Lung ultrasound to understand response to treatment in premature infants who have breathing difficulty due to lung immaturity

Completed

• Conditions: Respiratory distress syndrome of newborn,

• Registration Number: CTRI/2023/07/055318
• Lead Sponsor: Dr Anup Thakur

Brief Summary

**AIMS AND OBJECTIVES**

**AIM -** To evaluate the role of lung USG score in management of preterm neonates ≤34 weeks gestation with RDS.

**Primary Objective**

·       To evaluate the predictive ability of lung USG score for response to surfactant replacement therapy inpreterm neonates £34 weeks with respiratory distress syndrome, requiring respiratory support within 6 hours of birth.

**Secondary Objectives**

To evaluate the following in preterm neonates £34 weeks with respiratory distress syndrome needing respiratory support within 6 hours of birth:

·       Predictive ability of lung USG score to identify neonates who would need FiO2 > 0.30 in first 6 hours of life.

·       Predictive ability of lung USG score for successful extubation in first 72 hours of life.

·       Predictive ability of lung USG score for successful discontinuation of non-invasive ventilation (CPAP or HHHFNC) in first week of life.

·       Lung USG scores pre-surfactant and 6 hours post surfactant therapy.

·       Correlation of lung USG score with oxygenation indices pre-surfactant and 6 hours post surfactant therapy.

**METHODS**

**Study area:** The study will be conducted in the NICU of Sir Ganga Ram Hospital, New Delhi.

**Study design:** This will be aprospective observational study.

**Study duration:** The study will be conducted after approval from institutional ethics committee till completion of sample size.

**Study population:** All intramural preterm neonates ≤ 34 weeks gestational age will be screened for enrolment.

Inclusion Criteria

·       Preterm neonates ≤ 34 weeks gestational age, who need respiratory support within 6 hours of birth will be included.

Exclusion Criteria:

The following neonates will be excluded from the study:

·       Gestational age less than 26 weeks.

·       Extramural neonates.

·       Suspected chromosomal anomalies or major congenital malformations.

·       Suspected meconium aspiration syndrome or congenital pneumonia.20

·       Neonates who receive surfactant in delivery room.

·       Neonates who are hemodynamically unstable and require inotropes.

·       Neonates who need extensive delivery room resuscitation such as chest compression and or medications.

·       Failure to obtain parental consent.

**Outcome measures:**

**Primary Outcome Measure**

Predictive ability of lung USG score for response to surfactant replacement therapy in preterm neonates £34 weeks with respiratory distress syndrome requiring respiratory support within 6 hours of birth.

**Secondary Outcome Measures**

·       Lung USG score to identifyneonates who would need FiO2 > 0.30 in first 6 hours of life.

·       Lung USG score for successful extubation in first 72 hours of life.

·       Lung USG score for successful discontinuation of non-invasive ventilation (CPAP or HHHFNC) in first week of life.

·       Lung USG scores pre-surfactant and 6 hours post surfactant replacement therapy.

·       Lung USG score and oxygenation indices pre-surfactant and 6 hours post surfactant replacement therapy.

**M****ethodology**

All preterm neonates ≤34 weeks gestation who develop respiratory distress at or within 6 hours of birth will be assessed for eligibility. Resuscitation in delivery room will be done as per neonatal resuscitation protocol (NRP) guidelines.21 Respiratory distress will be defined as presence of intercostal and subcostal retraction or grunting shortly after birth and will be graded by Downe score.22 Neonates who develop respiratory distress after birth will be started on continuous positive airway pressure (CPAP) in delivery room by T piece resuscitator and will be transferred to neonatal intensive care unit (NICU) after stabilization in a transport incubator on nasopharyngeal CPAP. Neonates who require intubation in delivery room will be transferred to NICU on mechanical ventilation. In the NICU, neonates requiring respiratory support in the form of heated humidified high flow nasal cannula (HHHFNC) or CPAP or invasive ventilation will be enrolled. Informed consent will be obtained from either parent before enrolment.

