending abdominal aorta. How do we call this scenario? What are the risk factors? Treatment?

c)     Normal anatomical heart (SDS), ductus arteriosus is large and right to left, hypertrophy of the RV, RV and LV systolic function preserved. Slight retrograde flow in sub-hepatic veins with RA dilation. PFO right to left. Septum bowing in systole. UVL seen at the entrance of the right atrium. UAL seen in the descending abdominal aorta. How do we call this scenario? What are the risk factors? Treatment?

d)    Interrupted aortic arch, ductus arteriosus large and right to left, LV systolic function mildly decreased (EF 47% by Simpson’s), marked LV dilation, normal RV function. Septum flat in systole and round in diastole. PFO left to right with mean gradient of 10. UVL seen at the entrance of the right atrium. UAL seen in the descending abdominal aorta. What clinical element in the scenario indicates that this is not the compatible echocardiography with this patient.

His first arterial gaz is: 7.24/65/18/-4.2; Lactate 4.5. PaO2 28.

Calculate the oxygenation index:

Questions:

Definition of pulmonary hypertension?

Cut-offs for pulmonary hypertension suspicion / diagnosis?

Mimickers of pulmonary hypertension?

Classification of pulmonary hypertension?

Complications of iNO, mechanisms of iNO?

Case – followup:

His course was complicated by:

a)     Necrotizing enterocolitis with perforation requiring surgery at 10 days of life

b)    Prolonged TPN with cholestasis

c)     Prolonged antibiotics coverage (meropenem) due to Enterobacter bacteremia and absesses (intra-abdominal)

d)    IVH grade 2 bilateral

e)    Multiple attempts to extubation with exposure to 3 courses of post-natal steroids (Dexamethasone)

At 36 weeks Post-menstrual age, he is on bCPAP+8 with FiO2 35%. He is 1220 grams. He is fed by continuous gavage in gastric position and has an ileostomy. He is tolerating his full feeds at 120 mL/kg/day with EBM [100]. He is on Hydro/spiro; hydrocortisone maintenance at 10 mg/m2/day (failed ACTH stim test), Calicum/phosphorus/iron/mulvitamins. An echocardiography is done and reads:

3 Scenarios possible to be understand the differences between these 3 presentations:

A)   Echocardiography A: Ductus has spontaneously closed. Normal intra-cardiac anatomy, PFO stretched bidirectional, retrograde flow in the hepatic veins, dilated right atrium, dilated right ventricle with hypertrophy, TAPSE 5.2 mm, Tricuspid regurgitant Jet of 85 for sBP of 55/32 (M41). Septal curve bowing at end of systole in the LV cavity. Pulmonary veins at osteum visualized and bi-triphasic pattern maintained. PI jet (peak) of at least 30 mmHg. A large brightness of 1.5 x 2 x 3cm is seen at the entrance of the IVC to the RA with slight turbulence of low, likely secondary to previous position of the UVL.

B)  Echocardiography B: Large ductus arteriosus Left to right (unrestrictive), the size of the left pulmonary artery. LA/Ao of 2.1. Dilated Left ventricle, dilated left atrium. Normal LV and RV function. TR of 85 for systemic pressure of 90/55. Increased velocity of flow in pulmonary veins with bi-triphasic pattern maintained. TAPSE 10mm. Septum is flat at end of systole. A large brightness of 1.5 x 2 x 3cm is seen at the entrance of the IVC to the RA with slight turbulence of low, likely secondary to previous position of the UVL.

C)   Echocardiography C (sBP 100/50): Very small restrictive ductus seen by colour only, left to right (gradient max of 10 in systole), ASD left to right (0.4cm), TR not obtained, TAPSE of 9.5mm, no RV dilation. Peak PI of at least 20 mmHg. Pulmonary veins at ostum x 4 seen, with normal biphasic/triphasic pattern. A large brightness of 1.5 x 2 x 3cm is seen at the entrance of the IVC to the RA with slight turbulence of low, likely secondary to previous position of the UVL.

