Pulmonary Hypertension Crises

A 7 month old ex-26 week male was transferred from the outside hospital to our PICU for tracheostomy evaluation. Patient was intubated on second day of life. He had a prolonged course, on inhaled Nitric Oxide for first 2-3 months of life in the setting of severe pulmonary hypertension, requiring HFOV for a prolonged period of time. Failed extubation attempts multiple times. Received steroid burst x2. BPD settings trialed (lower rate, longer iTime, high PEEP, larger TV) without improvement. At time of transfer he was in PRVC mode on the ventilator — TV ~10ml/kg, 50%, PEEP 8, rate 28 (Peak pressures 27-32). Patient received albuterol Q4 for bronchospasm/wheezing and pulmicort BID. Patient was deeply sedated with morphine and midazolam. Interstitial lung disease panel was negative. ECHO showed: systolic septal flattening, moderate RV hypertrophy with normal systolic functioning. Patient was not on any PH medications at transfer. Patient is also on furosemide, hydrochlorothiazide and spironolactone.

Patient has completed a course of antibiotics for klebsiella tracheitis from a ETT CX a week prior to admission to our picu. Patient tolerated feeds via an NJ tube.

The team continues to evaluate his case as the Patient continues to have episodes of acute desaturation, tachycardia, cool extremities and poor perfusion.

To summarize key elements from this case, we have a 7month old who is ex-26 week premie

Patient has BPD and is on high vent settings and failing extubation
Abnormal echocardiogram with flat septum and hypertrophied Right ventricle
Episodes of cold shock-tachycardia, poor perfusion, and cool extremities
Hypoxia

All of which bring up a concern for acute pulmonary hypertensive crisis

Rahul Let's transition into some history and physical exam components of this case?

What are key history features in this infants who presents with an acute pulmonary hypertensive crisis

Prematurity
BPD

Remember BPD is defined by a requirement of oxygen supplementation either at 28 days postnatal age or 36 weeks postmenstrual age.

Are there some red-flag symptoms or physical exam components which you could highlight?

Presence of cold shock: tachycardia, cool extremities and poor perfusion
Hypoxia
Cardiac exam will reveal a bounding right ventricle, prominent loud single S2
Although not obvious in this patient: some patients can have a palpable liver, cardiac gallop, peripheral edema and jugular venous distention

S2 heart sound represents the closure of the PV very close to AV — In pulmonary hypertension this PE sign is seen with equal right and left ventricular pressures.

To continue with our case, the patient's labs were consistent with:

Respiratory acidosis (PCO2 > 100)
CMP, CBC are normal
BNP < 100, serum lactate normal

Echocardiography findings in these patients can show tricuspid regurgitation. We can estimate right ventricular systolic pressure on echo and, by extension, systolic PAP (sPAP), by using tricuspid regurgitant (TR) jet velocity in combination with other echocardiographic findings. Using the modified bernoulli principle 4 x TR jet velocity squared, we can estimate the sPAP. If sPAP >2/3 systemic sBP with severe flattening or posterior bowing of the interventricular septum the patient can be diagnosed with severe pHTN.

Pradip, what if the patient had a PDA on echo — what would you see?

Rahul, when you see Predominantly right-to-left shunting across the PDA suggests suprasystemic sPAP. And as a result these patients can be hypoxemic

Ok, to summarize, we have:

A 7-month ex-26 week premie infant old with shock with signs of poor perfusion +bounding right ventricle and loud single second heart sound, which brings us to the concern for acute pulmonary hypertensive crises.
Let's start with a short multiple choice question:

The best treatment for an acute pulmonary hypertension crises in an six month old ex-26 week with premie without congenital heart disease who is mechanically ventilated secondary to RSV bronchiolitis is

A) Sildenafil

B) Hypoventilation

C) Milrinone

D) Sedation and paralysis

Rahul the correct answer is D sedation and paralysis. Although not a choice the I would recommend giving 100% O2 which is a potent vasodilator preferably with bag-mask hyperventilation (which causes alkalemia and causes pulmonary vasculature vasodilatation). Of the choices given in the above question none will be helpful in an acute PH crises although they are frequently used to treat PH in children. Milrinone is a PDE-3 inhibitor (increases cAMP) where as sildenafil is a PDE-5 inhibitor (increases cGMP). Hypoventilation will increase PCO2 which is a potent stimulus for PH crises. If available nitric oxide could be used.

To summarize, acute pHtn you have to think about the pulmonary vasculature — which is responsive to changes in 02, pH, and Co2.

As you think about our case, what would be your differential?

Cold shock (although the in patients without PH-the cardiac exam will not reveal a loud single S2 or hyperdynamic right ventricle
"Tet spell"-cyanotic spells typically seen in infants with congenital heart disease with a VSD such as tetralogy of fallot. deoxygenated blood is shunted across fro the right to the left across the VSD due to increased PVR. Cardiac exam may reveal reduced intensity or no murmur (as the murmur due to right ventricular outflow tract obstruction is proportional to the blood flow to the pulmonary circuit).
We should also be vigilant of obstruction/Kinking of ETT in a patient resulting in hypoxia, bradycardia and cardiac arrest- which may look like a PH crises

Remember due to inc RV afterload you are going to have impairment of forward flow thus clinically presenting with hypoxemia and signs of poor perfusion

If you had to work up this patient with what would be your diagnostic approach?

