Effects of Non-invasive Ventilation With Helium-oxygen Mixture in Premature Infants With Respiratory Distress Syndrome

NCT04404816 | Completed Phase 1

• 1 other identifier: 072015
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

The use of a mixture of helium with oxygen (heliox) as a breathing gas may be beneficial due to its unique physical properties, such as low density and high carbon dioxide (CO2) diffusion coefficient. In previous studies in neonates with respiratory failure, conventional ventilation with heliox was associated with improved oxygenation and selected respiratory parameters. The use of heliox may increase the effectiveness of intermittent nasal positive pressure ventilation (NIPPV), but knowledge about the effects of such therapy on newborns is limited.The use of non- invasive neurally adjusted ventilatory assist (NIV-NAVA) allows synchronization and assessment of electrical activity of the diaphragm (EaDI) during heliox administration in premature babies with respiratory failure.

Conditions

Respiratory Distress Syndrome; Premature Infants

Keywords

heliox; respiratory distress syndrome (RDS); non-invasive ventilation; NIRS; EaDI; Edi; NIV; NAVA; helium-oxygen

Outcome Measures

Primary Outcomes (49)

• baseline minimal electric activity of the diaphragm (EaDI min)

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV, microvolts\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured at baseline

• baseline mean electric activity of the diaphragm (EaDI mean)

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured at baseline

• baseline maximal electric activity of the diaphragm (EaDI max)

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured at baseline

• minimal electric activity of the diaphragm (EaDI min) after 15 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 15 minutes of heliox ventilation

• mean electric activity of the diaphragm (EaDI mean) after 15 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 15 minutes of heliox ventilation

• maximal electric activity of the diaphragm (EaDI max) after 15 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 15 minutes of heliox ventilation

• minimal electric activity of the diaphragm (EaDI min) after 60 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 60 minutes of heliox ventilation

• mean electric activity of the diaphragm (EaDI mean) after 60 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 60 minutes of heliox ventilation

• maximal electric activity of the diaphragm (EaDI max) after 60 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 60 minutes of heliox ventilation

• minimal electric activity of the diaphragm (EaDI min) after 180 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 180 minutes of heliox ventilation

• mean electric activity of the diaphragm (EaDI mean) after 180 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 180 minutes of heliox ventilation

• maximal electric activity of the diaphragm (EaDI max) after 180 minutes of heliox

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 180 minutes of heliox ventilation

• minimal electric activity of the diaphragm (EaDI min) after 15 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 15 minutes since the return to ventilation with standard mixture

• mean electric activity of the diaphragm (EaDI mean) after 15 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 15 minutes since the return to ventilation with standard mixture

• maximal electric activity of the diaphragm (EaDI max) after 15 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 15 minutes since the return to ventilation with standard mixture

• minimal electric activity of the diaphragm (EaDI min) after 60 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 60 minutes since the return to ventilation with standard mixture

• mean electric activity of the diaphragm (EaDI mean) after 60 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 60 minutes since the return to ventilation with standard mixture

• maximal electric activity of the diaphragm (EaDI max) after 60 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 60 minutes since the return to ventilation with standard mixture

• minimal electric activity of the diaphragm (EaDI min) after 180 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI min \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 180 minutes since the return to ventilation with standard mixture

• mean electric activity of the diaphragm (EaDI mean) after 180 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI mean \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 180 minutes since the return to ventilation with standard mixture

• maximal electric activity of the diaphragm (EaDI max) after 180 minutes of standard mixture

  Using the NAVA (neurally adjusted ventilatory assist) module of the Maquet Servo-i ventilator and "Servo-tracker" software EaDI max \[mcV\] values will be recorded during the study and their values will be compared between the heliox and air-oxygen NIV (non -invasive ventilation).

  measured after 180 minutes since the return to ventilation with standard mixture

• baseline PIP (peak inspiratory pressure)

  PIP \[cm H2O, centimeters of water\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured at baseline

• baseline PEEP (positive end-expiratory pressure)

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured at baseline

• baseline MAP (mean airway pressure)

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured at baseline

• PIP (peak inspiratory pressure) after 15 minutes of heliox

  PIP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes of heliox ventilation

• PIP (peak inspiratory pressure) after 60 minutes of heliox

  PIP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes of heliox ventilation

• PIP (peak inspiratory pressure) after 180 minutes of heliox

  PIP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes of heliox ventilation

• PIP (peak inspiratory pressure) after 15 minutes of standard mixture

  PIP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes since the return to ventilation with standard mixture

• PIP (peak inspiratory pressure) after 60 minutes of standard mixture

  PIP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes since the return to ventilation with standard mixture

• PIP (peak inspiratory pressure) after 180 minutes of standard mixture

  PIP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes since the return to ventilation with standard mixture