At 45 weeks post-menstrual age, Michael is still on CPAP (now 6) – 30%, with last gaz done earlier during the week at 7.34/58/32/4.5. A chest radiography done at the same time was strongly suspicious for aspiration pneumonia, with a right upper lobe consolidation. Overnight, he decompensated and was re-intubated due to: fever, numerous desaturations and a new pleural effusion. He is now on conventional mechanical ventilation: 7 mL/Kg; PEEP of 8, Ti 0.5, Rate of 30. FiO2 is 100%. You request an echocardiography:

Echocardiography done at bedside on patient unstable hemodynamically. Hydrocortisone 1mg/kg IV q8hr, epinephrine 0.08 mcg/kg/min, iNO 20 ppm started overnight. cBG results at beginning of echo: 7.01/42/10/-12 Lactate of 9.0. sBP 55/32 (for usual sBP 100/52). Severe RV dilatation, severe RV failure pancacking the LV (septum bowing in systole and diastole). TR of 110 with severe RA dilatation. PFO is not seen. LV systolic function is within normal limit, with very restrictive filling due to RV dilatation impending on LV cavity. PI peak jet of at least 45 mmHg. Dilatation of sub-hepatic veins. The clot previously seen in in the IVC is still present. Pulmonary veins not visualized.  

A central venous line is placed and indicates a central venous pressure of 15 mmHg. What does the information tell you?

If the report said: The large clot in the IVC is now seen in the Right atrium, but smaller in size. What does that change in your assessment and differential diagnosis?

Management of PH crisis?

Management of chronic PH?

-       Mechanism of action of each drugs, side effects and advantage of each drugs

o   Treprostinil / Epoprostenol /

o   Sildenafil / Tadalafil

o   Bosentan / Macitentan /Ambrisentan

o   Orenitram / Selexipag

-       What about other modality of treatments:

o   Diuretics?

o   Nutritional?

o   Oxygen?

o   Anti-coagulation?

Michael is now tracheostomized and 6 months of age. He is brought to the cath lab. The report mentions:

A)    mPAP 45, severely stenosed LLPV, RLPV, RUPV and atretic RLPV. sPAP 100 for sBP 85. RV output decreased. What does it tell you, what are treatment to consider? What would be the findings on the X-ray of this patient? How do these patient present? Evolve? What type of PH?

B)    mPAP 45, normal pulmonary veins, PVRI of 9.2 WU·m2 with PVR/SVR ratio of 0.5, no response to iNO, IV adenosine, and oxygen.

C)    What about if the report tells you that the venous blood coming from the pulmonary veins was saturated at 92% - what does this tell you?

At 3 years of age, you decide to refer Michael to a geneticist. His maternal aunt died of pulmonary hypertension at 3 years of age, and he has been refractory to Treprostinil / Sildenafil combination, with iso-systemic pulmonary pressures and a deterioration of his RV function. He was recently started on Digoxin 5 μg/kg orally twice daily and Diltiazem 0.5 mg/kg orally 3 times daily  after his last cath evaluation that indicated a positive response at Vasoreactivity testing. His last NT-proBNP is 8430 (compared to 3461 - 3 months ago). What are you suspecting. Please outline some of the genetical elements that you would like to rule out. What are other genetic disease that are PH mimickers in early infancy?

If your medical therapies fail, what are other options for Michael?

-       Discuss: POTT / Fenestration / Transplant.

How would altitude impact the condition of Michael?

Case 2:

A 32-year-old mother, known for severe anxiety disorder, is pregnant at 42 weeks of estimated gestational age. Her pregnancy was initially followed by a midwife. She was referred early in pregnancy to the MUHC, as there was suspicion of a left-sided congenital diaphragmatic hernia. The ultrasound at the MUHC ruled out the anomaly and the mother was transferred back to the care of the midwife.

The patient presented at 34 weeks with clear vaginal discharge. At the time, her serologies were protective and her group B strep (GBS) status was unknown. The mother was referred by the midwife to the nearest community hospital and a fibronectin test came back positive. Swabs were sent and confirmed the presence of GBS. She was diagnosed with preterm premature rupture of membrane. She was advised by the local obstetrician to be treated with antibiotics and to induce the labor. As she preferred to have everything “natural”, she left against medical advice.

She was followed in the community by the midwife. She refused further testing, including diabetic testing. She persisted to have ongoing vaginal discharge, but preferred to go along with “what nature has intended for her and her baby”. Her labor started at 42 weeks. At the time, her temperature was 39.7 Celcius but she refused to go to the hospital, as she always had “dreamed of a home birth”. The midwive, at the time, note some vaginal meconial discharge.

The baby was born about 1 hour ago. The delivery was vaginal after difficult extraction and McRoberts maneuver for shoulder dystocia. He was born at 4.2 kg. Apgar were 0-0-2-4-7. Initially, he was born flat, required positive pressure ventilation, LMA placement after 4 failures for intubation by the midwife, chest compression x 9 minutes and 2 doses of epinephrine by a low-line umbilical venous access. The baby was transferred to the local level 2 hospital by ambulance. You are called at the bedside of this baby. The nurse for the nursery tells you that “the baby is saturating at 76% on 100% FiO2 and that the blood pressure is 36/10”.

