Breathing Variability and NAVA in Neonates

Prematurity Clinical Trial

— BRAVe NANO  

Official title:

Breathing Pattern Variability in Preterm Infants: Effect of Non-invasive Neurally Adjusted Ventilatory Assist (NAVA-NIV) Versus Nasal Intermittent Positive Pressure Ventilation (PC-NIV), a Crossover Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04000568
• Other study ID #: BRAVe NANO (NIV)
• Status: Completed
• Start date: May 2, 2019
• Est. completion date: November 30, 2022

Study information

• Verified date: March 2023
• Source: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The current study is a crossover trial, aiming at evaluating the effect of NAVA -NIV compared to Nasal Intermittent Positive Pressure Ventilation (PC-NIV) at the same level of peak inspiratory pressure, in terms of: breath-by-breath variability of tidal breathing amplitude, variability of the other breathing patterns; lung mechanics; gas exchange; rate of episodes of apnea; bradycardia and desaturations; respiratory asynchrony and comfort, in preterm infants < 37+0 weeks+days post-menstrual age.

Description:

Preterm infants matching the inclusion criteria (listed elsewhere) will be enrolled in a cross- over trial of two modes of non-invasive respiratory support: nasal intermittent positive pressure ventilation (PC-NIV) and NAVA NIV (Sevo-n Neonatal Ventilator, GETINGE, Solna, Sweden). Parental consent will be collected prior to the study. A 20-minute registration of ventilator parameters during assistance on NAVA-NIV will allow calculating the mean PIP (peak inspiratory pressure), in order to compare the two modes at the same level of PIP. The ventilator settings other than PIP (i.e. FiO2 (fraction of inspired oxygen), PEEP (positive end-expiratory pressure), IT (inspiratory time), RR (respiratory rate), NAVA level) will be based on the setting optimized by the attending physicians prior to the study entry. FiO2 will be adjusted in order to maintain SpO2 88-93% in infants ≤ 32 weeks of postconceptional age, 90-95% in infants > 32 weeks of postconceptional age. Infants will then receive a randomized sequence of 1-hour assistance by NAVA NIV and 1-hour assistance PC-NIV or vice-versa. Infants will receive respiratory support in a standardized supine position during the study period.

Two, high-resolution, small cameras will be placed in the infant's incubator to detect chest and abdominal movements, by means of two markers placed on the infant's chest and abdomen. Ventilators parameters (flow, pressure, volume, the electrical activity of the diaphragm), vital signs (SpO2, HR (heart rate), ABP( arterial blood pressure)), transcutaneous gases, changes in end-expiratory lung volume will be collected continuously. Episodes of apnea, bradycardia or desaturations and the number of interventions required by the nurses and the attending physicians during the study (e.g. adjustment of the interface, suctioning, interventions to provide comfort or optimize the respiratory support...) will be also collected during the study. Patients' comfort will be assessed at the end of each sequence by the attending nurse by means of the COMFORT scale. Lung mechanics will be measured at the end of each sequence by means of the Forced Oscillation Technique.

Data will be then analysed and compared offline.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: November 30, 2022
• Est. primary completion date: September 30, 2022
• Gender: All
• Age group: 1 Day to 3 Months

Eligibility

Inclusion Criteria:

• preterm birth < 37 weeks of gestational age

• need of non-invasive respiratory support

• parental consent

Exclusion Criteria:

• Major congenital abnormalities of the cardio-respiratory systems

• Severe Respiratory Failure requiring intubation and mechanical ventilation at the time of the study; pH < 7.25 pCO2> 65 mmHg; pulmonary hypertension of the newborn requiring pharmacological treatment (Nitric Oxide, Sildenafil)

• Hypoxic-Ischaemic Encephalopathy, neurological disorders which may compromise the integrity of the neural transmission from the brain to the diaphragm

• Contraindication to orogastric tube insertion (e.g. oesophageal atresia, gastric perforation...)

• Haemodynamic instability requiring inotropic agents

• Any condition that would expose the patient to undue risk as deemed by the attending physician

Related Conditions & MeSH terms

• Hyaline Membrane Disease
• Neonatal Respiratory Distress Syndrome
• Prematurity
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn

Intervention

Other:
• Respiratory support: NAVA -NIV and PC-NIV
The infants enrolled will receive respiratory assistance by NAVA-NIV and PC-NIV in a randomized order

Locations

Country	Name	City	State
Italy	NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico	Milan	MI

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico	Politecnico di Milano

Country where clinical trial is conducted

Italy, 

References & Publications (28)