RDS will be managed according to standard guidelines.2 Target pre-ductal saturation for neonates on any form of respiratory support will be 90-94%. Neonates on invasive ventilation will be given SRT via endotracheal tube, if FiO2 requirements increase beyond 0.30. Neonates who are supported on HHHFNC will be started on a flow rate of 6-8 l/min and FiO2 will be titrated as per target saturation. In case of failure of HHHFNC, neonates will be rescued by CPAP and supported on PEEP of at least 5 cm of H2O.  Neonates who need CPAP with FiO2 requirements of more than 0.30 and PEEP of at least 6 cm H2O will be given surfactant either through endotracheal tube or via laryngeal mask airway (Surfactant administration through laryngeal and supraglottic airways; SALSA technique) at discretion of attending neonatologist. Extubation will be attempted in neonates who receive SRT through endotracheal tube as per unit protocol to follow the Intubation Surfactant Extubation (InSurE) strategy. Following SRT by SALSA/ InSurE technique, neonates will be put on CPAP/HHHFNC support. Discontinuation of non-invasive ventilation will be considered for neonates on CPAP at a PEEP of <5 cm of H2O and on HHHFNC at flow rates of <6l/min with FiO2 0.21. All neonates less than 30 weeks gestation will receive caffeine loading dose at 20 mg/kg followed by maintenance dose of 5 mg/kg/day. Neonates between 30-34 weeks of gestation will be given caffeine in cases of repeated desaturations or any episode of apnea requiring stimulation. Blood gases and chest radiography will be done if deemed necessary as per the discretion of attending neonatologist. Oxygenation index or oxygen saturation index and ratio of preductal SPO2/FiO2 will be calculated before and 6 hours after SRT.

Neonates who fail on CPAP or HHHFNC following SRT will be intubated if any of the following occurs: apnoea despite caffeine therapy, Downe score >7, severe respiratory acidosis with pH < 7.2, PCO2 > 65 mmHg or FiO2 requirements >0.50. A second dose of SRT will be given if FiO2 requirements remain above 0.40 even after 6-8 hours of previous SRT. For neonates who need invasive ventilation, titration of ventilator parameters will be done to achieve a tidal volume 4-6ml/kg, oxygen saturation of 90-94% and acceptable blood gas parameters. Once mean airway pressure (MAP) decreases to less than 9 cm of H2O and FiO2 requirements are less than 0.30, extubation to HHHFNC/CPAP will be considered. Management of apnoea, pain, sedation, nutrition and fluid requirements will be done as per unit protocol. Morbidities such as BPD23, Intraventricular haemorrhage (IVH) ³ grade 324, Necrotising enterocolitis stage 2 or beyond25 and sepsis will be defined as per standard criteria.

**Ultrasound protocol**

Enrolled neonates will be evaluated with lung USG and score will be calculated. Care will be taken to ensure adequate oxygenation and temperature regulation throughout the USG study. Bedside nurse will be available to assist in calming the neonate. One of investigators certified in lung and critical ultrasound will provide training to two other investigators over a period of two weeks. Following satisfactory completion of training, lung USG will be performed on 20 neonates with RDS and score will be assigned by all three investigators blinded to each other findings. Inter-observer agreement will be tested by Kendall’s W coefficient of concordance.

Longitudinal scans of anterior, lateral and posterior chest wall will be performed using portable Sonosite M turbo USG machine with linear probe of 8-13 MHz frequency. The lung USG transducer will be adjusted until a bat sign is achieved and depth will be adjusted till sharpest pleural line is seen. Both static images and video clips will be recorded and stored in flashcard of USG machine. Lung USG score will be calculated by dividing each lung into 3 chest areas: anterior, lateral, and posterior. Anterior area will be defined as area between sternum and anterior axillary line, lateral area between anterior and posterior axillary line and posterior area between posterior axillary line and the spine as shown in figure 4 and 5. USG probe will be kept at midclavicular line for anterior area, anterior axillary line for lateral area and at posterolateral alveolar and pleural syndrome (PLAPS) point12 (as posterior as possible to the posterior axillary line) for posterior area.

Lung USG score of 0-3 pointswill be given to each area as described below-

·       Score of 0 will be assigned when only A pattern and lung sliding is present.

·       Score of 1 will be assigned if there is presence of more than 3 well-spaced B lines

·       Score of 2 will be assigned for crowded or compact B lines with or without sub-pleural consolidations.

·       Score of 3 will be assigned for extended consolidations.

Total lung USG score will range from 0-18. A Pattern/ B Lines /sub-pleural consolidations /extensive consolidation will be defined as per Lichenstein lung USG criteria.26

**Time Points of Lung USG**

Lung USG will be performed within 30 minutes of NICU admission (pre-surfactant), 6 hours after SRT, before extubating to non-invasive ventilation (CPAP or HHHFNC), before discontinuation of  non-invasive ventilation (CPAP or HHHFNC) and before surfactant re-treatment.