You will be asked to do the initial assessment and management of this newborn.

Pulmonary Hypertension Guidelines

Pulmonary Hypertension in the context of Bronchopulmonary dysplasia (Mandatory read)

Echocardiography in Pulmonary Hypertension

Transitional physiology

Building a dedicated pulmonary hypertension program - Optional read

Pulmonary Hypertension in Congenital Diaphragmatic Hernia - Optional read

Pulmonary Hypertension in Trisomy 21 (Down Syndrome) - Optional read

Acute Vaso-Reactive Testing in the Cath Lab (Optional)

Classification of Pediatric Pulmonary Hypertension (Optional)

Other references (optional)

Test your knowledge - Quiz:

Question 1:

A 32-year-old women has her pregnancy complicated by a flair-up of her rheumatoid arthritis for which she was on etanercept (anti TNF-apha - biologics). However, due to persistence of pain and arthritic changes at the spine level, she was put on very high dose naproxen (NSAIDs) during the pregnancy starting 18 weeks with serial monitoring of fetal wellbeing. The decision is made to go for C-section at 34 weeks, as the baby is poorly growing and is at an estimated fetal weight of less than the 3rd percentile, with abnormal venous Doppler (diastolic retrograde flow). Mother is bethametasone complete prior to delivery. The obstetrician suspects a placental insufficiency secondary to the chronic inflammation in the mother. At birth, the baby weights 1200 grams (1st percentile for weight). The baby requires positive pressure ventilation, followed by intubation due to prolonged apnea. The baby is brought to the NICU with 100% FiO2 and receives surfactant. Despite the surfactant, the saturation is 75% on right arm and 75% on left leg, at 100% FiO2. The WBC are 2.3, hemoglobin is 235 and platelets are of 35. The arterial blood gaz at 2 hrs post surfactant shows: pH 7.19, pCO2 55, PaO2 38, Bicarbonate 16, Base excess of -7, while on high frequency oscillatory ventilation with Mean of 15, Volume guarantee of 2 mL/kg (Amplitude generated of 28) and Hertz of 11. The chest X-Ray is compatible with mild RDS but the lung fields are very black. You are discussing with your colleague the reason for the profound hypoxia, and you tell him:

A)    This baby is hypoxic because of the severe lung disease. You do not believe it is persistence pulmonary hypertension of the newborn (PPHN) because there is no pre and post-ductal differences. Because this baby is premature with a low birth weight, the respiratory distress syndrome is particularly severe and he might need another dose of surfactant right away.

B)     This baby has severe PPHN. Because the CO2 is 55, you will adjust your ventilator to optimize ventilation, and you might even start inhaled nitric oxide and a fentanyl infusion.

C)     This baby is probably infected because of the abnormal CBC. The etanercept is an IgG and will pass the placental barrier. This puts the baby at very high risk of perinatal infection and pneumonia. You believe this is the cause of the severe hypoxia.

D)    This presentation is classic for a congenital heart defect. The absence of pre and post ductal saturation differences indicates that he has likely an interrupted aortic arch.

Question 2:

A baby is born at your hospital (level 2 nursery) by C-section due to profound decelerations. The baby is term, 3.4 kg. The pregnancy was unremarkable with normal prenatal ultrasounds. You are called by anesthesia at 30 minutes of life because the baby has a saturation of 42%. Upon doing the C-section, it was noticed that there was meconium stained fluid. The baby was intubated in the C-Section room by Anesthesia and an endotracheal tube is fixed at 9.5 cm at the lip. The baby is still being ventilated. The saturation on his right arm is 42% and right leg 75%. Your most likely approach will be:

a)     This baby likely has Total anomalous pulmonary venous return; this baby should be transferred as soon as possible to the local tertiary care center for an emergency cardiac surgery.

b)     This baby has meconium aspiration syndrome. The X-ray, which shows homogenous reticulo-nodular changes, would be compatible with the diagnosis.

c)     The baby has likely respiratory distress syndrome from being born by C-Section. Hence, you should give a dose of surfactant.

d)     This presentation is highly suggestive of transposition of the great arteries with a component of PPHN. You will start PGE (prostaglandins) and transfer this baby to a referral tertiary care center. 

