Abstract
Purpose
Concerns remain on different alveolar deposition of surfactant between LISA and INSURE methods. Ultrasound evaluation of diaphragm kinetics may provide clinical evidence on this issue, as indirect representation of the respiratory system compliance.
Methods
This was a prospective-observational pilot study. The inclusion criterion was CPAP-supported infants ≤ 32 weeks with RDS receiving surfactant via minimally invasive technique. 52 patients randomized for surfactant administration via LISA or INSURE methods were enrolled. Right diaphragm (RD) global mean peak velocity (MPV) by Pulsed-Wave Tissue Doppler Imaging (PTDI) was recorded before and two hours after surfactant administration with simultaneous measurements of oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) (SF ratio). Mechanical ventilation ≤ 72 h from birth represented treatment failure.
Results
LISA infants had significantly higher gestational age (p = 0.029) and birth weight (p = 0.030) with lower CRIB-II scores (p = 0.030) than INSURE infants. LISA infants showed higher median MPV at baseline RD-PTDI US assessment (p = 0.024), but post-surfactant median MPV and other the investigated variables were similar at the adjusted analysis for gestational age and sedation. 8/52 (15%) infants who failed treatment had a significantly lower SF ratio (p = 0.002) and higher median MPV at RD-PTDI US (p = 0.004) after surfactant administration, despite the higher CPAP support level before (p = 0.007) and after (p = 0.001) surfactant administration. A full course of antenatal steroids was protective against mechanical ventilation (p = 0.038).
Conclusions
Different minimally invasive surfactant administration techniques do not appear to influence diaphragm kinetics evaluated by RD-PTDI US.
Keywords: CPAP, Diaphragm ultrasound, INSURE, LISA, Preterm infant
Introduction
The current trend in neonatal intensive care unit (NICU) is to provide early non-invasive respiratory support with continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) in the spontaneously breathing preterm infants with respiratory distress syndrome (RDS), to prevent the risks associated with even brief periods of tracheal intubation [1–3]. This means that conventional method of surfactant administration is unavailable. To address potential harms of late/ineffective surfactant administration [4], LISA (Less Invasive Surfactant Administration) or INtubation-SURfactant-Extubation (INSURE) methods are currently used to meet both lung protection and surfactant supplementation needs [5, 6], despite the risk of overestimating the clinical potential of the LISA technique [7]. However, as many as one-third of extremely preterm infants require mechanical ventilation, with increased mortality and major morbidity [8, 9]. Now, the question we should attempt to answer is how to improve our clinical practice to reduce this dangerous failure rate.
Point-of-care-ultrasound (POCUS) is used for a broad range of diagnostic and procedural applications in NICU [10]. While POCUS applications have spread to include the assessment of diaphragm motion in both adults and children [11, 12], limited information is still available in term and preterm infants [13–20], who are particularly prone to develop diaphragmatic dysfunction in case of increased respiratory workload. Among available US techniques, right diaphragmatic (RD) Pulsed-Wave Tissue Doppler Imaging (PTDI) may be useful in neonatology due to its repeatability, fast learning curve, availability of normative data and wide diffusion of software package in current US machines [21, 22]. Allowing real-time assessment of the velocity of the tissue movement during contraction and relaxation, RD-PTDI has recently been proposed as a means to evaluate diaphragm kinetics both in healthy individuals and in intubated patients weaning from mechanical ventilation [22, 23] as well as in the CPAP-supported preterm infants with RDS [24].
The rationale for measuring RD-PTDI parameters of the peak inspiratory (I-Peak) and expiratory (E-Peak) velocities of diaphragm excursions is that the greater the diaphragmatic activation, as evidenced by the increase of peak velocities of the diaphragm excursion, the greater the diaphragmatic fatigue [22].
The aim of this study was to investigate whether any changes in diaphragm kinetics, as assessed by RD-PTDI US, occur in CPAP-supported preterm infants with RDS due to the different minimally invasive method of surfactant administration used. As secondary endpoints, we looked for any early signs of diaphragm impairment in infants who subsequently fail the “gentle” respiratory management strategy, as well as potential effects of sedation/analgesia on diaphragm kinetics in this population of infants.
