The Use of Hydrocortisone in the Management of

Persistent Pulmonary Hypertension of the Newborn

Samia Aleem, Veeral Tolia, Kanecia O. Zimmerman, Ronald N. Goldberg, and
Rachel G. Greenberg

Presented by Samia Aleem, MD, PGY-5

March 25th, 2019
Background

• Persistent pulmonary hypertension of the newborn (PPHN) is

characterized by hypoxemia and elevated pulmonary vascular
resistance
• The prevalence of PPHN ranges from 0.4 – 6.8 per 1000 live
births1
• The mortality of PPHN ranges between 7 -15%2-4
• Inhaled nitric oxide (iNO) is the only US Food and Drug
Administration approved agent for management of PPHN
Background

• Glucocorticoids have been shown to be beneficial in

pulmonary hypertension secondary to meconium aspiration
syndrome (MAS)5
• Genetic studies have revealed an association between
variants in the cortisol pathway and PPHN6
• In the neonatal lamb model, hydrocortisone improved
oxygenation by decreasing PDE5 expression and activity and
increasing cGMP7,8
• Hydrocortisone also reduced damage caused by oxidative
stress by reducing levels of reactive oxygen species (ROS)7,8
• These data suggest that hydrocortisone therapy may have a
potential role in the management of PPHN
Objective

• Characterize the association between hydrocortisone use and

hospital outcomes of infants with PPHN
Methods

• Multicenter, retrospective cohort study of infants ≥ 34 weeks

gestational age admitted to NICUs in the Pediatrix Medical
Group from 2010 to 2016
• Inclusion criteria:
– Diagnosis of PPHN, MAS, or congenital diaphragmatic hernia (CDH) <
7 days of age
– Received iNO at < 7 days of age
• Exclusion criteria:
– Receipt of hydrocortisone after iNO was weaned off
– Major congenital anomalies, except CDH
Methods

• We compared demographic and clinical characteristics of

infants who received hydrocortisone during the first course of
iNO and those who did not
• We hypothesized that infants who received hydrocortisone
might have different clinical characteristics from those who did
not
– Hydrocortisone receipt could be a marker for severity of illness
– We used propensity scores to perform inverse-probability-weighted
regression-adjustment to estimate the average treatment effect of
hydrocortisone treatment on the outcomes of interest
Outcomes of Interest

• Death prior to discharge

• Chronic Lung Disease (CLD)
– Defined as receipt of supplemental oxygen or respiratory support
continuously from a postnatal age of 28 – 34 days9
• Oxygen at discharge
Results
• A total of 2743 infants met the inclusion criteria, and 810
(30%) received hydrocortisone

Percentage of infants receiving hydrocortisone by year of discharge

Results
Unadjusted comparisons of demographics and clinical characteristics
Hydrocortisone iNO alone
P-value
+ iNO (n=810) (n=1933)
Covariates used in estimation of
propensity scores
Gestational age, weeks, n (%) 0.26
34 - 36 162 (20) 390 (20)
37 - 38 230 (28) 605 (31)
> 38 418 (52) 938 (49)
Male, n (%) 492 (61) 1119 (58) 0.17
Race/Ethnicity, n (%) <0.001
White 362 (47) 995 (54)
Black 126 (16) 377 (21)
Hispanic 220 (29) 344 (19)
Other 62 (8) 115 (6)
Birth weight, grams, n (%) 0.40
<2500 66 (8) 179 (9)
2500 - 3499 432 (53) 1057 (55)
> 3500 311 (38) 697 (36)
Small for gestational age, n (%) 57 (7) 141 (7) 0.85

• The median (25th – 75th percentile) gestational age was 38 (37-40) weeks
• The median (25th – 75th percentile) birth weight was 3280 (2890-3711) grams
Results
Unadjusted comparisons of demographics and clinical characteristics

Hydrocortisone iNO alone

P-value
+ iNO (n=810) (n=1933)