Question 3:

Which of the following is true regarding the fetal circulation?

a)     The oxygenated blood is transported from the placenta, to the fetus, via the umbilical arteries.

b)     The fetal pulmonary blood flow is low during fetal life. About 10-15% of the blood ejected from the right ventricle is reaching the lungs. 

c)     The ductus arteriosus will shunt right to left for most of the pregnancy, but starts shunting left to right starting 32 weeks of gestational age, as the ductus is progressively constricting

d)     The foramen ovale is an essential structure to shunt the blood from the pulmonary artery to the aorta.

Question 4:

A baby was born at 40 weeks’ gestational age with APGAR 1-1-3-7 after protracted labor that required a stat C-section due to profound fetal decelerations. The cord pH arterial was pH 6.82/pCO2 65/ Bicarbonate 12/ Base Excess -21. In the delivery room, the baby was intubated, required chest compression after efficient ventilation was established for at least 30 seconds, and received 2 doses of epinephrine intravenous, as well as, 10 mL/kg of pRBC transfusion over 5 minutes in the delivery room. You bring the baby to your unit. Despite the transfusion, the baby has profound anemia with hemoglobin of 42. A Kleihauer-betke test in the mother is positive and you suspect a fetal maternal hemorrhage. You give 40 mL/kg of pRBC over 2 hours, while installing the umbilical venous and arterial line. The baby is lethargic and has poor spontaneous activity. You suspect some seizure activity at 45 minutes of life and give him a loading dose of 20 mg/kg of phenobarbital. The therapeutic hypothermia is started. The lactate at 1 hour of life is 18 and the blood gas arterial reveals: pH is 6.89 / CO2 32 / Bic 8 / Base Excess of -17. Which of the following is true:

a)     The high lactate is secondary to an underlying mitochondrial syndrome. The seizures are compatible with this diagnosis. You should stop the cooling immediately and consider hemodialysis.

b)     The high lactate is the reflection of underlying poor tissue perfusion. The presence of profound anemia, contributes to the poor tissue oxygenation. The cooling should be stopped and you should do an exchange-transfusion because the anemia is caused by the maternal blood that reacted in the fetal circulation.

c)     This baby is at high risk for neurodevelopmental disorder at a pediatric age, or early death. His profound anemia, combined with the perinatal distress, lead to a state of profound tissue hypoxia explaining the metabolic acidosis and high lactate. The baby should be restricted in fluid because he will likely be in SiADH and acute kidney injury. You should follow the potassium because of the high need of transfusion and the likely kidney injury.

d)     This baby should receive immunoglobulins 1g/kg because of the fetal-maternal hemorrhage causing fetal hemolysis.

Question 5:

Which of these medications is not a pulmonary arterial vasodilator:

a)     Inhaled Nitric Oxide

b)     Sildenafil

c)     Epoprostenol (prostacyclin)

d)     Dopamine

e)     Milrinone

Question 6:

Which of the following is true:

a)     The diagnosis of pulmonary hypertension is based on the presence of a pre-post ductal saturation difference. If there is a difference, this is only because of pulmonary hypertension.

b)     The diagnosis of pulmonary hypertension is ruled out in a newborn with the same pre-post ductal saturations.

c)     Pulmonary hypertension is the manifestation of an underlying disease such as: PPHN, BPD, idiopathic pulmonary arterial hypertension, congenital heart disease.

d)     Pulmonary hypertension is diagnosed if the systolic pulmonary arterial pressure is more than 25 mmHg.

Question 7: SHORT ANSWER – NEED ALL THE RIGHT ANSWERS TO GET THE POINTS:

For each of these scenario, please provide the direction of the shunt (Right to Left VERSUS Left to Right):

a)     The direction of the shunt of a small ventricular septal defect during systole in a baby with severe supra-systemic pulmonary pressures:

b)     The direction of the shunt through a small restrictive patent ductus arteriosus in a baby at 4 days of age with normal extra-uterine transition, low PVR and high SVR.

c)     The direction of the shunt through a foramen ovale during fetal life:

d)     The direction of the shunt through a PDA in a newborn with very low blood pressure due to sepsis and high pulmonary vascular resistance.

e)     The direction of the shunt through a PDA in a newborn with interrupted aortic arch.

f)      The direction of the shunt through a foramen ovale in a baby with no right ventricle and no tricuspid valve (tricuspid atresia)

g)     The direction of the shunt via the PDA of a newborn with pulmonary valve atresia:

Question 9: SHORT ANSWER:

A newborn has been on iNO at 40 ppm for the past 2 weeks. iNO has a toxicity profile. What should you monitor to avoid iNO toxicity?

Question 10: SHORT ANSWER:

What are the two normal mechanisms involved in the closure of the ductus arteriosus in the first few days after birth?