Dexmedetomidine for Lisa Procedure: a Single Center Experience

Dexmedetomidine for Lisa Procedure: a Single Center Experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Dexmedetomidine for Lisa Procedure: a Single Center Experience Beatrice Galeazzo, Tormena Francesca, Papappicco Cinzia Anna Maria, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6438065/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Italian Journal of Pediatrics → Version 1 posted 5 You are reading this latest preprint version Abstract Background Respiratory Distress Syndrome (RDS) is the most common respiratory problem of preterm newborns. The preferred way to manage RDS is with Less Invasive Surfactant Administration (LISA), which involves direct laryngoscopy in spontaneously breathing infants. Despite its widespread diffusion, the optimal sedation protocol for LISA remains unclear. Dexmedetomidine, an α2-adrenergic agonist, offers sedative and analgesic properties with minimal respiratory depression. This pilot study evaluates the efficacy and safety of dexmedetomidine for analgesia and sedation during the LISA procedure. Methods This is a prospective observational study conducted in our tertiary Italian NICU from May 2021 to July 2024. We enrolled preterm neonates aged between 26 +0 to 36 +6 weeks, diagnosed with RDS who required LISA. Dexmedetomidine (1 mcg/kg) was administered intravenously before LISA. Primary outcomes included pain control assessed by Neonatal Infant Pain Scale (NIPS) score, sedation adequacy assessed by Neonatal Pain, Agitation, and Sedation Scale (N-PASS), and success rate of the procedure. We also assessed the safety of the procedure evaluating adverse events, such as intubation rates, apneas/desaturations, bradycardia, and hypotension. We divided the newborns into two groups based on a cut-off of 32 weeks. Results Forty seven preterm newborns received dexmedetomidine. The median (IQR) gestational age, birth weight (grams) and age (hours) at LISA were respectively 29+6 (28+5, 33+1), 1421 (1069-2074), 3(2.5-6). Pain scores indicated adequate pain control during the procedure (NIPS <4 in 76% during laryngoscopy). Mild sedation (N-PASS -2 to -5) was observed in 23% of patients before the procedure, lasting up to 60 minutes. Excessive sedation (N-PASS < -5) occurred in 7% of babies (3 patients). Laryngoscopy conditions were optimal in 90% of neonates (Goldberg score <6). Apnea/desaturation with/without bradycardia occurred in 13% of newborns. Six patients were intubated (13%) within 72 hours after the procedure. Hypotension was noted in 6.4% of patients. Conclusion Dexmedetomidine provided effective analgesia and facilitated laryngoscopy but did not consistently achieve mild sedation during LISA. While its safety profile was acceptable, a more rapid-onset sedative may be preferable for this procedure. Further randomized controlled trials are needed to establish an optimal sedation strategy for LISA in preterm newborns. Trial registration Register: ClinicalTrials.gov, number ID NCT04820101, enregistered 03-29-2021, https://clinicaltrials.gov/study/NCT04820101?cond=RDS&term=dexmedetomidine&rank=1#study-record-dates RDS LISA sedation dexmedetomidine Figures Figure 1 Figure 2 Figure 3 Figure 4 BACKGROUND Respiratory distress syndrome (RDS) is the most common respiratory problem in preterm newborns( 1 ). The combination of exogenous surfactant administration and non-invasive ventilation is the most effective approach to manage RDS ( 2 – 4 ). Among the various techniques for surfactant delivery, the European Consensus Guidelines on RDS management, recommend Less Invasive Surfactant Administration (LISA) as the preferred method for spontaneously breathing newborns on CPAP with worsening RDS (FiO₂ > 0.30 on CPAP pressure ≥ 6 cmH₂O)( 1 ). This technique reduces the need for invasive mechanical ventilation during the first 72 hours, lowers the incidence of major outcomes and decreases the risk of death or BPD among survivors ( 5 – 9 ) . LISA involves the use of a semirigid catheter inserted through the trachea via direct laryngoscopy to administer surfactant while the infant maintains spontaneous breathing and the vocal cords sustain auto-PEEP ( 10 ). While a premedication for non-urgent direct laryngoscopy is strongly recommended ( 11 , 12 ), there is no consensus on sedation for LISA procedure. Surveys revealed that neonatologists in Europe ( 13 ) and in the USA ( 14 ) don't use sedation for LISA, but they apply non-pharmacological measures such as intra-oral sucrose and swaddling. These measures seem to be effective in achieving comfort in almost 60% of