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\begin{document}

\title{Continuous Versus Intermittent Intravenous Sildenafil in Critically Ill
Infants with Pulmonary Hypertension}



\author[1]{Chetan Sharma}%
\author[2]{Joseph  Burns}%
\author[2]{Aparna  Kulkarni}%
\author[2]{Jane  Cerise}%
\author[2]{Fernando Molina Berganza}%
\author[3]{Denise A. Hayes}%
\affil[1]{Baylor College of Medicine}%
\affil[2]{Cohen Children's Medical Center}%
\affil[3]{Cohen Childrens Med Ctr}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Abstract Continuous intravenous (IV) sildenafil may avoid the acute
systemic vasodilatory effects of bolus dosing in infants with pulmonary
hypertension (PH). We aimed to examine the tolerability of different
methods of IV sildenafil administration. Methods: We retrospectively
evaluated subjects less than 12 months old with PH, who had been started
on IV sildenafil. Vital signs, oxygen requirement, and
vasoactive-inotropic score (VIS) before and after sildenafil initiation
were noted, as was the need for discontinuation due to side effects.
Results: Forty-three subjects were identified (23 continuous, 20
intermittent dosing). There were no statistically significant
differences between groups in gender or gestational age, but higher
baseline inspired oxygen (FiO2) and VIS in the continuous group
suggested a higher baseline severity of illness (p=0.012). After
sildenafil initiation, there were no significant differences in the
change in blood pressure, oxygen saturation, FiO2, or VIS between
groups, and no difference in the number of subjects requiring
discontinuation due to side effects (4 in the continuous group, 1
intermittent, p=0.35). Eight subjects (34.8\%) in the continuous group
and 3 (15\%) in the intermittent group died (p=0.024). 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.%
\end{abstract}%



\sloppy


\textbf{Continuous Versus Intermittent Intravenous Sildenafil in
Critically Ill Infants with Pulmonary Hypertension}

Chetan Sharma, M.D.\textsuperscript{1}, Joseph Burns,
M.D.\textsuperscript{2}, Aparna Kulkarni, M.D.\textsuperscript{1}, Jane
E. Cerise, Ph.D.\textsuperscript{3}, Fernando Molina Berganza,
M.D.\textsuperscript{1}, Denise A. Hayes, M.D\textsuperscript{1}

\begin{enumerate}
\tightlist
\item
  Division of Pediatric Cardiology, Cohen Children's Medical Center --
  Northwell Health, 1111 Marcus Ave, Suite M15, New Hyde Park, NY 11042.
\item
  Division of Pediatrics, Cohen Children's Medical Center, 269-01
  76\textsuperscript{th} Avenue, New Hyde Park, NY 11040.
\item
  Division of Biostatistics, Feinstein Institute for Medical Research,
  125 Community Drive, Great Neck, NY 11021.
\end{enumerate}

\textbf{Corresponding Author:}

Denise A. Hayes, MD (dhayes2@northwell.edu) -- Division of Pediatric
Cardiology, Cohen Children's Medical Center -- Northwell Health, 1111
Marcus Ave, Suite M15, New Hyde Park, NY 11042.

\textbf{Pages: 10}

\textbf{Word Count:} 2755

\textbf{Article Type:} Original Article

\textbf{Key Words:} Sildenafil, Pulmonary Hypertension

\textbf{Abstract}

Continuous intravenous (IV) sildenafil may avoid the acute systemic
vasodilatory effects of bolus dosing in infants with pulmonary
hypertension (PH). We aimed to examine the tolerability of different
methods of IV sildenafil administration.

\textbf{Methods:}

We retrospectively evaluated subjects less than 12 months old with PH,
who had been started on IV sildenafil. Vital signs, oxygen requirement,
and vasoactive-inotropic score (VIS) before and after sildenafil
initiation were noted, as was the need for discontinuation due to side
effects.

\textbf{Results:}

Forty-three subjects were identified (23 continuous, 20 intermittent
dosing). There were no statistically significant differences between
groups in gender or gestational age, but higher baseline inspired oxygen
(FiO2) and VIS in the continuous group suggested a higher baseline
severity of illness (\emph{p} =0.012). After sildenafil initiation,
there were no significant differences in the change in blood pressure,
oxygen saturation, FiO2, or VIS between groups, and no difference in the
number of subjects requiring discontinuation due to side effects (4 in
the continuous group, 1 intermittent, \emph{p} =0.35). Eight subjects
(34.8\%) in the continuous group and 3 (15\%) in the intermittent group
died (\emph{p} =0.024).

\textbf{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.

\textbf{Introduction}

Pulmonary hypertension (PH) is defined as an abnormally high pulmonary
artery pressure and pulmonary vascular resistance, often secondary to
cardiac or pulmonary disease\textsuperscript{1}. The gold standard for
diagnosis of PH is a mean pulmonary arterial pressure of [?]25 mmHg by
right heart catheterization\textsuperscript{2}. The clinical spectrum of
presentation varies from a transient neonatal condition to a disabling
disease of infancy and childhood\textsuperscript{3}. 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
dysplasia\textsuperscript{4}. The incidence of severe persistent
pulmonary hypertension in newborns is estimated at 0.2\% of live-born
term infants\textsuperscript{4}.

Treatment of PH involves selective pulmonary vasodilation, with multiple
therapeutic options including phosphodiesterase type 5 (PDE-5)
inhibitors\textsuperscript{3}. Among these, the PDE-5 inhibitor
sildenafil is commonly used to treat PH in newborns and
infants\textsuperscript{5}. 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-life\textsuperscript{5}. IV delivery is sometimes chosen for
critically-ill neonates in whom there are concerns of poor absorption of
enteral medications\textsuperscript{5}.

Intermittent bolus IV sildenafil has demonstrated efficacy in various
studies\textsuperscript{6}, however systemic hypotension has been
reported as an adverse effect of IV bolus delivery\textsuperscript{7}.
Studies investigating the occurrence of hypotension in IV versus oral
delivery have failed to demonstrate a statistically significant
difference in safety outcomes\textsuperscript{8}.

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.

\textbf{Materials and Methods}

\textbf{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
outcome\textsuperscript{9}. 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
al\textsuperscript{10}). 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.

\textbf{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 \emph{p} -value \textless{} 0.05 was considered statistically
significant. All analyses were conducted using SAS version 9.4 (SAS
Institute Inc., Cary, NC).

\textbf{Results}

\textbf{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 (\emph{p} =0.069). Median gestational age was 38.7 weeks (IQR: 36
- 40) in the continuous group, and 37.8 weeks (IQR: 26 - 39),\emph{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 (\emph{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), \emph{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\%), \emph{p} =0.012). SBP, DBP, and MAP pre-sildenafil were
similar between continuous and intermittent groups.

\textbf{Changes in Clinical Parameters After Sildenafil Administration,
and Need for Discontinuation of Therapy}Changes 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.

\textbf{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, \emph{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 \textless{}
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 \textless{} 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 \textless{} 0.001). No statistically significant
differences were observed in mortality rates by gestational age, ECMO
(yes/no), PH degree (dichotomized), or RV function.

\textbf{Discussion}

The incidence of severe persistent PH of the newborn is 2/1000 live
births\textsuperscript{11}. Among infants born prematurely, the risk of
PH is estimated to be more than three times higher than in full term
births\textsuperscript{12}. 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 oxygenation\textsuperscript{14}.
Although well tolerated for most patients, the side effect of systemic
hypotension remains a significant concern in many neonates with
unfavorable hemodynamics\textsuperscript{8,13}. 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.

\textbf{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.

\textbf{References}

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