Covariates used in estimation of

propensity scores

Presence of PROM, n (%) 38 (5) 81 (4) 0.54

Exposed to prenatal steroids, n (%) 28 (3) 85 (4) 0.26
Apgar score at 5 minutes, n (%) 0.02
0–3 125 (16) 244 (13)
4–6 196 (25) 412 (22)
7 – 10 469 (59) 1210 (65)
Mechanical ventilation when iNO started, n (%) 771 (95) 1654 (86) <0.001
Received surfactant, n (%) 515 (64) 1095 (57) 0.001
Antibiotics while on iNO, n (%) 784 (97) 1768 (91) <0.001
Use of vasopressors while on iNO, n (%) 744 (92) 1105 (57) <0.001
Sedatives/paralytics while on iNO, n (%) 773 (95) 1551 (80) <0.001

PROM: Prolonged rupture of membranes; ECMO: Extracorporeal membrane oxygenation

Results
Unadjusted comparisons of outcomes of interest

Hydrocortisone iNO alone

P-value
+ iNO (n=810) (n=1933)

Outcomes of interest

Death, n (%) 64 (9) 118 (8) 0.25

Chronic lung disease, n (%) 82 (12) 85 (6) <0.001

Oxygen at discharge, n (%) 56 (9) 131 (10) 0.75

Results
Estimated average effect of hydrocortisone exposure on outcomes
after inverse-probability weighting regression adjustment

Coefficient (95% CI) P-value

Death prior to discharge -0.004 (-0.033, 0.026) 0.80

Chronic lung disease 0.026 (-0.007, 0.059) 0.12

Oxygen at discharge -0.065 (-0.108, -0.022) 0.003

Conclusions

• In our cohort, there was an association between the use of

hydrocortisone during iNO and a decreased need for oxygen
at discharge
• There was no association between the use of hydrocortisone
during iNO use with death, or with CLD
• Further prospective studies are needed to evaluate the safety
and effectiveness of hydrocortisone in this population
References
1. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn
in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000;105(1 Pt 1):14-20.
2. Roberts JD, Jr., Fineman JR, Morin FC, 3rd, et al. Inhaled nitric oxide and persistent pulmonary
hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med.
1997;336(9):605-610.
3. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary
hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med.
2000;342(7):469-474.
4. Neonatal Inhaled Nitric Oxide Study G. Inhaled nitric oxide in full-term and nearly full-term infants
with hypoxic respiratory failure. N Engl J Med. 1997;336(9):597-604.
5. Mokra D, Mokry J. Glucocorticoids in the treatment of neonatal meconium aspiration syndrome.
Eur J Pediatr. 2011;170(12):1495-1505.
6. Byers HM, Dagle JM, Klein JM, et al. Variations in CRHR1 are associated with persistent
pulmonary hypertension of the newborn. Pediatr Res. 2012;71(2):162-167.
7. Perez M, Lakshminrusimha S, Wedgwood S, et al. Hydrocortisone normalizes oxygenation and
cGMP regulation in lambs with persistent pulmonary hypertension of the newborn. Am J Physiol
Lung Cell Mol Physiol. 2012;302(6):L595-603.
8. Perez M, Wedgwood S, Lakshminrusimha S, Farrow KN, Steinhorn RH. Hydrocortisone
normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with
persistent pulmonary hypertension of the newborn. Pulm Circ. 2014;4(1):71-81.
9. Trembath A, Hornik CP, Clark R, et al. Comparative effectiveness of surfactant preparations in
premature infants. J Pediatr. 2013;163(4):955-960 e951.
Acknowledgements

• Dr. Rachel G. Greenberg

• Dr. Ronald N. Goldberg
• Dr. Veeral Tolia
• Dr. Kanecia Zimmerman
• Duke Clinical Research Institute
• Dr. Reese Clark
• Pediatrix Medical Group
• Dr. C. Michael Cotten