Really you don't need any investigation during an acute crises especially in a patient with h/o PHTN, h/o chronic lung disease, BPD or an infant with known cyanotic heart disease. Once patient is stable- consider chest radiograph (to check ETT tube position), blood gas for adequacy of ventilation. If patient is febrile then a CBC with differential + blood culture should be considered. An EKG may show RAH, RVH, ECHO may reveal findings suggestive of PH such as enlarged RA/RV, increased RV pressure, systolic flattening of the septum.

Rahul: What is the pathophysiology of an acute PHTN crises?

A pulmonary hypertensive crisis occurs when the pulmonary vasculature presents such a high resistance that there is little or no preload to the left ventricle and a massive, unsustainable afterload to the failing right ventricle. This can be triggered by multiple causes including parenchymal lung disease, Fever,pain, anxiety, tracheal suctioning, hypovolemia, increased cardiac demand, acidemia, aspiration, GE reflux, accidental interruption of prostanoid infusion. The acute massive loss of left ventricular preload and right ventricular afterload results in a drop in systemic cardiac output and coronary blood flow. Decreased coronary flow causes worsening right ventricular function. The higher than systemic right ventricular pressure pushes the interventricular septum into the left ventricle and that further worsens left ventricular filling. A vicious cycle ensues resulting in worsened left ventricular performance, syncope, bradycardia, and asystole.

Once this point is reached, it is rare that cardiopulmonary resuscitation will successfully return sufficient cardiac output without significant multiorgan damage.
If our history, physical, and diagnostic investigation led us to acute PH crises as our diagnosis what would be your general management of framework?
Although PH management depends on the underlying cause-during a acute PH crises the following can be tried:
If patient is on the ventilator-bag-mask ventilation with 100% O2 will vasodilate the pulmonary vasculature. O2 is a potent vasodilator and hyperventilation will decrease the PCO2 also causing vasodilation
Bolus of sedation (decreases sympathetic drive) and a dose of NMB such as rocuronium will further relax the vasculature
Nitric oxide can be used (start at 20-40ppm) if available-as it is a direct pulmonary vasodilator (works by increasing cGMP), causes selective pulmonary vasodilation (improves VQ matching as well as PVR)
Great rahul - further, Correct metabolic acidosis using NAHCO3
Treat bradycardia and hypotension
Use fluid bolus if patient is dehydrated or over diuresed.
After acute crises is mitigated - consideration for anti-reflux therapy of treatment of infection should be highly considered. A short course of steroids can also be used to decrease inflammation although these may not help in an acute crises.
We have used epoprostenol (PGI2) infusion more to treat acute PH rather than in a crises. Typically started at 2ng/kg/min and slowly increased by 2ng/kg/min to a max of 9-11ng/kg/min.

OK to summarize, long term management focuses on modulating NO pathway, endothelin pathway, and prostacyclin pathway.

Are there any recent publications related to acute PH crises?

We have posted references on our website picudoconcall.org (should NOT go through all below but just say posted in our shownotes)
Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017 Oct;14(10):603-614. doi: 10.1038/nrcardio.2017.84. Epub 2017 Jun 8. PMID: 28593996.
Hansmann G. Pulmonary Hypertension in Infants, Children, and Young Adults. J Am Coll Cardiol. 2017 May 23;69(20):2551-2569. doi: 10.1016/j.jacc.2017.03.575. PMID: 28521893.
Krishnan U, Feinstein JA, Adatia I, Austin ED, Mullen MP, Hopper RK, Hanna B, Romer L, Keller RL, Fineman J, Steinhorn R, Kinsella JP, Ivy DD, Rosenzweig EB, Raj U, Humpl T, Abman SH; Pediatric Pulmonary Hypertension Network (PPHNet). Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr. 2017 Sep;188:24-34.e1. doi: 10.1016/j.jpeds.2017.05.029. Epub 2017 Jun 20. PMID: 28645441.
Del Pizzo J, Hanna B. Emergency Management of Pediatric Pulmonary Hypertension. Pediatr Emerg Care. 2016 Jan;32(1):49-55. doi: 10.1097/PEC.0000000000000674. PMID: 26720067.

Rahul, where can more information can be found:

Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 53: Diseases of the Pulmonary Circulation by Zhang H et al.
Rahul what are the key objective take-aways:

Acute PHTN crises is a life threatening event that requires immediate therapy using oxygen, sedation+paralysis, inhaled nitric oxide, prevention of bradycardia and hypotension.
A multidisciplinary team approach with specialists from cardiology, pulmonary teams are needed in the management of patients with PH in the picu. Intensivists should understand the triggers for acute PH crises and try to avoid these triggers to prevent such crises.

This concludes our episode on acute pulmonary hypertensive crises. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is hosted by myself Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!