Bronchopulmonary Dysplasia, Bronchopulmonary Dysplasia Associated Pulmonary Hypertension, Chronic Lung Disease of Prematurity, Premature Birth, Pulmonary Hypertension
Conditions
Keywords
Bronchopulmonary dysplasia, Pulmonary hypertension, Citrulline
Brief summary
Oral L-citrulline supplementation may prevent and/or decrease the severity of chronic lung disease associated with pulmonary hypertension in preterm infants. Since oral L-citrulline supplementation has never been studied in preterm infants before, the side effect profile and appropriate dosing are still unknown. In this pilot study, the investigators will determine the safety profile, efficacy and appropriate dosing of oral L-citrulline in preterm infants. In the future, information from this study will be utilized to conduct a randomized placebo-controlled trial to evaluate the role of L-citrulline supplementation in treating BPD\_PH.
Detailed description
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants (PI). Preterm birth causes disruption in pulmonary vascular growth that leads to decreased vascular surface area that increases pulmonary vascular resistance (PVR). Increased PVR leads to altered vasoreactivity and structural remodeling with intimal hyperplasia and increased muscularization of the small pulmonary arteries. There is no definite treatment for BPD\_PH. Nitric Oxide: Nitric Oxide (NO) is a potent pulmonary vasodilator. Endothelial Nitric oxide synthase (eNOS) mediates production of NO from L-Arginine. L-citrulline is a precursor for L-arginine. L-Arginine is a precursor of nitric oxide (NO). In infants with BPD\_PH, there are decreased levels of L-arginine & L-citrulline with decreased production of NO (measured by urinary nitrates & nitrites) leading to increased PVR. Several studies have shown the benefit of oral L-citrulline supplementation in increasing serum citrulline levels, increasing NO production and reducing pulmonary hypertension. Oral L-arginine was not effective in increasing NO production in previous studies and it was due to increased break down of oral L-arginine by intestinal arginases. Source of L-arginine in preterm infants: Routinely, extremely premature infants receive nutrition as total parental nutrition (TPN i.e. infants get infusion of protein, fat and carbohydrate via central venous line) that contains L-arginine (approximately 1mg/1mL) to metabolize ammonia via urea cycle. PIs receive adequate amount of intra venous arginine from TPN. Routinely, PIs are started with small volumes of enteral feeds which are increased slowly overtime. TPN is slowly decreased as enteral feeds are increasing. As the TPN is going down, intra venous L-arginine intake also drops down and ultimately when the PI are off TPN, they don't get any IV supplemental L-arginine. Why oral citrulline: Enteral feeds (formula as well as breast milk) is poor source of arginine. Once PIs are on full enteral feed, an enteral feed is the only source of arginine. Interestingly, 40% of enteral arginine gets metabolized by arginase enzyme present in intestine. We speculate that plasma levels of arginine drop once TPN is discontinued and infants are on full feeds. Oral L-arginine has poor bio-availability that is why oral L-arginine supplementation does not increase blood levels of arginine. Since oral citrulline has high bioavailability, the best way to increase serum arginine levels is by oral citrulline supplementation. Oral supplementation of L-citrulline in preterm infants once they are off TPN will likely to increase arginine levels and NO production. Safety of oral citrulline: L-citrulline has been safely used for decades in patients with urea cycle defects. It has been used in pediatric patients with sickle cell disease and in infants undergoing cardiac surgery. No side effects were reported in these studies. In a study in newborn rats exposed to hyperoxia, L-citrulline caused a marked increase in arginase-2 expression in the lungs and this could have an impact on lung development and remodeling. However, this is only a theoretical risk.
Interventions
DIETARY_SUPPLEMENTEnteral L-citrulline
L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient. Administration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion. Study drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere.
Sponsors
The University of Texas Medical Branch, Galveston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Previous studies in patients undergoing cardiac surgery have shown that post-operative pulmonary hypertension did not develop in patients with citrulline level \> 37 micromol/L. A cross-sectional study reported that citrulline levels \< 29 micromol/L was associated with BPD\_PH (100% sensitivity and 75% specificity) hence this may be used as a screening tool for BPD\_PH2. The investigators will use the higher levels of citrulline of the reported levels as our goal (\>37µmol/L). The investigators will supplement infants with 3 different dosages and check serum levels to see what dose is required to achieve the optimal plasma level of citrulline (\>37µmol/L).
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Weeks
Healthy volunteers
No
Inclusion criteria
* Infants less than or equal to 30 weeks' gestational age born at UTMB, Galveston. * Parents have provided informed consent/assent in a manner that is approved by the IRB
Exclusion criteria
* Known congenital or chromosomal anomalies. * Congenital heart disease affecting cardio-respiratory system (other than PDA, PFO or ASD) * Necrotizing enterocolitis, sepsis, or any condition requiring surgery prior to recruitment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | During the week of intervention (day 0 - day 7) | L-arginine and citrulline levels in the plasma will be measured via liquid chromatography-mass spectroscopy (LCMS) and a change (increase) in plasma levels of 20% on day 7 from baseline on day 0 will be considered significant. |
| Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event | During the week of intervention (day 0 - day 7) | Measured by at least one adverse event that are determined to be related to the study drug. |
| Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L | During the week of intervention (day 0 - day 7) | Previous studies have shown that a plasma level of \> 37 micromol/L was effective in preventing pulmonary hypertension. This study sought to identify the dosing group of L-citrulline required to increase the plasma level of L-citrulline \> 37 micromol/L. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Dose 50 mg/kg given two times a day (100 mg/kg/day) for total 7 days.
Enteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.
Administration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.
Study drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere. | 14 |
| Medium Dose 100 mg/kg given two times a day (200 mg/kg/day) for total 7 days
Enteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.
Administration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.
Study drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere. | 13 |
| High Dose 150 mg/kg given two times a day (300 mg/kg/day) for total 7 days.
Enteral L-citrulline: L-Citrulline as 10 % solution (100 mg/ml) will be provided to the bedside nurse by the Investigational Pediatric Pharmacy. The drug will be given via gavage feeding by bolus infusions followed by a 0.5 ml water flush twice daily (0900 and 2100). Bolus dosing will be needed due to the small volumes (0.5-1.5 ml per dose in most infants). The volume of nasogastric tubing used in preterm infants (Ameritus 4.0 Fr 50 cm) is 0.48 ml, therefore we will follow the administration with 0.5 ml of saline/water flush to ensure all the study drug is delivered to the patient.
Administration of study drug - Will be given via gavage feeding tube twice daily (0900 +/- 30 mins, 2100 +/- 30 mins). L-citrulline will be given by the bedside nurse as a bolus followed by 0.5 ml water flush. L-citrulline will be given separate from feeds to avoid any confusion.
Study drug will be started when infant has been off of TPN for at least 3 days so that IV arginine in TPN does not interfere. | 13 |
| Total | 40 |
Baseline characteristics
| Characteristic | Low Dose | Medium Dose | High Dose | Total |
|---|---|---|---|---|
| Age, Continuous | 30 Weeks STANDARD_DEVIATION 2.1 | 29.6 Weeks STANDARD_DEVIATION 2.5 | 29 Weeks STANDARD_DEVIATION 1.5 | 29.4 Weeks STANDARD_DEVIATION 2.1 |
| Birth Weight | 1125 grams STANDARD_DEVIATION 383.5 | 1272 grams STANDARD_DEVIATION 460 | 1250 grams STANDARD_DEVIATION 350 | 1250 grams STANDARD_DEVIATION 393 |
| Race/Ethnicity, Customized African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 6 Participants | 6 Participants | 8 Participants | 20 Participants |
| Race/Ethnicity, Customized Hispanic | 8 Participants | 5 Participants | 5 Participants | 18 Participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 10 Participants | 26 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 3 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 14 | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach
L-arginine and citrulline levels in the plasma will be measured via liquid chromatography-mass spectroscopy (LCMS) and a change (increase) in plasma levels of 20% on day 7 from baseline on day 0 will be considered significant.
Time frame: During the week of intervention (day 0 - day 7)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Citrulline level (day 0) | 24 micromol/L | Standard Deviation 9.5 |
| Low Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Citrulline level (day 7) | 112 micromol/L | Standard Deviation 85 |
| Low Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Arginine level (day 0) | 56 micromol/L | Standard Deviation 63 |
| Low Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Arginine level (day 7) | 91 micromol/L | Standard Deviation 63 |
| Medium Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Arginine level (day 7) | 134 micromol/L | Standard Deviation 62 |
| Medium Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Citrulline level (day 0) | 33 micromol/L | Standard Deviation 17 |
| Medium Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Arginine level (day 0) | 56 micromol/L | Standard Deviation 62 |
| Medium Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Citrulline level (day 7) | 150 micromol/L | Standard Deviation 89 |
| High Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Arginine level (day 7) | 162 micromol/L | Standard Deviation 67 |
| High Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Citrulline level (day 7) | 171 micromol/L | Standard Deviation 139 |
| High Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Arginine level (day 0) | 59 micromol/L | Standard Deviation 30 |
| High Dose | Change in Plasma Levels of L-arginine and L-citrulline as Measured by LCMS Approach | Citrulline level (day 0) | 26 micromol/L | Standard Deviation 11 |
Primary
Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L
Previous studies have shown that a plasma level of \> 37 micromol/L was effective in preventing pulmonary hypertension. This study sought to identify the dosing group of L-citrulline required to increase the plasma level of L-citrulline \> 37 micromol/L.
Time frame: During the week of intervention (day 0 - day 7)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose | Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L | 8 Participants |
| Medium Dose | Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L | 10 Participants |
| High Dose | Number of Participants With an Increase Plasma Level of L-citrulline > 37 Micromol/L | 10 Participants |
Primary
Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event
Measured by at least one adverse event that are determined to be related to the study drug.
Time frame: During the week of intervention (day 0 - day 7)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose | Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event | 0 Number of Adverse Events |
| Medium Dose | Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event | 0 Number of Adverse Events |
| High Dose | Safety of L-citrulline in Preterm Infants: Measured by at Least One Adverse Event | 0 Number of Adverse Events |