Materials and methods
Beginning in July 2017, we planned to investigate the adaptations of RD movement to CPAP support and minimally invasive surfactant delivery techniques by means of two subsequent and closely related clinical trials. Both studies were conducted following the ethical standards of the responsible regional committee on human experimentation (Ethical Committee of the Health Authorities of the Umbria Region—CER) and with the Helsinki Declaration of 1975. All patients’ parents/caregivers and healthcare professionals have signed a written informed consent. Since the studies were closely related in terms of enrollment and treatment criteria, the possibility of using the patient data belonging to the first study also for the second without the need to provide further consent to data processing was implicit.
All spontaneously breathing preterm infants consecutively born at our institution ≤ 32 weeks of gestational age, with RDS and CPAP support from the delivery room, were eligible for both clinical trials. Exclusion criteria included chromosomal abnormalities or complex congenital malformations, congenital lung diseases, early onset severe sepsis as well as septic shock, the need for surgery in the first week of life, congenital heart defects, and any ventilation support due to non-respiratory disease. Respiratory care was provided according to the European guidelines [25] as below reported, with no substantial changes occurred during the entire period of the two clinical studies. Mechanical ventilation was mandatory at any time if significant respiratory effort was concomitant with increased oxygen demand (FiO2 ≥ 0.3) and respiratory acidosis (ph < 7.25), otherwise, infants remained supported merely by CPAP. Minimally invasive administration of poractant α (Curosurf; Chiesi Farmaceutici, Parma, Italy) (200 mg/kg) was mandatory within the first hours of life if FiO2 was ≥ 0.3 despite CPAP support and if chest X-ray demonstrated RDS due to hyaline membrane disease. Patients’ assignment to the LISA or INSURE technique was established prior to the start of both clinical studies and based on a list obtained by simple randomization, hidden from the neonatologist in charge of treatment and saved in a password-protected file stored on an external server, which was accessible only to the study director (MR). The decision to randomize the minimally invasive surfactant administration technique from the outset was motivated by the possibility to use data records of patients who received surfactant in the first clinical study also for the second, given the low number of admissions to our NICU at these low gestational ages. Furthermore, since our NICU has never adopted one of these two minimally invasive surfactant administration techniques as standard practice, this would have helped to avoid potential selection bias.
The first clinical trial (study code: MOV PG-03; CER registration number: 3095/17) [24] consisted of a two-year prospective observation focusing on differences in diaphragm kinetics among preterm infants with early CPAP failure (defined as surfactant administration by the LISA or INSURE method and/or mechanical ventilation ≤ 72 h after birth) compared to those who remained stable on CPAP support.
In the current clinical trial, started on July 2019, (study code: MOV PG-04; CER registration number: 3800/19) we focused on differences of diaphragm kinetics potentially attributable to the different minimally invasive surfactant administration techniques. Mechanical ventilation due to a worsening RDS within 72 h from birth represented treatment failure in the current trial. Mechanical ventilation due to other non-respiratory causes was not considered as failure in both clinical trials. A required sample size of 26 infants for each group at study in this pilot study was calculated to gain 90% power to detect differences between the LISA and INSURE methods in the future main trial at a small-standardized difference. Since the enrollment, treatment and evaluation criteria have been the same for both studies, data from CPAP-supported preterm infants treated with minimally invasive surfactant administration from the first clinical trial [24] were also used for the analysis in the current one. The incidence of any grade of cerebral hemorrhage (ICH), pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD), hemodynamically significant ductus arteriosus (HSDA), periventricular leukomalacia (PLV), necrotizing enterocolitis (NEC), pneumothorax (PNX) as well as the duration of invasive and non-invasive ventilation, oxygen requirement and hospital stay were reported and analyzed as secondary outcomes.
Respiratory care
CPAP was applied from the delivery room employing a T-Piece device (Neopuff™—Fisher & Paykel Healthcare Ltd, Panmure, Auckland 1741,NZ), and continued thereafter using the Infant Flow® LP CPAP system (Care Fusion, Yorba Linda, CA) connected to the face mask. Pressure support was set at 6 cm H2O and FiO2 adjusted to maintain pre-ductal oxygen saturation within the target range of 90 to 94%. Intravenous caffeine citrate (20 mg/Kg) was administered as soon as the umbilical venous catheter was placed.