• PEEP (positive end-expiratory pressure) after 15 minutes of heliox

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes of heliox ventilation

• PEEP (positive end-expiratory pressure) after 60 minutes of heliox

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes of heliox ventilation

• PEEP (positive end-expiratory pressure) after 180 minutes of heliox

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes of heliox ventilation

• PEEP (positive end-expiratory pressure) after 15 minutes of standard mixture

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes since the return to ventilation with standard mixture

• PEEP (positive end-expiratory pressure) after 60 minutes of standard mixture

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes since the return to ventilation with standard mixture

• PEEP (positive end-expiratory pressure) after 180 minutes of standard mixture

  PEEP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes since the return to ventilation with standard mixture

• MAP (mean airway pressure) after 15 minutes of heliox

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes of heliox ventilation

• MAP (mean airway pressure) after 60 minutes of heliox

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes of heliox ventilation

• MAP (mean airway pressure) after 180 minutes of heliox

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes of heliox ventilation

• MAP (mean airway pressure) after 15 minutes of standard ventilation

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes since the return to ventilation with standard mixture

• MAP (mean airway pressure) after 60 minutes of standard ventilation

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes since the return to ventilation with standard mixture

• MAP (mean airway pressure) after 180 minutes of standard ventilation

  MAP \[cm of water / cm H2O\] will be recorded by Servo-tracker software and the values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes since the return to ventilation with standard mixture

• baseline NIV leakage

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured at baseline

• NIV leakage after 15 minutes of heliox

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes of heliox ventilation

• NIV leakage after 60 minutes of heliox

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes of heliox ventilation

• NIV leakage after 180 minutes of heliox

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes of heliox ventilation

• NIV leakage after 15 minutes of standard mixture

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured after 15 minutes since the return to ventilation with standard mixture

• NIV leakage after 60 minutes of standard mixture

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured after 60 minutes since the return to ventilation with standard mixture

• NIV leakage after 180 minutes of standard mixture

  gas leakage fraction \[%\] during NIV (non-invasive ventilation) recorded by Servo-tracker software their values will be compared between the heliox and air-oxygen NIV.

  measured after 180 minutes since the return to ventilation with standard mixture

Secondary Outcomes (31)

• baseline cerebral oxygenation

  measured at baseline

• Cerebral oxygenation after 15 minutes of heliox

  measured after 15 minutes of heliox ventilation

• Cerebral oxygenation after 60 minutes of heliox

  measured after 60 minutes of heliox ventilation

• Cerebral oxygenation after 180 minutes of heliox

  measured after 180 minutes of heliox ventilation

• Cerebral oxygenation after 15 minutes of standard mixture

  measured after 15 minutes since the return to standard mixture ventilation

Study Arms (2)

Group 1

EXPERIMENTAL

premature infants born \< 33 G.A. enrolled in the first 72 hours after birth, with respiratory distress syndrome, requiring non-invasive ventilation with FiO2 \<0.4

Drug: heliox

Group 2

EXPERIMENTAL

premature infants born \< 33 G.A. with respiratory insufficiency requiring mechanical ventilation, after more than 1 failed extubation attempt

Drug: heliox

Interventions

heliox DRUG

NIV-NAVA with a conventional gas mixture (air-oxygen) at baseline, 3 hours of NIV-NAVA with heliox and return to NIV-NAVA with air-oxygen.

Also known as: helium-oxygen gas mixture

Group 1; Group 2

Eligibility Criteria

• Age: 1 Hour+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• GA under 33 weeks GA
• Need for NIV due to clinical symptoms of respiratory distress in course of RDS
• FiO2=0.25-0.4
• Enrollment within first 72 hours of life
• Parental consent
• GA under 33 weeks GA
• Need for MV due to clinical symptoms of respiratory distress
• at least one failed attempted extubation
• Parental consent

You may not qualify if:

• Major congenital anomalies
• Deteriorating pulmonary function despite NIV and the need for intubation and conventional mechanical ventilation (CMV) (Preliminary criteria: pH\< 7.22, carbon dioxide partial pressure (pCO2) \>65)

Sponsors & Collaborators

• Poznan University of Medical Sciences: lead
• European Society for Paediatric Research: collaborator

Study Sites (1)

Gynecological and obstetric teaching hospital, Departament of Neonatology, Polna street 33

Poznan, Great Poland, 60-535, Poland

Location

Related Publications (13)

• Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Vento M, Halliday HL; European Association of Perinatal Medicine. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants--2013 update. Neonatology. 2013;103(4):353-68. doi: 10.1159/000349928. Epub 2013 May 31.

  PMID: 23736015 BACKGROUND

• Elleau C, Galperine RI, Guenard H, Demarquez JL. Helium-oxygen mixture in respiratory distress syndrome: a double-blind study. J Pediatr. 1993 Jan;122(1):132-6. doi: 10.1016/s0022-3476(05)83506-1.

