Are there more adverse effects given IV intermittent sildenafil vs continuous infusion sildenafil in neonates and infants? Does history of preterm birth impact the risks for hypotension or infusion-related adverse effects?

Comment by InpharmD Researcher

Only one study directly compares intermittent sildenafil infusion versus continuous infusion in neonates, showing no significant differences in tolerability. Other retrospective studies of intermittent sildenafil infusion have also found it to be safe. Unfortunately, IV sildenafil use in preterm neonates is lacking, with one small study [Table 4] suggesting a risk of pulmonary hemorrhage.

Background

In 2009, the U.S. FDA approved intravenous sildenafil, primarily for use in critically ill patients. The formulation has been explored in several studies concerning its use in neonates, particularly with congenital diaphragmatic hernia (CDH) or pulmonary hypertension (PH). Mukherjee et al. conducted a notable pharmacokinetic trial on term neonates receiving intravenous sildenafil within 72 hours of birth. One standard dosing regimen involves a loading infusion followed by a continuous maintenance infusion to stabilize plasma concentrations, which has since been a basis for clinical practice and further investigations. Steinhorn et al. conducted a dose-escalation trial in near-term and term neonates, confirming improved oxygenation with a loading dose followed by maintenance infusion, verified by pharmacokinetic modeling. Kipfmueller et al. observed significant oxygenation improvement in congenital diaphragmatic hernia (CDH) neonates with the same dosing schedule. Studies have evaluated intermittent dosing in full-term neonates, showing increased oxygenation and decreased respiratory support needs with 0.4-2 mg/kg q6h (1-3 hour infusions). Another study, by Darland et al. [Table 2], found neonates receiving intravenous sildenafil had a higher, but not statistically significant, incidence of hypotension compared to another cohort. Rapid infusions were associated with hypotension, suggesting safer regimens would involve slower and continuous infusions. Research on IV sildenafil in preterm neonates remains sparse, though early studies indicate potential benefits of intravenous sildenafil for correcting hemodynamic instability in critically ill preterms. [1]

References:

[1] Li Z, Lv X, Liu Q, Dang D, Wu H. Update on the use of sildenafil in neonatal pulmonary hypertension: a narrative review of the history, current administration, and future directions. Transl Pediatr. 2021;10(4):998-1007. doi:10.21037/tp-20-277
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Are there more adverse effects given IV intermittent sildenafil vs continuous infusion sildenafil in neonates and infants? Does history of preterm birth impact the risks for hypotension or infusion-related adverse effects?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

 

Continuous and intermittent administration of intravenous sildenafil in critically ill infants with pulmonary hypertension
Design

Retrospective, single-center, observational cohort study

N= 43
Objective

To compare the use and short-term tolerability of continuous versus intermittent intravenous sildenafil delivery methods in critically ill infants with pulmonary hypertension
Study Groups

Continuous IV sildenafil (n= 23)

Intermittent IV sildenafil (n= 20)
Inclusion Criteria

Subjects less than 12 months old who received IV sildenafil for pulmonary hypertension between 2011-2019
Exclusion Criteria

Subjects previously treated with oral sildenafil
Methods

This was a retrospective evaluation of subjects treated with IV sildenafil at a single center in New York. The continuous group received 1.3-1.6 mg/kg/day with an optional 0.4 mg/kg starting dose. The intermittent group received 0.5 mg/kg every 8 hours over 15-60 minutes, with an optional 0.25 mg/kg test dose. 

The choice of sildenafil administration type was at the discretion of the medical team, although there was a shift in practice around 2016 from frequent use of a continuous infusion to regular use of intermittent dosing.
Duration

01/01/2011 to 12/30/2019
Outcome Measures

Primary: Need for sildenafil discontinuation due to side effects

Secondary: Mortality, changes in FiO2, SpO2, SBP, DBP, MAP, VIS, and PH degree after sildenafil initiation
Baseline Characteristics  

Continuous (n= 23)

 Intermittent (n= 20)

Male

 11 (47.8%) 15 (75%)

Gestational age, weeks (IQR)

Age at treatment, days (IQR)

38.71 (36.00-40.00)