Minimally invasive surfactant administration
In the LISA technique, surfactant was administered to the CPAP-supported infants in approximately 1 to 2 min via a 3.5 Fr. umbilical catheter, orally introduced into the larynx under direct laryngoscopy.
In the INSURE technique, infants were intubated with an appropriately sized endotracheal tube and received surfactant as a rapid bolus. During the procedure, infants underwent synchronized intermittent positive pressure ventilation, setting parameters to achieve a tidal volume of 8 mL/kg, as per our usual practice. All infants were extubated immediately after a few minutes from surfactant administration and again supported with CPAP.
Analgesia/sedation for surfactant administration
Analgesia/sedation for the procedure was not mandatory but decided by the neonatologist in charge of the treatment, while premedication with atropine was never used. In case of administration, it was possible to use only one of the following schemes: fentanyl, administered i.v. at 1 mcg/kg in 10 min, or fentanyl, administered i.v. at 2 mcg/kg in 10 min, or propofol, administered i.v. at 0.5 mg/kg as rapid bolus, or a combination thereof. A 4-point Likert scale compiled independently by both the operator and an external observer was used to define the patient's tolerance to the procedure. The level of patient-perceived agitation was defined as none, mild, moderate, and severe. The number of attempts to perform surfactant administration as well as any complications occurred during the procedure was also annotated. Heart rate, respiratory rate, blood pressure, and SF ratio were recorded in each infant before surfactant administration and after 1, 5 and 15 min.
Right diaphragm–pulsed-wave tissue doppler imaging (RD-PTDI)
A thorough description about the rationale for using this technique in the newborn, methodology, reproducibility, and neonatal reference values is reported elsewhere [21]. Infants were assessed by using a Doppler US scanner (Vivid S5; GE Healthcare, Milwaukee, WI) connected to a 5-MHz sector transducer. The I-Peak and E-Peak velocities of the RD diaphragm excursion were recorded in the PTDI mode, as shown in Fig. 1, immediately before and two hours after surfactant administration. Measurements were derived from ten respiratory cycles and the resulting global mean peak velocity (MPV) of diaphragm excursion was used for the analysis in each infant.
Fig. 1.
Right diaphragm pulsed wave tissue Doppler imaging. A B-mode imaging of the right hemidiaphragm. The white arrow shows the right diaphragmatic line beneath the hepatic vein confluence chosen as the anatomic landmark. B Pulsed wave tissue Doppler spectral trace of the right hemidiaphragm motion
Other measured parameters
Along with both RD-PTDI assessments, we reported the level of CPAP support, transcutaneous partial pressure of carbon dioxide (PCO2), FiO2, and pre-ductal SpO2 (to derive the SF ratio) as measures of RDS severity.
Statistical analysis
A pilot trial sample size of 26 infants for each group at study allows a 90% powered future main trial at a small [26] (0.1 ≤ δ < 0.3) standardized difference [27]. A simple randomization of the study subjects to receive surfactant via the LISA or INSURE methods was performed by using the Excel function = RAND ().
The Shapiro–Wilk test was used to assess the normal distribution of variables and due to their asymmetry, the Mann–Whitney's U-test was applied for comparisons of non-normally distributed continuous and discrete variables. The Chi-square test with Yate’s continuity correction and Fisher’s exact test were used for the comparisons of categorical variables. Correlations was checked using the Spearman’s rho correlation coefficient.
To adjust the main effects between the subject factors for covariates we performed the Generalized Linear Models (GLMs) analysis that can be used when measuring the effect of a treatment in groups with different basal characteristics and is robust to violations of the assumption of normality of the residuals [28]. GLMs can also be applied to count or binary responses. To check the goodness of fit of linear models (continue variables) we inspected the pattern of residuals, whereas for logistic models (binary variables) we applied the Hosmer and Lemeshow test. Multicollinearity was checked using the Variance Inflation Factor (VIF) and if present (VIF > 2.5) has been addressed removing some of the highly correlated covariates [29].