  PMID: 8419600 BACKGROUND

• Colnaghi M, Pierro M, Migliori C, Ciralli F, Matassa PG, Vendettuoli V, Mercadante D, Consonni D, Mosca F. Nasal continuous positive airway pressure with heliox in preterm infants with respiratory distress syndrome. Pediatrics. 2012 Feb;129(2):e333-8. doi: 10.1542/peds.2011-0532. Epub 2012 Jan 30.

  PMID: 22291116 BACKGROUND

• Szczapa T, Gadzinowski J, Moczko J, Merritt TA. Heliox for mechanically ventilated newborns with bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2014 Mar;99(2):F128-33. doi: 10.1136/archdischild-2013-303988. Epub 2013 Nov 15.

  PMID: 24239984 BACKGROUND

• Szczapa T, Gadzinowski J. Use of heliox in the management of neonates with meconium aspiration syndrome. Neonatology. 2011;100(3):265-70. doi: 10.1159/000327531. Epub 2011 Jun 23.

  PMID: 21701217 BACKGROUND

• Jassar RK, Vellanki H, Zhu Y, Hesek A, Wang J, Rodriguez E, Wu J, Shaffer TH, Wolfson MR. High flow nasal cannula (HFNC) with Heliox decreases diaphragmatic injury in a newborn porcine lung injury model. Pediatr Pulmonol. 2014 Dec;49(12):1214-22. doi: 10.1002/ppul.23000. Epub 2014 Feb 5.

  PMID: 24500982 BACKGROUND

• Sinderby C, Beck J, Spahija J, Weinberg J, Grassino A. Voluntary activation of the human diaphragm in health and disease. J Appl Physiol (1985). 1998 Dec;85(6):2146-58. doi: 10.1152/jappl.1998.85.6.2146.

  PMID: 9843538 BACKGROUND

• Beck J, Reilly M, Grasselli G, Qui H, Slutsky AS, Dunn MS, Sinderby CA. Characterization of neural breathing pattern in spontaneously breathing preterm infants. Pediatr Res. 2011 Dec;70(6):607-13. doi: 10.1203/PDR.0b013e318232100e.

  PMID: 21857389 BACKGROUND

• Brooks LJ, DiFiore JM, Martin RJ. Assessment of tidal volume over time in preterm infants using respiratory inductance plethysmography, The CHIME Study Group. Collaborative Home Infant Monitoring Evaluation. Pediatr Pulmonol. 1997 Jun;23(6):429-33. doi: 10.1002/(sici)1099-0496(199706)23:63.0.co;2-d.

  PMID: 9220525 BACKGROUND

• Nawab US, Touch SM, Irwin-Sherman T, Blackson TJ, Greenspan JS, Zhu G, Shaffer TH, Wolfson MR. Heliox attenuates lung inflammation and structural alterations in acute lung injury. Pediatr Pulmonol. 2005 Dec;40(6):524-32. doi: 10.1002/ppul.20304.

  PMID: 16193495 BACKGROUND

• Kuligowski J, Escobar J, Quintas G, Lliso I, Torres-Cuevas I, Nunez A, Cubells E, Rook D, van Goudoever JB, Vento M. Analysis of lipid peroxidation biomarkers in extremely low gestational age neonate urines by UPLC-MS/MS. Anal Bioanal Chem. 2014 Jul;406(18):4345-56. doi: 10.1007/s00216-014-7824-6. Epub 2014 May 11.

  PMID: 24817352 BACKGROUND

• Kuligowski J, Torres-Cuevas I, Quintas G, Rook D, van Goudoever JB, Cubells E, Asensi M, Lliso I, Nunez A, Vento M, Escobar J. Assessment of oxidative damage to proteins and DNA in urine of newborn infants by a validated UPLC-MS/MS approach. PLoS One. 2014 Apr 2;9(4):e93703. doi: 10.1371/journal.pone.0093703. eCollection 2014.

  PMID: 24695409 BACKGROUND

• Oei GT, Weber NC, Hollmann MW, Preckel B. Cellular effects of helium in different organs. Anesthesiology. 2010 Jun;112(6):1503-10. doi: 10.1097/ALN.0b013e3181d9cb5e.

  PMID: 20460992 BACKGROUND

MeSH Terms

Conditions

Respiratory Distress Syndrome; Premature Birth

Interventions

heliox

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Tomasz Szczapa, M.D. PhD

  Department of Neonatology - Poznan University of Medical Sciences

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy Head - Department of Neonatology; Head - Neonatal Biophysical Monitoring and Cardiopulmonary Therapies Research Unit

Study Record Dates

• First Submitted: May 5, 2020
• First Posted: May 28, 2020
• Study Start: January 1, 2017
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: June 9, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1)