Ancel PY, Goffinet F; EPIPAGE-2 Writing Group; Kuhn P, Langer B, Matis J, Hernandorena X, Chabanier P, Joly-Pedespan L, Lecomte B, Vendittelli F, Dreyfus M, Guillois B, Burguet A, Sagot P, Sizun J, Beuchee A, Rouget F, Favreau A, Saliba E, Bednarek N, Morville P, Thiriez G, Marpeau L, Marret S, Kayem G, Durrmeyer X, Granier M, Baud O, Jarreau PH, Mitanchez D, Boileau P, Boulot P, Cambonie G, Daude H, Bedu A, Mons F, Fresson J, Vieux R, Alberge C, Arnaud C, Vayssiere C, Truffert P, Pierrat V, Subtil D, D'Ercole C, Gire C, Simeoni U, Bongain A, Sentilhes L, Roze JC, Gondry J, Leke A, Deiber M, Claris O, Picaud JC, Ego A, Debillon T, Poulichet A, Coline E, Favre A, Flechelles O, Samperiz S, Ramful D, Branger B, Benhammou V, Foix-L'Helias L, Marchand-Martin L, Kaminski M. Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr. 2015 Mar;169(3):230-8. doi: 10.1001/jamapediatrics.2014.3351. Erratum In: JAMA Pediatr. 2015 Apr;169(4):323. Alberge, Catherine [Corrected to Alberge, Corine]. — View Citation

Arold SP, Bartolak-Suki E, Suki B. Variable stretch pattern enhances surfactant secretion in alveolar type II cells in culture. Am J Physiol Lung Cell Mol Physiol. 2009 Apr;296(4):L574-81. doi: 10.1152/ajplung.90454.2008. Epub 2009 Jan 9. — View Citation

Arold SP, Malavia N, George SC. Mechanical compression attenuates normal human bronchial epithelial wound healing. Respir Res. 2009 Feb 12;10(1):9. doi: 10.1186/1465-9921-10-5. — View Citation

Arold SP, Mora R, Lutchen KR, Ingenito EP, Suki B. Variable tidal volume ventilation improves lung mechanics and gas exchange in a rodent model of acute lung injury. Am J Respir Crit Care Med. 2002 Feb 1;165(3):366-71. doi: 10.1164/ajrccm.165.3.2010155. — View Citation

Arold SP, Suki B, Alencar AM, Lutchen KR, Ingenito EP. Variable ventilation induces endogenous surfactant release in normal guinea pigs. Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L370-5. doi: 10.1152/ajplung.00036.2003. — View Citation

Bartolak-Suki E, Noble PB, Bou Jawde S, Pillow JJ, Suki B. Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs. Front Physiol. 2017 Jun 23;8:425. doi: 10.3389/fphys.2017.00425. eCollection 2017. — View Citation

Baudin F, Wu HT, Bordessoule A, Beck J, Jouvet P, Frasch MG, Emeriaud G. Impact of ventilatory modes on the breathing variability in mechanically ventilated infants. Front Pediatr. 2014 Nov 25;2:132. doi: 10.3389/fped.2014.00132. eCollection 2014. — View Citation

Bellardine CL, Hoffman AM, Tsai L, Ingenito EP, Arold SP, Lutchen KR, Suki B. Comparison of variable and conventional ventilation in a sheep saline lavage lung injury model. Crit Care Med. 2006 Feb;34(2):439-45. doi: 10.1097/01.ccm.0000196208.01682.87. — View Citation

Berry CA, Suki B, Polglase GR, Pillow JJ. Variable ventilation enhances ventilation without exacerbating injury in preterm lambs with respiratory distress syndrome. Pediatr Res. 2012 Oct;72(4):384-92. doi: 10.1038/pr.2012.97. Epub 2012 Jul 17. — View Citation

Bhandari V. The potential of non-invasive ventilation to decrease BPD. Semin Perinatol. 2013 Apr;37(2):108-14. doi: 10.1053/j.semperi.2013.01.007. — View Citation

Costeloe K, Hennessy E, Gibson AT, Marlow N, Wilkinson AR. The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics. 2000 Oct;106(4):659-71. doi: 10.1542/peds.106.4.659. — View Citation

de la Oliva P, Schuffelmann C, Gomez-Zamora A, Villar J, Kacmarek RM. Asynchrony, neural drive, ventilatory variability and COMFORT: NAVA versus pressure support in pediatric patients. A non-randomized cross-over trial. Intensive Care Med. 2012 May;38(5):838-46. doi: 10.1007/s00134-012-2535-y. Epub 2012 Apr 6. — View Citation

Doyle LW, Carse E, Adams AM, Ranganathan S, Opie G, Cheong JLY; Victorian Infant Collaborative Study Group. Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years. N Engl J Med. 2017 Jul 27;377(4):329-337. doi: 10.1056/NEJMoa1700827. — View Citation