All statistical analysis were performed using IBM-SPSS® version 26.0 (IBM Corp., Armonk, NY, USA, 2019). In all analyses, a two-sided p-value < 0.05 was considered significant.
Results
In this prospective observational pilot trial, 52 infants were randomly assigned to the LISA (n = 26) or INSURE (n = 26) methods.
INSURE infants had significantly lower gestational age and birth weight and, consequently, higher CRIB-II scores than LISA infants. Although LISA infants showed greater diaphragmatic activity at baseline, as expressed by higher median MPV values, this difference was no longer observed after surfactant administration, as well as for all the other variables analyzed, at the GLMs analysis adjusted for gestational age and analgesia/sedation (Table 1). 8/52 (15%) infants required mechanical ventilation within 72 h from birth due to a worsening RDS. Among these, 3 infants belonged to the LISA group and 5 to the INSURE group. A significantly lower SF ratio and higher median MPV at RD-PTDI assessment two hours after surfactant administration characterized these newborns, suggesting a worsening RDS despite the higher level of CPAP support before and after surfactant administration. A full course of antenatal steroids was protective against mechanical ventilation (Table 2).
Table 1.
Comparison of demographic, maternal, perinatal variables and measurements between newborns belonging to the LISA and INSURE groups
| Variables | LISA group | Insure group | p | Gestational age and sedation adjusted GLMs analysis** |
|---|---|---|---|---|
| 26 infants | 26 infants | p | ||
| CRIB-II score† | 4 (1–15) | 8 (2–14) | 0.030 | – |
| Gestational age, wks† | 30 (24–32) | 28 (24–32) | 0.029 | – |
| Birth weight, gr* | 1296 ± 425 | 1045 ± 403 | 0.030 | – |
| Male gender‡ | 10 (38) | 13 (50) | 0.577 | – |
| Antenatal steroids [full course]‡ | 18 (69) | 17 (65) | 1.000 | – |
| Cesarean section‡ | 20 (77) | 19 (73) | 1.000 | – |
| Multiple pregnancy‡ | 6 (23) | 6 (23) | 1.000 | – |
| Apgar 5’ * | 9 ± 1 | 9 ± 1 | 0.779 | – |
| Silverman-Andersen score (DR)† | 6 (3–9) | 6 (2–9) | 0.278 | – |
| FiO2 (DR), % * | 0.41 ± 0.16 | 0.52 ± 0.23 | 0.053 | – |
| Surfactant administration, minutes from birth† | 180 (90–1127) | 177 (60–300) | 0.245 | – |
| No procedural sedoanalgesia‡ | 6 (23) | 1 (4) | 0.099 | – |
| MV ≤ 72 h from birth‡ | 3 (11) | 5 (19) | 0.703 | – |
| CPAP(cm H2O), baseline† | 6 (5–9) | 6 (5–9) | 0.757 | 0.188 |
| CPAP(cm H2O), 120 min† | 6 (4–9) | 6 (4–10) | 0.673 | 0.125 |
| PCO2 (mmHg), baseline† | 55 (33–71) | 55 (37–76) | 0.685 | 0.259 |
| PCO2, 120 min† | 50 (35–66) | 49 (38–69) | 0.922 | 0.429 |
| SpO2/FiO2 (SF ratio), baseline† | 280 (157–471) | 317 (157–471) | 0.721 | 0.311 |
| SpO2/FiO2 (SF ratio), 120 min† | 452 (180–476) | 384 (211–471) | 0.136 | 0.844 |
| RD-PTDI (I + E peak velocity mean), baseline (cm/s)† | 1.52 (1.16–2.80) | 1.34 (1.14–1.94) | 0.042 | 0.024 |
| RD-PTDI (I + E peak velocity mean), 120 min (cm/s)† | 1.31 (1.12–1.59) | 1.38 (1.08–2.40) | 0.241 | 0.096 |
CPAP Continuous positive airway pressure, DR delivery room, E-Peak expiratory peak velocity, FiO2 fraction of inspired oxygen, I-Peak inspiratory peak velocity, LISA less invasive surfactant administration, INSURE intubation-surfactant-extubation, MV mechanical ventilation, PCO2 partial pressure of carbon dioxide, RD right diaphragm excursion, SpO2 pre-ductal oxygen saturation at pulse oximetry, PTDI pulsed-wave tissue doppler imaging
*Mean (S.D.)