7 (3-10)

37.79 (26.14-39.28)

27 (7-132)
Treated before 2016

22 (95.7%)

 0

Pulmonary arterial hypertension

Pulmonary hypertension due to lung disease/hypoxia

13 (56.5%)

10 (43.5%)

6 (30%)

14 (70%)

IQR: interquartile range
Results  

Continuous (n= 23)

 Intermittent (n= 20) p-value
Change in vasoactive-inotropic score (IQR) 0 (0 to 5)

0 (0 to 0)

 0.152

Change in SBP, mm Hg (IQR)

Change in DBP, mm Hg (IQR)

Change in MAP, mm Hg (IQR)

-6 (-14 to -1)

-4 (-10 to 0)

-4 (-10 to 0)

-1 (-9 to +6)

-4 (-8 to +3)

-1 (-8 to +2)

0.135

0.545

0.359
Change in SpO2, % (IQR) 0 (-5 to +1)

-1 (-2 to 0)

 0.788
Change in FiO2 (IQR) 0 (0 to 0)

0 (0 to 0)

 0.152

PH degree improved by ≥1 category

 14/18 (77.8%) 6/18 (33.3%) 0.007

Discontinued due to side effects

 4 (17.4%) 1 (5%) 0.351

Mortality

 8 (34.8%) 3 (15%) 0.024
Adverse Events

Sildenafil was discontinued due to side effects in 4 (17.4%) of the continuous group and 1 (5.0%) in the intermittent group. Side effects included hypotension and worsening hypoxemia.
Study Author Conclusions

In this small cohort, there were no significant differences in short-term tolerability between continuous and intermittent IV sildenafil dosing. Higher mortality in the continuous group may be due to greater baseline illness severity.
Critique

The study highlights important findings on the use of IV sildenafil in critically ill infants but is limited by its retrospective design, small sample size, and differences in baseline characteristics between groups. The era effect and differences in PH etiology and severity of illness between groups may confound results, limiting the ability to draw definitive conclusions. Larger, prospective studies are needed to validate these findings.

 

References:

Sharma C, Burns J, Kulkarni A, Cerise JE, Molina Berganza F, Hayes DA. Continuous and intermittent administration of intravenous sildenafil in critically ill infants with pulmonary hypertension. Pediatr Pulmonol. 2021;56(9):2973-2978. doi:10.1002/ppul.25539

 

Evaluating the Safety of Intermittent Intravenous Sildenafil in Infants With Pulmonary Hypertension
Design

Retrospective matched-cohort study

N= 40
Objective

To compare the occurrence of hypotension following administration of intermittent intravenous (IV) and enteral sildenafil for treatment of pulmonary hypertension (PH) in infants
Study Groups

IV sildenafil (n= 20)

Enteral sildenafil (n= 20)
Inclusion Criteria

Patients less than 1 year of age who received intermittent sildenafil for PH between October 2010 and October 2013
Exclusion Criteria

Concurrent extracorporeal membrane oxygenation during the initiation of sildenafil, utilization of sildenafil as a one-time dose, continuation of home-dosing regimen, or inclusion in the other cohort
Methods

This was a retrospective matched-cohort analysis conducted at Texas Children’s Hospital. Patients were matched 1:1 based on postmenstrual age and primary diagnosis. Institutional protocols generally gave intermittent IV sildenafil over 20-30 minutes. The mean IV initiation dose was 0.32 mg/kg/dose (range, 0.06-0.53 mg/kg/dose). Most patients (in both groups) were on q6h dosing.
Duration

October 2010 to October 2013
Outcome Measures

Primary: Requirement for a hypotension intervention

Secondary: Flushing occurrences, ICU length of stay, ventilator days, ECMO initiation, hearing loss, retinopathy of prematurity, mortality
Baseline Characteristics  

IV (n= 20)

 ENT (n= 20) p-value

Male

 13 (65%) 13 (65%) 1.0

Postmenstrual age, weeks

Gestational age, weeks

Postnatal age, days

52 ± 12.9

35 ± 5.5

130 ± 94.7

51 ± 12.1

34 ± 6.3

123 ± 92.1

0.85

0.81

0.69

Birth weight, kg

Study weight, kg

2.3 ± 1.1

4.5 ± 1.4

2.7 ± 1.2

4.6 ± 1.7

0.33

0.83

Median Apgar 1 min (range)

