Conclusions:
In this small cohort of infants
with PH treated with continuous or intermittent IV sildenafil, there
were no statistically significant differences between groups in the
change in vital signs, VIS, and oxygen requirement, or the need for
discontinuation of therapy due to side effects. A higher mortality rate
in the continuous infusion group may be explained by higher baseline
illness severity.
Introduction
Pulmonary hypertension (PH) is defined as an abnormally high pulmonary
artery pressure and pulmonary vascular resistance, often secondary to
cardiac or pulmonary disease1. The gold standard for
diagnosis of PH is a mean pulmonary arterial pressure of ≥25 mmHg by
right heart catheterization2. The clinical spectrum of
presentation varies from a transient neonatal condition to a disabling
disease of infancy and childhood3. Three of the most
common causes of PH in infants are classified by the World Health
Organization as (1) pulmonary arterial hypertension including persistent
PH of the newborn, (2) PH associated with left heart disease, and (3) PH
associated with lung disease and/or hypoxemia including developmental
lung disease, congenital diaphragmatic hernia, or bronchopulmonary
dysplasia4. The incidence of severe persistent
pulmonary hypertension in newborns is estimated at 0.2% of live-born
term infants4.
Treatment of PH involves selective pulmonary vasodilation, with multiple
therapeutic options including phosphodiesterase type 5 (PDE-5)
inhibitors3. Among these, the PDE-5 inhibitor
sildenafil is commonly used to treat PH in newborns and
infants5. Sildenafil is unique in that it may be
delivered orally or intravenously (IV). It has a larger volume of
distribution in neonates than adults, resulting in a longer terminal
half-life5. IV delivery is sometimes chosen for
critically-ill neonates in whom there are concerns of poor absorption of
enteral medications5.
Intermittent bolus IV sildenafil has demonstrated efficacy in various
studies6, however systemic hypotension has been
reported as an adverse effect of IV bolus delivery7.
Studies investigating the occurrence of hypotension in IV versus oral
delivery have failed to demonstrate a statistically significant
difference in safety outcomes8.
A continuous IV sildenafil infusion may be a feasible alternative to
enteral or intermittent dosing, and this method of delivery has been
suggested as a possible way of avoiding the acute systemic vasodilatory
effects of bolus dosing. To date, there is a dearth of data on the
continuous use of IV sildenafil, and no studies comparing continuous to
intermittent IV dosing in pediatric PH.
The primary aim of this retrospective study was to describe and examine
the tolerability of the different methods of IV sildenafil
administration in critically-ill infants with PH, including the
incidence of hypotension, the need for increased inspired oxygen or
vasoactive support, and the need for treatment discontinuation due to
side effects.
Materials and Methods
Design and Patients
This was a single-center retrospective observational study. Subjects
less than 12 months of age admitted to the neonatal or pediatric
intensive care unit, who received intravenous sildenafil for PH between
01/01/2011 and 12/30/2016, were included. Data on patients receiving
continuous IV sildenafil were compared with subjects receiving
intermittent IV sildenafil dosing.
Baseline clinical characteristics just prior to initiation of IV
sildenafil including oxygen saturation (SpO2), fraction of inspired
oxygen (FiO2), systolic blood pressure (SBP), diastolic blood pressure
(DBP), mean arterial pressure (MAP), and vasoactive-inotropic score
(VIS). VIS as described by Belletti et al can be used to objectively
quantify the degree of hemodynamic support and several studies have
demonstrated a correlation between high VIS and poor
outcome9. These data were also obtained at a time
point 2 to 8 hours after the initiation of continuous IV sildenafil
infusion, or 30 minutes to 2 hours after the first full IV bolus
sildenafil dose (for group 2). The time frame of data collection for the
IV bolus sildenafil group was chosen based on the time to maximum
observed plasma drug concentration of the main metabolite of sildenafil
(35 minutes after bolus IV dosing, as described by Vachiery et
al10). As bolus dosing was administered three times
per day, the chosen time frame of data collection for the continuous IV
sildenafil group was that in which the patient received up to one third
of the daily dose by infusion. During these specified periods after
sildenafil initiation, the lowest FiO2, SBP, DBP, and MAP, and the
highest FiO2 and VIS were recorded. The need for sildenafil
discontinuation due to side effects at any point in the 7 days following
initiation was noted.