**Since birth weight and gestational age are highly correlated (rho = 0.827) we used only the latter to adjust for baseline differences to avoid collinearity problems in the GLMs
†Median (min–max)
‡n (%)
Table 2.
Comparison of demographic, maternal, perinatal variables and measurements based on treatment failure
| Variables | Failure | Non-failure | p | Gestational age and sedation adjusted GLMs analysis** |
|---|---|---|---|---|
| 8 infants | 44 Infants | p | ||
| CRIB-II score† | 8 (2–14) | 7 (1–15) | 0.243 | |
| Gestational age, wks† | 28 (24–32) | 29 (24–32) | 0.233 | – |
| Birth weight, gr* | 1002 ± 438 | 1200 ± 426 | 0.187 | – |
| Male gender‡ | 3 (37) | 20 (45) | 1.000 | – |
| Antenatal steroids [full course]‡ | 2 (25) | 33 (75) | 0.038 | – |
| Cesarean section‡ | 5 (62) | 34 (77) | 0.396 | – |
| Multiple pregnancy‡ | 1 (12) | 7 (16) | 0.663 | – |
| Apgar 5’ * | 8 ± 2 | 9 ± 1 | 0.069 | – |
| Silverman-Andersen score (DR)† | 6 (5–8) | 6 (2–9) | 0.756 | – |
| FiO2 (DR), % * | 0.55 ± 0.26 | 0.45 ± 0.19 | 0.299 | – |
| Surfactant administration, minutes from birth† | 180 (105–230) | 177 (60–1127) | 0.889 | – |
| LISA infants‡ | 3 (37) | 23 (52) | 0.703 | – |
| No procedural sedoanalgesia‡ | 0 | 7 (16) | 0.579 | – |
| CPAP(cm H2O), baseline† | 8 (6–9) | 6 (5–9) | 0.023 | 0.007 |
| CPAP(cm H2O), 120 min† | 7 (6–10) | 6 (4–9) | 0.008 | 0.001 |
| PCO2 (mmHg), baseline† | 58 (38–65) | 54 (33–76) | 0.244 | 0.170 |
| PCO2, 120 min† | 51 (38–69) | 48 (35–66) | 0.424 | 0.546 |
| SpO2/FiO2 (SF ratio), baseline† | 235 (180–376) | 313 (157–471) | 0.040 | 0.144 |
| SpO2/FiO2 (SF ratio), 120 min† | 285 (211–418) | 432 (180–476) | 0.005 | 0.002 |
| RD-PTDI (I + E peak velocity mean), baseline (cm/s)† | 1.50 (1.22–2.01) | 1.37 (1.14–2.80) | 0.379 | 0.330 |
| RD-PTDI (I + E peak velocity mean), 120 min (cm/s)† | 1.61 (1.28–2.09) | 1.32 (1.08–2.40) | 0.012 | 0.004 |
CPAP Continuous positive airway pressure, DR delivery room, E-Peak expiratory peak velocity, FiO2 fraction of inspired oxygen, I-Peak inspiratory peak velocity, LISA less invasive surfactant administration, INSURE intubation-surfactant-extubation, MV mechanical ventilation, PCO2 partial pressure of carbon dioxide, RD right diaphragm excursion, SpO2 pre-ductal oxygen saturation at pulse oximetry, PTDI pulsed-wave tissue doppler imaging
*Mean (S.D.)