Median Apgar 5 min (range)

5 (1-8)

8 (2-9)

8 (1-9)

9 (4-9)

0.48

0.91

Diagnosis

Congenital heart disease

Congenital diaphragmatic hernia

Bronchopulmonary dysplasia

Arteriovenous malformation

 

8 (40%)

6 (30%)

5 (25%)

1 (5%)

 

8 (40%)

6 (30%)

5 (25%)

1 (5%)

 

1.0

1.0

1.0

1.0

Mean arterial pressure, mm Hg

 58 ± 15 58 ± 10 0.96

Brain natriuretic peptide, pg/mL (range)

 314 (8-4,764) 124 (2.8-2,089) 0.20
Results   IV (n= 20)

ENT (n= 20)

 p-value
Hypotension intervention required 6 (30%)

2 (10%)

 0.24

ICU length of stay, days (range)

 145 (2-433) 97 (16-283) 0.31
Ventilator days (range)

88 (0-397)

 40 (9-435) 0.19

Hearing loss

 3/7 (43) 3/11 (27) 0.35

Retinopathy of prematurity

 4/5 (80) 3/6 (50) 0.55

Mortality

 6 (30) 1 (5) 0.09
Adverse Events

See results
Study Author Conclusions

There were no statistically significant differences in safety outcomes between intermittent IV and enteral sildenafil in infants with PH. Hemodynamic parameters should be monitored closely upon sildenafil initiation.
Critique

The study's retrospective nature and small sample size limit its power to detect significant differences in hypotension incidence. The study was conducted at a single institution, which may limit the generalizability of the findings. Larger, prospective studies are needed to validate these safety findings and evaluate dosing and efficacy of intermittent IV sildenafil.

 

References:

Darland LK, Dinh KL, Kim S, et al. Evaluating the safety of intermittent intravenous sildenafil in infants with pulmonary hypertension. Pediatr Pulmonol. 2017;52(2):232-237. doi:10.1002/ppul.23503

 

Evaluation of the Tolerability of Intermittent Intravenous Sildenafil in Pediatric Patients With Pulmonary Hypertension
Design

Retrospective chart review

N= 37
Objective

To determine the tolerability of intermittent intravenous (IV) sildenafil for the treatment of pulmonary hypertension in pediatric patients and to evaluate parameters related to efficacy
Study Groups

All patients (n= 37)
Inclusion Criteria

Pediatric patients under age 18 years treated with intermittent doses of IV sildenafil for pulmonary hypertension from January 2013 to August 2014
Exclusion Criteria

Patients ≥ 18 years of age or received sildenafil for other indications
Methods

This was a retrospective chart review of pediatric patients treated with intermittent IV sildenafil from a single center in Illinois. Sildenafil was initiated at 0.25 mg/kg every 6 to 8 hours, increased to a maximum of 1 mg/kg or 10 mg, infused over 15 minutes. For patients switching from oral to IV, the dose was decreased by 50%. Measures collected included blood pressure and heart rate before and after administration, as well as adverse events. 
Duration

January 2013 to August 2014
Outcome Measures

Primary: Tolerability of IV sildenafil (changes in blood pressure and heart rate, adverse events)

Secondary: Efficacy parameters (oxygenation index, pH, PO2, PCO2, bicarbonate)
Baseline Characteristics  

All patients (n= 37)
Age, months (range)

11.7 ± 17.3 (0.2-87.5)
Male

16 (43.2%)

Congenital heart disease

 28 (75.7%)

Previous oral sildenafil

 21 (56.8%)

Number of IV sildenafil doses (range)

Duration of IV sildenafil, days (range)

51.8 ± 55.8 (1-235)

12.9 ± 13.7 (0.2-58.4)

Ventilator duration, days (range)

ICU length of stay, days (range)

Hospital length of stay, days (range)

37.8 ± 29.1 (0.7-102.7)