The primary endpoint was the need for IV sildenafil discontinuation due
to side effects. Secondary endpoints included mortality, and the change
in FiO2, SBP, DBP, and VIS after sildenafil initiation. Mortality was
defined as death at any time after the start of sildenafil until the
last date of data collection (December 2019), irrespective of the time
of stopping sildenafil.
Statistical Analysis
Descriptive statistics are reported for each variable stratified by
sildenafil group. Continuous variables were reported as medians and
interquartile ranges (IQR: 25th percentile to 75th percentile).
Categorical variables were reported as frequencies and percentages.
Tests for association between groups were conducted using Wilcoxon rank
sum tests for continuous variables, and chi-square or Fisher’s exact
tests for categorical variables, as appropriate. Wilcoxon rank sum tests
were used for all continuous variables because several of the variables
did not meet the distribution assumptions required to perform t-tests,
and for those variables that met assumptions, results were qualitatively
the same between those obtained using a t-test and those obtained using
a Wilcoxon rank sum test.
In order to examine the relationship between mortality and sildenafil
group, a Cox proportional hazard model was used. Because we expect the
cause of mortality to be multifactorial, univariable Cox proportional
hazards models were used to examine the relationship of time from
initiation of sildenafil to time of death or last follow-up with
gestational age, and the baseline measures of PH degree, right
ventricular function, SBP, DBP, and VIS. We were restricted to
univariable models because of the limited sample size and the small
number of events. Subjects were followed for the maximum time on record,
such as to the date of death or latest follow-up visit.
A p -value < 0.05 was considered statistically
significant. All analyses were conducted using SAS version 9.4 (SAS
Institute Inc., Cary, NC).
Results
Baseline Demographic and Clinical Characteristics
Forty-three subjects were included in the study; 53% (n=23) received a
continuous IV sildenafil infusion, and 47% (n=20) received intermittent
IV bolus dosing (table 1). Males comprised 48% (n=11) of subjects in
the continuous group and 75% (n=15) of patients in the intermittent
group (p =0.069). Median gestational age was 38.7 weeks (IQR: 36 -
40) in the continuous group, and 37.8 weeks (IQR: 26 - 39),p =0.13. Classes of PH included lung disease/hypoxia
(specifically, prematurity-related chronic lung disease), pulmonary
arterial hypertension (specifically, persistent PH of the newborn), and
PH due to left heart disease. Although not statistically significant,
the dominant diagnosis in the continuous infusion group was persistent
PH of the newborn, and in the intermittent group was PH associated with
lung disease (p=0.07). In the continuous infusion group 13 of 23 (56%)
had persistent PH of the newborn, 1 of 23 (4%) had PH due to left heart
disease, and 9 of 23 (39%) had PH associated with lung disease. In the
intermittent group 5 of 20 (25%) had persistent PH of the newborn, 1 of
20 (5%) had PH due to left heart disease, and 14 of 20 (70%) had PH
associated with lung disease. Twelve (52%) subjects in the continuous
group and 6 (30%) subjects in the intermittent group were being
supported with extracorporeal membrane oxygenation prior to initiation
of Sildenafil (p =0.14).
The median continuous IV dose was 1.6 mg/kg/day (range 1.3-1.6), and the
intermittent IV dose was 0.5 mg/kg/dose every 8 hours. There were no
significant differences in gender, gestational age, or type of PH
between continuous and intermittent groups.
Table 2 demonstrates baseline clinical parameters prior to sildenafil
initiation. Median baseline VIS was higher in the continuous group
compared to the intermittent group (10 (IQR: 3 to 20) vs. 4 (IQR: 0 to
6.5), p =0.012). Baseline FiO2 was higher as well in subjects who
received continuous IV sildenafil (93% (IQR: 55% to 100%) vs. 46%
(36% to 78%), p =0.012). SBP, DBP, and MAP pre-sildenafil were
similar between continuous and intermittent groups.