**Since birth weight and gestational age are highly correlated (rho = 0.827) we used only the latter to adjust for baseline differences to avoid collinearity problems in the GLMs
†Median (min–max)
‡n (%)
45/52 (86%) infants received analgesia/sedation for the procedure. Fentanyl was by far the most used drug (77%) at a dose of 1 mcg/kg in 45% and 2 mcg/kg in 55% of newborns. Propofol alone was used in 4/52 (8%) infants, and with fentanyl (1 mcg/kg) in one infant. Administration of analgesia/sedation in LISA was lower than in INSURE infants (23% vs. 4%), although this difference did not reach statistical significance (Table 1). We observed no significant changes in vital signs and SF ratio at scheduled assessments whether or not infants received analgesia/sedation for the procedure nor compared to baseline values; furthermore, the use of analgesia/sedation did not influence the incidence of mechanical ventilation within 72 h of birth (Table 2). Similar first-attempt procedure success rates [sedated infants 37/45 (82%) vs. non-sedated infants 5/7 (72%); (p = 1.000)] and incidence of minor complications [sedated infants 7/45 (15%) vs. non-sedated infants 0/7; (p = 0.574)] were observed whether or not analgesia/sedation was administered for the procedure. Both operator and external observer Likert scales confirmed optimal tolerance for the procedure (none to mild agitation) in infants not receiving analgesia/sedation, while moderate to severe agitation was reported in 7/45 (17%) in those treated; however, comparison of the Likert scales did not reveal any significant differences between the two groups of infants (p = 0.322; p = 0.536).
Regarding secondary outcomes, LISA infants had a significantly lower incidence of any grade BPD at discharge than INSURE infants (Table 3), while the only significant difference between failure and non-failure infants was the prolonged mechanical ventilation in the latter (Table 4).
Table 3.
Short-term outcomes differences between LISA and INSURE infant groups
| Variables | LISA group | INSURE group | p | Gestational age and sedation adjusted GLMs analysis** |
|---|---|---|---|---|
| 26 infants | 26 infants | p | ||
| CPAP support, hrs† | 151 (18–1357) | 504 (0–1512) | 0.048 | 0.594 |
| HFNC support, hrs† | 132 (0–1104) | 274 (0–1776) | 0.310 | 0.774 |
| MV support, hrs† | 0 (0–204) | 0 (0–971) | 0.460 | 0.265 |
| O2, hrs† | 36 (0–1598) | 48 (0–2347) | 0.557 | 0.774 |
| Hospital stay, days* | 45 ± 29 | 64 ± 31 | 0.014 | 0.248 |
| ICH‡ | 7 (27) | 9 (35) | 0.836 | 0.910 |
| BPD‡ | 1 (4) | 9 (35) | 0.012 | 0.049 |
| ROP‡ | 3 (12) | 9 (35) | 0.093 | 0.335 |
| LPV‡ | 0 | 2 (4) | 0.491 | 0.999 |
| NEC‡ | 0 | 1 (8) | 1.000 | 0.999 |
| HSDA‡ | 3 (12) | 4 (15) | 1.000 | 0.751 |
| PPHN‡ | 2 (8) | 3 (12) | 1.000 | 0.885 |
| DEATH‡ | 3 (12) | 0 | 0.235 | 0.999 |
BPD Bronchopulmonary dysplasia, CPAP continuous positive airway pressure, HFNC high-flow nasal cannula, HSDA hemodynamically significant ductus arteriosus, ICH intracranial haemorrhage, LISA less invasive surfactant administration, LPV periventricular leukomalacia, INSURE intubation-surfactant-extubation, MV mechanical ventilation, NEC necrotizing enterocolitis, O2 oxygen supplemention, PNX pneumothorax, PPHN persistent pulmonary hypertension of the newborn, ROP retinopathy of prematurity
*Mean (S.D.)
**Sedation and gestational age adjusted models. Since birth weight and gestational age are highly correlated (rho = 0.827) we used only the latter to adjust for baseline differences and thus avoid collinearity problems in the GLMs
†Median (min–max)
‡n (%)
Table 4.