68.4 ± 75.1 (1.3-337.9)

74.8 ± 73.8 (2.0-360.9)
Results  

Before IV Sildenafil

 After IV Sildenafil p-value

Systolic blood pressure, mm Hg

 86.08 ± 16.27 78.92 ± 15.40 0.0045

Diastolic blood pressure, mm Hg

 47.97 ± 10.35 45.24 ± 13.05 0.09

Heart rate, bpm

 130.05 ± 24.90 130.81 ± 24.33 0.72

Oxygenation index, median (IQR)

 10.81 (6.54-16.07) 11.11 (5.69-16.07) 0.607

pH

 7.39 ± 0.08 7.39 ± 0.09 0.593

pCO2, mm Hg

 48.77 ± 10.84 47.98 ± 10.67 0.468

Median pO2, mm Hg (IQR)

 61 (44-104) 65 (46-104) 0.833

Bicarbonate, mmol/L

 30.61 ± 6.06 30.52 ± 5.55 0.319
Adverse Events

Adverse events occurred in 5 patients (13.5%), primarily hypotension. One patient experienced priapism, which resolved with dose reduction. No patients discontinued medication due to adverse events.
Study Author Conclusions

Sildenafil, when administered as intermittent IV doses, was tolerated by the majority of patients evaluated in this study. Intermittent IV sildenafil may be considered as an alternative administration option for pediatric patients with pulmonary hypertension when enteral or continuous IV administration is not feasible.
Critique

The study provides valuable insights into the tolerability of intermittent IV sildenafil in pediatric patients, but its retrospective design and lack of a comparison group limit the ability to draw definitive conclusions about efficacy. The study's findings are also limited by variations in practice between units and the small sample size.

 

References:

Fender RA, Hasselman TE, Wang Y, Harthan AA. Evaluation of the Tolerability of Intermittent Intravenous Sildenafil in Pediatric Patients With Pulmonary Hypertension. J Pediatr Pharmacol Ther. 2016;21(5):419-425. doi:10.5863/1551-6776-21.5.419

 

Intravenous Sildenafil i.v. as Rescue Treatment for Refractory Pulmonary Hypertension in Extremely Preterm Infants
Design

Retrospective analysis

N= 6
Objective

To describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome
Study Groups

All patients (n= 6)
Inclusion Criteria

Critically ill extremely preterm infants born below 28 weeks of gestational age; admitted in 2012; pulmonary hypertension (PH) refractory to first-line treatment
Exclusion Criteria

Not specified
Methods

This was a retrospective review of records of 6 preterm infants who received intravenous sildenafil as ultima ratio treatment for refractory PH. Sildenafil was administered as a loading dose of 0.1 mg/kg over 45 min, followed by a continuous infusion of 0.5 to 1.2 mg/kg/day.
Duration

2012
Outcome Measures

Primary: Resolution of severe PH, hemodynamic and respiratory changes

Secondary: Occurrence of pulmonary hemorrhage
Baseline Characteristics Characteristic

All patients (n= 6)
Mean birth weight, g (range)

667 ± 201 (440-1,046)
Mean gestational age was below 28 weeks
Results  

All patients (n= 6)

Resolution of severe PH

 4/6 (67%)

Pulmonary hemorrhage

 2/6 (33%)

Death

 4/6 (67%)
Adverse Events

Pulmonary hemorrhage occurred in 2 patients after significant improvement of pulmonary hypertension
Study Author Conclusions

Intravenous sildenafil treatment seems effective in improving severe PH and hemodynamic instability in extremely preterm infants with refractory PH. Pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients.
Critique

The study is limited by its small sample size and retrospective design, which may affect the generalizability of the findings. The occurrence of pulmonary hemorrhage as a potential adverse effect highlights the need for careful monitoring and consideration of risks when using sildenafil in this population.

 

References:

Steiner M, Salzer U, Baumgartner S, et al. Intravenous sildenafil i.v. as rescue treatment for refractory pulmonary hypertension in extremely preterm infants. Klin Padiatr. 2014;226(4):211-215. doi:10.1055/s-0034-1375697