Dumpa V, Bhandari V. Surfactant, steroids and non-invasive ventilation in the prevention of BPD. Semin Perinatol. 2018 Nov;42(7):444-452. doi: 10.1053/j.semperi.2018.09.006. Epub 2018 Oct 2. — View Citation

Firestone KS, Beck J, Stein H. Neurally Adjusted Ventilatory Assist for Noninvasive Support in Neonates. Clin Perinatol. 2016 Dec;43(4):707-724. doi: 10.1016/j.clp.2016.07.007. — View Citation

Garcia-Munoz Rodrigo F, Urquia Marti L, Galan Henriquez G, Rivero Rodriguez S, Hernandez Gomez A. Neural breathing patterns in preterm newborns supported with non-invasive neurally adjusted ventilatory assist. J Perinatol. 2018 Sep;38(9):1235-1241. doi: 10.1038/s41372-018-0152-5. Epub 2018 Jun 18. — View Citation

Gibu CK, Cheng PY, Ward RJ, Castro B, Heldt GP. Feasibility and physiological effects of noninvasive neurally adjusted ventilatory assist in preterm infants. Pediatr Res. 2017 Oct;82(4):650-657. doi: 10.1038/pr.2017.100. Epub 2017 Jul 12. — View Citation

Hennessy EM, Bracewell MA, Wood N, Wolke D, Costeloe K, Gibson A, Marlow N; EPICure Study Group. Respiratory health in pre-school and school age children following extremely preterm birth. Arch Dis Child. 2008 Dec;93(12):1037-43. doi: 10.1136/adc.2008.140830. Epub 2008 Jun 18. — View Citation

Lee J, Kim HS, Jung YH, Shin SH, Choi CW, Kim EK, Kim BI, Choi JH. Non-invasive neurally adjusted ventilatory assist in preterm infants: a randomised phase II crossover trial. Arch Dis Child Fetal Neonatal Ed. 2015 Nov;100(6):F507-13. doi: 10.1136/archdischild-2014-308057. Epub 2015 Jul 15. — View Citation

Longhini F, Ferrero F, De Luca D, Cosi G, Alemani M, Colombo D, Cammarota G, Berni P, Conti G, Bona G, Della Corte F, Navalesi P. Neurally adjusted ventilatory assist in preterm neonates with acute respiratory failure. Neonatology. 2015;107(1):60-7. doi: 10.1159/000367886. Epub 2014 Nov 7. — View Citation

Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB; COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008 Feb 14;358(7):700-8. doi: 10.1056/NEJMoa072788. Erratum In: N Engl J Med. 2008 Apr 3;358(14):1529. — View Citation

Peng CK, Havlin S, Stanley HE, Goldberger AL. Quantification of scaling exponents and crossover phenomena in nonstationary heartbeat time series. Chaos. 1995;5(1):82-7. doi: 10.1063/1.166141. — View Citation

Stein H, Alosh H, Ethington P, White DB. Prospective crossover comparison between NAVA and pressure control ventilation in premature neonates less than 1500 grams. J Perinatol. 2013 Jun;33(6):452-6. doi: 10.1038/jp.2012.136. Epub 2012 Oct 25. — View Citation

Stein H, Beck J, Dunn M. Non-invasive ventilation with neurally adjusted ventilatory assist in newborns. Semin Fetal Neonatal Med. 2016 Jun;21(3):154-61. doi: 10.1016/j.siny.2016.01.006. Epub 2016 Feb 16. — View Citation

Stein H, Firestone K. Application of neurally adjusted ventilatory assist in neonates. Semin Fetal Neonatal Med. 2014 Feb;19(1):60-9. doi: 10.1016/j.siny.2013.09.005. Epub 2013 Nov 13. — View Citation

SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network; Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, Yoder BA, Faix RG, Das A, Poole WK, Donovan EF, Newman NS, Ambalavanan N, Frantz ID 3rd, Buchter S, Sanchez PJ, Kennedy KA, Laroia N, Poindexter BB, Cotten CM, Van Meurs KP, Duara S, Narendran V, Sood BG, O'Shea TM, Bell EF, Bhandari V, Watterberg KL, Higgins RD. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010 May 27;362(21):1970-9. doi: 10.1056/NEJMoa0911783. Epub 2010 May 16. Erratum In: N Engl J Med. 2010 Jun 10;362(23):2235. — View Citation

Thammanomai A, Hueser LE, Majumdar A, Bartolak-Suki E, Suki B. Design of a new variable-ventilation method optimized for lung recruitment in mice. J Appl Physiol (1985). 2008 May;104(5):1329-40. doi: 10.1152/japplphysiol.01002.2007. Epub 2008 Mar 13. Erratum In: J Appl Physiol. 2008 Jun;104(6):1856. — View Citation