Short-term outcomes differences between failure and non-failure infant groups
| Variables | Failure | Non failure | p | Gestational age and sedation adjusted GLMs analysis** |
|---|---|---|---|---|
| 8 infants | 44 infants | p | ||
| CPAP support, hrs† | 339 (0–1176) | 210 (18–1512) | 0.558 | 0.146 |
| HFNC support, hrs† | 384 (0–744) | 144 (0–1776) | 0.755 | 0.513 |
| MV support, hrs† | 102 (19–552) | 0 (0–971) | < 0.0001 | 0.015 |
| O2, hrs† | 1111 (9–1992) | 24 (0–2347) | 0.024 | 0.124 |
| Hospital stay, days* | 66 ± 43 | 53 ± 30 | 0.794 | 0.196 |
| ICH‡ | 3 (37) | 13 (30) | 0.694 | 0.927 |
| BPD‡ | 2 (25) | 8 (18) | 0.306 | 0.551 |
| ROP‡ | 2 (25) | 10 (23) | 0.644 | 0.960 |
| LPV‡ | 1 (12) | 1 (2) | 0.297 | 0.224 |
| NEC‡ | 1 (12) | 0 | 0.160 | 0.999 |
| HSDA‡ | 3 (37) | 4 (9) | 0.068 | 0.117 |
| PPHN‡ | 2 (25) | 3 (7) | 0.170 | 0.227 |
| Death‡ | 0 | 3 (7) | 1.000 | 0.416 |
BPD Bronchopulmonary dysplasia, CPAP continuous positive airway pressure, HFNC high-flow nasal cannula, HSDA hemodynamically significant ductus arteriosus, ICH intracranial haemorrhage, LISA less invasive surfactant administration, LPV periventricular leukomalacia, INSURE intubation-surfactant-extubation, MV mechanical ventilation, NEC necrotizing enterocolitis, O2 oxygen supplemention, PNX pneumothorax, PPHN persistent pulmonary hypertension of the newborn, ROP retinopathy of prematurity
*Mean (S.D.)
**Sedation and gestational age adjusted models. Since birth weight and gestational age are highly correlated (rho = 0.827) we used only the latter to adjust for baseline differences and thus avoid collinearity problems in the GLMs
†Median (min–max)
‡n (%)
Discussion
Early CPAP support or NIV in combination with the LISA or INSURE methods have become established practice in the NICU [1–3, 5, 30], but concerns remain about the clinical potential of the LISA technique [7], especially due to the conflicting results related to different alveolar deposition of surfactant from animal studies [31, 32]. Moreover, the failure rate of this “gentle” respiratory supportive management is still too high, with increased mortality and major morbidity [8, 9].
We believe that diaphragmatic POCUS may allow identification of altered muscle function potentially due to the different surfactant administration technique used, if any, considering it as an indirect representation of the respiratory system compliance. In addition, bedside monitoring of diaphragmatic movement by US may also detect early signs of diaphragm fatigue, suggesting failure of the “gentle” respiratory management strategy.
The diaphragm bears most of the respiratory workload in newborn infants and is prone to dysfunction when respiratory failure occurs, due to lower muscle mass, flattened shape, and low content of fatigue-resistant muscle fibers, especially in preterm infants [18]. Compliance of the respiratory system fulfils a significant role in diaphragmatic motion, and pulmonary disease is associated with diaphragmatic dysfunction detectable by bedside US [33, 34].
While the US assessment of diaphragm kinetics is increasing in the management of critically ill patients [11, 33, 34], scant attention is still paid to this topic in neonatal intensive care [35]. We formerly showed that RD-PTDI is an easy and reproducible US technique to evaluate diaphragm kinetics in the neonate [21], and that impairment of diaphragm function at RD-PTDI can predict early CPAP failure in preterm infants [24]. Real-time display of automatically calculated PTDI-derived parameter values, such as I-Peak and E-Peak velocities, provides an at-a-glance representation of the inverse relationship existing between diaphragm strength and velocity of movement, which may be useful for targeting respiratory support in preterm infants with worsening RDS. Individual studies and meta-analyses point out that LISA is more effective than INSURE, among others, in terms of preventing mechanical ventilation [36]. However, concerns remain about the potential suboptimal deposition of alveolar surfactant [7, 31], which may result in lack of improvement or worsening of respiratory system compliance. According to our data, diaphragm kinetics of preterm infants would not be particularly influenced by different minimally invasive techniques of surfactant administration. Furthermore, the reduction of the diaphragmatic MPV following surfactant administration by LISA (Table 1) seems to confirm adequate alveolar distribution, in line with recent animal results that reassure the adoption of this technique in neonatal units [32]. Conversely, preterm infants requiring mechanical ventilation showed higher diaphragmatic MPV with lower SF ratio after surfactant administration, suggesting a worsening respiratory system compliance potentially related to inadequate CPAP respiratory support; notably, the level of CPAP support was already higher at the baseline assessment in the failure infants. These findings lead us to assume that the optimal targeting of CPAP support represents a therapeutic cornerstone to reinforce “gentle” respiratory management strategy in the spontaneously breathing preterm infants with RDS. This could be achieved, inter alia, by adjusting CPAP support with bedside US monitoring of diaphragm motion to avoid muscle fatigue.