**Definitions of outcome measures**

·       Response to surfactant replacement therapy will be defined as decrease in FiO2 requirement to <0.30 and flow of <6 l/min on HHHFNC or PEEP of £ 6 cm of H2O on CPAP or MAP £ 8 cm of H2O on mechanical ventilation within 6 hours of SRT, with acceptable oxygen saturation (90-94%) sustained for at least one hour and no requirement of surfactant retreatment in next 24 hours.

·       Successful extubation will be defined as no requirement of invasive ventilation till 48 hours following extubation.

·       Discontinuation of non-invasive ventilation will be considered if neonate is on room air for at least 48 hours after stopping CPAP or HHHFNC.

·       Oxygenation parameters will be measured before and 6 hours after SRT. The following parameters will be noted-

o   SPO2/FiO2 (S/F) ratio: ratio of preductal SPO2 and FiO2

o   Oxygenation index (OI): FiO2/PaO2 ´ Mean airway pressure

o   Oxygen saturation index (OSI): FiO2/SPO2 ´ Mean airway pressure.

**Data collection methods**: Data will be collected in predesigned proforma and entered in MS Excel software. Data will include demographic profile, clinical data, lung USG score and other outcome measures.

**Statistical methods**

**Sample size**: Most studies on lung USG that have predicted the need for surfactant replacement therapy have an AUC between 0.70 to 0.94.5,6,13 Studies which have evaluated lung USG score for successful extubation have AUC between 0.70 to 0.95.9-11 Since there are no studies that have evaluated the predictive ability of lung ultrasound score for response to surfactant replacement therapy, we assume an expected AUC of at least 0.75. During last one year, in our NICU, 60 preterm neonates less than 34 weeks required SRT and out of them 12 required surfactant re-treatment. Therefore, we anticipate a ratio of SRT response (positive cases) to no response (negative cases) as 5:1. For an estimated power of 80 % and alpha error of less than 0.05, the calculated sample size is of 65 neonates of whom we will need 54 positive cases and 11 negative cases.

For estimation of sample size, the following formula has been used

n= Z2α/2 V (AUC)/d2

**Where:**

AUC is the expected area under the ROC curve

Zα/2= 1.96 for 95% confidence interval

d is the margin of error

V (AUC) = 0.0099 x exp (-a2/2). (6a2+16)

a = φ-1(AUC) x 1.414, Ï†-1 is inverse of the standard cumulative normal distribution

 **Statistical analytical methods**:

Analysis of data will be done by using SPSS software version 28. For evaluating the predictive value of lung USG score, Receiver operating characteristic (ROC) curves would be constructed to determine the optimal cut-off value and AUC will be determined for the outcome measures. For comparison of two ROC curves Hanley and McNeil method will be used.27 Kendall’s W coefficient of concordance will be used for measuring agreement of ultrasound measurements between the three investigators. Correlation will be calculated using Spearman / Pearson correlation coefficient. Diagnostic accuracy will be calculated using various statistical measures, such as sensitivity, specificity, positive predictive value, negative predictive value and likelihood ratio. P value of <0.05 will be considered statistically significant.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-01-08
• Study Completion: 2024-10-07
• Last Update Posted: 2024-10-07

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 65

Inclusion Criteria

Preterm neonates ≤ 34 weeks gestational age, who need respiratory support within 6 hours of birth will be included.

Exclusion Criteria

• The following neonates will be excluded from the study: 1.
• Gestational age less than 26 weeks.
• Extramural neonates.
• Suspected chromosomal anomalies or major congenital malformations.
• Suspected meconium aspiration syndrome or congenital pneumonia.
• Neonates who receive surfactant in delivery room.
• Neonates who are hemodynamically unstable and require inotropes.
• Neonates who need extensive delivery room resuscitation such as chest compression and or medications.

Study & Design

• Study Type: Observational
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Predictive ability of lung USG score for response to surfactant replacement therapy in preterm neonates less than 34 weeks with respiratory distress syndrome requiring respiratory support within 6 hours of birth.	within 6 hours of life

Secondary Outcome Measures

Name	Time	Method
1. Lung USG score to identify neonates who would need FiO2 more than 0.30 in first 6 hours of life.	2. Lung USG score for successful extubation in first 72 hours of life.

Trial Locations

Locations (1)

Sir Ganga Ram Hospital; 🇮🇳 Central, DELHI, India

Sir Ganga Ram Hospital

🇮🇳Central, DELHI, India

Dr Anup Thakur

Principal investigator

8800565956

dr.thakuranup@gmail.com