Zannin E, Veneroni C, Dellaca RL, Corbetta R, Suki B, Tagliabue PE, Ventura ML. Effect of continuous positive airway pressure on breathing variability in early preterm lung disease. Pediatr Pulmonol. 2018 Jun;53(6):755-761. doi: 10.1002/ppul.24017. Epub 2018 Apr 23. — View Citation

* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patient's comfort: COMFORT-B scale	Patient's comfort will be assessed by the attending nurse at the end of each step by means of the COMFORT-B scale (COMFORT behavioural scale). The COMFORT-B scale is a validated tool for assessing patients' comfort in Pediatric Intensive Care Unit.It includes the following items for comfort evaluation: alertness, calmness, respiratory response, cry, physical movements, muscle tone, facial tension. For each item a descriptive scale form 1 (the best) to 5 (the worst) is indicated and the operator can choose what is the most appropriate for the patient.	at the end of each 1-hour step
Other	Number of caregivers interventions required	The number of interventions required to the attending personnel during each step will be also recorded: for instance interventions to improve comfort, to adjust the ventilator interface, to optimize the efficacy of respiratory support, suctioning ...	at the end of each 1-hour step
Primary	Change in breath-by-breath variability of tidal breathing amplitude	Tidal breathing amplitude will be recorded continuously by mean of two, high-resolution cameras placed inside the infant's incubator and skin (non-invasive) markers. Data will be analysed a posteriori applying the DFA (Detrended Fluctuation Analysis) technique.	over the last 30 minutes of each step (crossover trial, 2 steps, 1 hour-step)
Secondary	Respiratory Rate	Respiratory rate (breaths/min) will be recorded from the ventilator	at the beginning of the study, at 10minutes, 20minutes, 30minutes, 35minutes, 40minutes, 45minutes, 50minutes, 55minutes, for each step, in a 2-step crossover trial, 1-hour step
Secondary	Inspiratory Time	Inspiratory time (msec) will be recorded from the ventilator tracing	at the beginning of the study, at 10minutes, 20minutes, 30minutes, 35minutes, 40minutes, 45minutes, 50minutes, 55minutes, for each step, in a 2-step crossover trial, 1-hour step
Secondary	Duty Cycle	Duty Cycle (Inspiratory Time/ Total Time), will be calculated from the ventilator tracing	at the beginning of the study, at 10minutes, 20minutes, 30minutes, 35minutes, 40minutes, 45minutes, 50minutes, 55minutes, for each step, in a 2-step crossover trial, 1-hour step
Secondary	Total Respiratory System Oscillatory Resistance	Total Respiratory System Oscillatory Resistance will be measured by the Forced Oscillation Technique (FOT) at the end of each step, by superimposing to the ventilator waveform an oscillatory pressure of small amplitude at 10 Hz (Fabian, ACUTRONIC Medical Systems AG, Switzerland).	at the end of each 1-hour step of the trial (crossover trial, 2 steps, 1 hour-step)
Secondary	Total Respiratory System Oscillatory Reactance	Total Respiratory System Oscillatory Reactance will be measured by the Forced Oscillation Technique (FOT) at the end of each step, by superimposing to the ventilator waveform an oscillatory pressure of small amplitude at 10 Hz (Fabian, ACUTRONIC Medical Systems AG, Switzerland).	at the end of each 1-hour step of the trial (crossover trial, 2 steps, 1 hour-step)
Secondary	SpO2/FiO2 (Fraction on inspired oxygen)	SpO2 and FiO2 will be monitored continuously and FiO2 will be adjusted to the target SpO2 88-93% in infants = 32 weeks of postconceptional age, SpO2 90-95% in infants > 32 weeks of postconceptional age.	at the beginning of the study, at 10minutes, 20minutes, 30minutes, 35minutes, 40minutes, 45minutes, 50minutes, 55minutes, for each step, in a 2-step crossover trial, 1-hour step
Secondary	tpCO2, Transcutaneous Carbon Dioxide Partial Pressure (mmHg)	tpCO2 will be monitrored continuously over the study period and recorded at specific time points	at the beginning of the study, at 10minutes, 20minutes, 30minutes, 35minutes, 40minutes, 45minutes, 50minutes, 55minutes, for each step, in a 2-step crossover trial, 1-hour step
Secondary	Rate of apneas, desaturations, bradycardias	Episodes of apnoeas, desaturations, bradycardias will be recorded over each study period	over 1 hour, for each step (in a 2-step crossover trial, 1-hour step)
Secondary	Rate of patient-ventilator asynchronies	Patient-ventilator asynchronies will be calculated by continuous recording of ventilator parameters (flow, pressure, volume and electrical diaphragmatic activity) and by continuous recording of abdominal and chest movements by high resolution cameras placed in the incubators and skin markers on abdomen and chest	over 1 hour, for each step (in a 2-step crossover trial, 1-hour step)