Changes in Clinical Parameters After Sildenafil
Administration, and Need for Discontinuation of TherapyChanges in clinical parameters after initiation of IV sildenafil are
displayed in table 3. The changes in MAP, SBP, DBP, SpO2, FiO2, and
VIS from before IV sildenafil to the specified time point after
administration were not significantly different between groups.
Sildenafil was documented as discontinued due to side effects in a
total of 5 subjects, including 4 (17.4%) in the continuous group
(hypotension=3, ventilation/perfusion mismatch=1) and 1 (5.0%) in the
intermittent group (hypotension). This difference in the need for
discontinuation was not statistically significant.
Mortality
Eleven subjects (25.6%) died, including 8 (34.8%) of the continuous
group and 3 (15%) of the intermittent group. Of the 11 patients who
died, six died while receiving sildenafil at a mean of 11.6 days from
initiation. The estimated hazard ratio for mortality in patients who
received continuous vs. intermittent sildenafil was 4.9 (HR = 4.9, 95%
CI: 1.231 to 19.540, p =0.024), possibly reflecting the baseline
higher severity of illness in those patients who received continuous
sildenafil. The 95% confidence interval indicates that the rate could
be as much as a 19-fold or as little as a 1.2-fold increase in the rate
of dying. In addition, significant associations were observed between
mortality and systolic BP, diastolic BP, and VIS. The estimated hazard
ratio for a 1 mmHg increase in systolic BP is 0.956. Patients with a 1
mmHg higher systolic BP died at a rate 4.4% lower than patients with
lower systolic BP (HR=0.956, 95% CI: 0.915 to 0.999, p <
0.043). The estimated hazard ratio for a 1 mmHg increase in diastolic BP
is 0.919. Patients with a 1 mmHg higher diastolic BP died at a rate
8.1% lower than patients with lower diastolic BP (HR=0.919, 95% CI:
0.853 to 0.989, p < 0.025). The estimated hazard ratio for a 1
unit increase in VIS is 1.05. Patients with a 1 unit increase in VIS
died at a rate 5% higher than patients with lower VIS (HR = 1.049, 95%
CI: 1.019 to 1.079, p < 0.001). No statistically significant
differences were observed in mortality rates by gestational age, ECMO
(yes/no), PH degree (dichotomized), or RV function.
Discussion
The incidence of severe persistent PH of the newborn is 2/1000 live
births11. Among infants born prematurely, the risk of
PH is estimated to be more than three times higher than in full term
births12. Infants with PH of many different etiologies
are often treated with the PDE-5 inhibitor sildenafil, which has been
shown in various studies to improve oxygenation14.
Although well tolerated for most patients, the side effect of systemic
hypotension remains a significant concern in many neonates with
unfavorable hemodynamics8,13. Critically ill neonates
who experience systemic hypotension with bolus IV sildenafil often have
limited drug choices for PH treatment.
IV sildenafil may have a role in the management of critically-ill
infants with PH, in whom there are concerns of poor absorption of
enteral medications. A continuous IV infusion may also be considered in
patients who have demonstrated intolerance of the acute systemic
vasodilatory effects of intermittent bolus dosing. A continuous infusion
may permit consistent, steady dosing rather than the natural
pharmacokinetic rise and decline of bolus doses.
The present study is one of the few in the literature that evaluates the
use of continuous IV sildenafil to treat critically ill infants with PH.
To our knowledge, there are no studies comparing intermittent bolus IV
dosing to continuous IV sildenafil infusion in this population. Our
findings demonstrate no statistically significant difference in the
tolerability of these dosing forms based on the lack of significant
change in multiple clinical parameters, in the escalation of vasoactive
medications, or the need for discontinuation of sildenafil due to side
effects. The notable (although not statistically significant)
differences in PH etiology and ECMO requirement between groups, and the
higher baseline severity of illness (higher VIS and FiO2) in subjects
who received continuous IV sildenafil may explain the higher mortality
rate in this group.