Our data remark, if necessary, the relevance of the prenatal administration of a comprehensive course of corticosteroids to women at risk of preterm delivery in reducing the need for mechanical ventilation [37], probably due to the improvement of the compliance of respiratory system in exposed infants, as confirmed by diaphragmatic muscle performance at RD-PTDI assessment. Whether or not to routinely sedate newborns for LISA and INSURE remains controversial, with significant differences in practice between centers [38]. Leaving the neonatologist free to decide whether or not to use analgesia/sedation drugs may seem strange; however, we just wanted to bring out what actually happens in clinical practice regarding the potential risk of different behaviors depending on the minimally invasive technique used. Analgesic or sedative drugs undoubtedly increase the comfort of the newborn and allow good procedural conditions, but there remains a certain reluctance to use them, especially with LISA method, as confirmed by our results. Based on our experience, no evident effects were attributable to the administration or not of drugs with an analgesic/sedative effect, neither between different minimally invasive surfactant administration techniques nor between failure and non-failure infants. However, we share the opinion that procedural analgesia and sedation should be based on an individualized and infant-centered assessment rather than a rigid and standardized approach [39].
Limitations of the study
Several drawbacks can influence the results of the study. First, the observed results do not allow us to exclude that different minimally invasive surfactant administration techniques may influence diaphragm kinetics when studied in a larger and more homogeneous patient cohort. Second, mild to moderate RDS may have influenced outcomes, not allowing for the exclusion of potential repercussions of different minimally invasive surfactant administration techniques when severe RDS occurs. Third, the time chosen for the post-surfactant evaluation, based on our previous experience (data not shown), cannot completely rule out some possible effects on diaphragm kinetics at the previous evaluation. Fourth, the lack of randomization and determination of the number of subjects needed does not allow for a conclusive statement regarding the potential effect on diaphragmatic kinetics of analgesia/sedation performed for minimally invasive surfactant administration.
Conclusion
LISA and INSURE techniques do not seem to have different impact on diaphragm kinetics, as assessed by RD-PTDI US, in CPAP-supported preterm infants with RDS and could be used interchangeably as usual. Larger well-powered studies are needed to confirm our results.
Acknowledgements
We thank the neonatal intensive care unit staff for their valuable contribution.
Author contributions
All authors made a substantial contribution to the concept and design of the work. MR, SP and PC drafted the manuscript, designed the data collection instruments, performed exams, collected as well as interpreted data, and critically revised the manuscript for important intellectual content. AF helped in the collection and interpretation of data, gave administrative, technical, and material support, and critically revised the manuscript for important intellectual content. MR and VB conceptualized, designed, coordinated, and supervised the study, performed the data analysis and interpretation, and critically reviewed. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Authors did not receive any funds for this study.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at: https://docs.google.com/spreadsheets/d/1z3Gil-uTw5rPDAwlTnWaL_I4Mr_ggwNh/edit?usp=sharing&ouid=108672324634995930721&rtpof=true&sd=true.
Declarations
Conflict of interest
The authors have no conflicts of interest relevant to this article to disclose.
Ethical approval
This study was conducted following the ethical standards of the Ethical Committee of the Health Authorities of the Umbria Region—CER [study code: MOV PG-04; CER registration number: 3800/19] and with the Helsinki Declaration of 1975.
Consent to participate
All patients’ parents/caregivers and healthcare professionals have signed a written informed consent.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at: https://docs.google.com/spreadsheets/d/1z3Gil-uTw5rPDAwlTnWaL_I4Mr_ggwNh/edit?usp=sharing&ouid=108672324634995930721&rtpof=true&sd=true.