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Grunting, Shunting, Confronting :

August 30, 2017

It is 1980, and I am a neonatal fellow working in 3 neonatal intensive care units (NICUs) in Chicago and Evanston, Illinois.

It is 1980, and I am a neonatal fellow working in 3 neonatal intensive care units (NICUs) in Chicago and Evanston, Illinois.

I have had a lot of clinical experience with a wide variety of patients, but one group of infants I was fascinated with were babies who presented with grunting and shunting and had “Persistence of the Fetal Circulation” (PFC) or “Persistent Pulmonary Hypertension of the Newborn” (PPHN).

The curious thing about them was how sick they were with their hypoxemia and how they required your constant presence at their bedsides as they continued to shunt blood right-to-left past the lungs across the patent ductus arteriosus and the foramen ovale (1).

It was during my fellowship that I talked with my mentor, Dr. Thomas Gardner, and Dr. Abby Adams, one of my fellow colleagues, and we began collecting data on these patients.

At that time, Dr. Bill Fox from Children’s Hospital of Philadelphia had written a lot about the diagnosis and management of PFC/PPHN (2). The management approach at that time involved respiratory alkalosis utilizing hyperventilation and subsequently metabolic alkalosis (using sodium bicarbonate), both of which would result in pulmonary vasodilation (2,3).

For all of you who cared for these babies during this time, we all had the experience of strengthening our forearm muscles when the patient would “clamp down” and we would spend hours manually hyperventilating them with an anesthesia bag with an FiO2 of 1.0. We also would “boost” their systemic blood pressure with normal saline boluses and dopamine infusions.

Since we did not have true selective pulmonary vasodilators, we used tolazoline (4, 5), and we also tried nitroglycerin, nitroprusside (6), and other vasoactive drugs with some selective pulmonary vasodilatory properties. (7) However, this led to further bedside stress as maintenance of systemic blood pressures then became another problem. This despite the fact that some of our patients’ color dramatically improved with systemic vasodilation.

I also talked about this project with Dr. Mike Schreiber, who at that time was one of my fellow residents, and asked him if he would like to work together. After his residency, he was on his way to the University of California, San Francisco, for his NICU/PICU fellowship, so he respectfully declined.

As a result of our efforts, we collected data from a total of 62 infants with primary or secondary PFC/PPHN, and this series was published in American Journal of Diseases of Children in 1984. (8) We also published a paper about predictors of survival (9), as well as air leak with our aggressive approach with hyperventilation. (10)

Figure. Management of acute persistent pulmonary hypertension of the newborn. Copyright Satyan Lakshminrusimha.  From: Lakshminrusimha S, Keszler M. Persistent Pulmonary Hypertension of the Newborn. NeoReviews. 2015;16(12):e680.
Figure. Management of acute persistent pulmonary hypertension of the newborn. Copyright Satyan Lakshminrusimha. From: Lakshminrusimha S, Keszler M. Persistent Pulmonary Hypertension of the Newborn. NeoReviews. 2015;16(12):e680.
Dr. Schreiber went to UCSF and worked with his mentors and other investigators to help discover and refine therapy first with characterization of the effectiveness of metabolic alkalosis (with sodium bicarbonate)(3) and then with inhaled nitric oxide, a truly selective pulmonary vasodilator that revolutionized the management of these critically ill infants (11,12).

The management of PPHN has evolved and become more refined, such that survival has improved from 71% overall in our study (8) to around 90% overall (13). The diagnosis is still based on awareness of at-risk groups and specific clinical findings, with confirmation by echocardiography. As Drs. Lakshminrusimha and Keszler noted in their recent NeoReviewsarticle, management involves treatment of the underlying conditions, such as with surfactant administration; basic ventilator management with avoidance of extreme pH, PCO2, PO2 and base excess; attention and support of systemic circulation; selective pulmonary vasodilation; and if necessary, high frequency ventilation or extracorporeal membrane oxygenation(13,14).

Our first paper is now cited with some frequency as a historical reference about “early efforts” with lower baseline survival rates (7).

References

1. Gersony WM, Due GV, Sinclair JC. ‘PFC’ syndrome (persistence of the fetal circulation) abstracted. Circulation. 1969;40(suppl 3):11.

2. Fox WW: Arterial blood gas evaluation and mechanical ventilation in the management of persistent pulmonary hypertension of the neonate, in Peckham G, Heymann M (eds): Cardiovascular Sequelae of the Newborn. Columbus, Ohio, Ross laboratories, 1982, pp 102-110.

3. Schreiber MD, Heymann MA, Soifer SJ. Increased arterial pH, not decreased PaCO2, attenuates hypoxia-induced pulmonary vasoconstriction in newborn lambs. Pediatric Research. 1986; 20:113-117.

4. Goetzman BW, Sunshine P, Johnson JD et al. Neonatal hypoxia and pulmonary vasospasm: Response to tolazoline. J Pediatr. 1976; 89:617-621.

5. Meadow W, Benn A, Giardini N, et al. Clinical correlates do not predict PaO2 response after tolazoline administration in hypoxic newborns.  Crit Care Med. 1986;14:548-551.

6. Schreiber MD, Dixit R, Rudinsky B, et al. Direct comparison of the effects of nebulized nitroprusside versus inhaled nitric oxide on pulmonary and systemic hemodynamics during hypoxia-induced pulmonary hypertension in piglets. Crit Care Med. 2002; 30:2560-2565.

7. Lakshminrusimha S, Mathew B, Leach CL. Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide. Semin Perinatol. 2016; 40:160-173.

8. Hageman JR, Adams MA, Gardner TH. Persistent pulmonary hypertension of the newborn (PPHN); Trends in incidence, diagnosis and management. AJDC. 1984; 138:592-595.

9. Hageman JR, Dusik J, Keuler H, et al. Outcome of persistent pulmonary hypertension in relation to severity of presentation. AJDC. 1988; 142:293-296.

10. Hageman JR, Adams MA, Gardner TH. Pulmonary complications of hyperventilation therapy for persistent pulmonary hypertension. Crit Care Med. 1985; 13:1013-1014.

11. Roberts JD, Fineman JR, Morin FC, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. New Eng J Med. 1997; 336:605-610.

12. Barrington KJ, Finer M, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at term or near term (review). Cochrane Collaboration 2017.

13. Lakshminrusimha S, Keszler M. Persistent pulmonary hypertension of the newborn. NeoReviews. 2015; 16:e680-e692.

14. Yallapragada S. Persistent pulmonary hypertension of the newborn. In Essential Guide to Clinical Neonatology, Hoenig JD, Chu A, Hageman JR (eds).  New York, Nova Scientific Publishers. 2017. pp. 173-178.

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