Limitations of the present study include its small sample size, which
allows only for the detection of large differences between IV groups,
and for the performance of univariable analyses, and results in a lack
of precision as evidenced by the large confidence intervals. In
addition, the higher baseline severity of illness in the group that
received continuous IV sildenafil could have confounded our results.
Conclusion:
In conclusion, in this small cohort of critically-ill infants with PH,
there were no statistically significant differences in the tolerability
of continuous IV sildenafil infusion compared to intermittent IV bolus
dosing, based on vital signs before and after initiation, vasoactive
infusion requirements, or the need for discontinuation of sildenafil due
to side effects. Larger, prospective studies are needed to definitively
evaluate the safety and efficacy of the different methods of
administration of IV sildenafil.
References
- Dewatcher L, Dewatcher C, Naeije
R. New therapies for pulmonary arterial hypertension: an update on
current bench to bedside translation. Expert Opinion on
Investigational Drugs. 2010; 4: 469-488.
- Badesch DB et al. Diagnosis and assessment of pulmonary arterial
hypertension. J AM Coll Cardiol. 2009; 54: S55-S66.
- Hoehn T. Therapy of pulmonary hypertension in neonates and infants.
Pharmacology & Therapeutics. 2007; 114 (3): 318-326.
- Simonneau G, Galie N, Rubin L, et al. Clinical classification of
pulmonary hypertension. J Am Coll Cardiol. 2004; 43 (Suppl 1): S4-S12.
- Mukherjee A, Dombi T, Wittke B, Lalonde R. Population pharmacokinetics
of sildenafil in term neonates: evidence of rapid maturation of
metabolic clearance in the early postnatal period. Clinical
Pharmacology & Therapeutics. 2008; 85 (1): 56-63.
- Stultz JC, Puthoff T, Backes C, et al. Intermittent intravenous
sildenafil for pulmonary hypertension management in neonates and
infants. American Journal of Health-System Pharmacy. 2013; 70 (5):
407-413.
- Fender RA, Hasselman TE, Wang Y, Harthan AA. Evaluation of the
tolerability of intermittent intravenous sildenafil in pediatric
patients with pulmonary hypertension. The Journal of Pediatric
Pharmacology and Therapeutics. 2018; 21 (5): 419-425.
- Darland LK, Dinh KL, Kim S, et al. Evaluating the safety of
intermittent intravenous sildenafil in infants with pulmonary
hypertension. Pediatric Pulmonology. 2016; 52 (2): 232-237.
- Belletti A, Lerose CC, Zangrillo
A, Landoni G. Vasoactive-Inotropic Score: Evolution, Clinical Utility,
and Pitfalls. J Cardiothorac Vasc Anesth. 2020 Sep
22:S1053-0770(20)31035-1. doi: 10.1053/j.jvca.2020.09.117. Epub ahead
of print. PMID: 33069558
- Vachiery JL, Huez S, Gillies H, Layton G, Hayashi N, Gao X, Naeije R.
Safety, tolerability and pharmacokinetics of an intravenous bolus of
sildenafil in patients with pulmonary arterial hypertension. Br J Clin
Pharmacol. 2011 Feb;71(2):289-92. doi:
10.1111/j.1365-2125.2010.03831.x. PMID: 21219411; PMCID: PMC3040551
- Walsh-Sukys MC, Tyson JE 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
- Naumburg E, Sodestrom L. Increased risk of pulmonary hypertension
following premature birth. BMC Pediatrics. 2019; 19: Article 288.
- Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in
infants with persistent pulmonary hypertension of the newborn: a pilot
randomized blinded study. Pediatr. 2006;117:1077–1083
- Kipfmueller F, Schroeder L, Berg C, et al. Continuous intravenous
sildenafil as an early treatment in neonates with congenital
diaphragmatic hernia. Pediatr Pulmonol. 2018; 53 (4): 452-460.