preterm newborns ( 15 ). Various drugs, including Propofol, Fentanyl, and Ketamine, have been evaluated in time, but evidences are low ( 16 – 21 ). Two recent systematic review concluded that the use of sedative drugs for LISA in preterm neonates increases the risk of desaturation and the need for NIPPV, although better comfort scores have been observed ( 22 , 23 ). With the widespread use of this technique, it is essential to establish a more standardized approach to sedation for LISA. An ideal drug for this context should have a fast onset, short duration of action, rapid offset, and provide good sedation and analgesia with minimal impact on respiratory drive. In the last decades, dexmedetomidine has become increasingly popular in neonatal and pediatric populations. It is an α2-adrenergic agonist that acts on the brainstem by inhibiting norepinephrine release, activating the receptors in the locus coeruleus and decreasing the release of substance P in the dorsal horn of the spinal cord. This leads to its sedative, anxiolytic and analgesic effects without impacting respiratory drive. It is an attractive agent to achieve procedural sedation and pain control in spontaneously breathing newborns (e.g., neuroimaging MRI)( 24 – 27 ). Recently, a single-center study was published that tested dexmedetomidine for the LISA procedure ( 28 ). It concluded that this drug is not associated with severe adverse events and that the rate of LISA success was favorable. However, this is a retrospective study, and pain control and sedation were not assessed. With this study we aim to evaluate: 1) the effectiveness of dexmedetomidine for analgesia and sedation during the LISA procedure; 2) the safety of this drug in preterm infants in a pilot study. MATERIALS AND METHODS Study Design and Population We conducted a prospective observational study in the tertiary NICU of Ca’ Foncello Hospital, Treviso, Italy, from May 2021 to July 2024 to assess our new protocol for the LISA procedure. We enrolled preterm newborns, with gestational ages ranging from 26 + 0 to 36 + 6 weeks (divided in two groups 26 + 0 -31 + 6 and 32 + 0 -36 + 6 weeks), who were hospitalized in our NICU, diagnosed with RDS and required surfactant therapy. The exclusion criteria were: need for emergency intubation in the delivery room, major congenital malformations (such as cardiopathies), chromosomal abnormalities, fetal hydrops, hypercapnia (CO₂ > 65 mmHg), pneumothorax, and hemodynamic compromise. Description of the Procedure Eligible infants were stabilized in the delivery room according to the ILCOR 2020 guidelines ( 29 ). If necessary, CPAP or non-invasive ventilation was applied and continued in Neonatal Intensive Care Unit (NICU). In accordance with the European guidelines for the management of RDS, LISA procedure was performed early in the course of the disease when the infants showed worsening symptoms, dyspnea, and required FiO₂ > 0.30 on CPAP with a pressure of at least 6 cmH₂O ( 1 ). A semirigid catheter for surfactant endotracheal instillation was inserted via the mouth in spontaneously breathing infants. Direct laryngoscopy was performed, and the probe was inserted beyond the vocal cords to the required depth. Once the probe was correctly positioned, surfactant (Poractant alfa, Curosurf, CHIESI Farmaceutici, Parma, Italy) was slowly infused over 2–3 minutes at an initial dose of 200 mg/kg. At the end of the administration, the catheter was immediately removed. The newborn remained continuously on NIPPV or CPAP delivered throughout nasal mask or prongs during the procedure. All operators were skilled in performing the LISA procedure. Before performing LISA, dexmedetomidine was administered at a dose of 1 mcg/kg intravenously in 10 minutes according to the guidelines published in the Neofarm-SIN App by the Italian Society of Neonatology ( 30 ). We performed LISA after newborns were adequately sedated . In each infant, non-pharmacological comfort techniques were applied, including the administration of 24% oral sucrose in the cheek pouch/tongue with a pacifier for at least 2 minutes before the procedure, and swaddling the infant to keep them contained. Data Collection We collected the following population characteristics: sex, gestational age, birth weight, Apgar score, type of respiratory support before LISA, fraction of inspired oxygen before LISA and hours of life at the time of the procedure. Pain during the procedure was assessed using the Neonatal Infant Pain Scale (NIPS) ( 31 ) which was evaluated before, during, and after LISA procedure. This score considers various parameters (such as crying, facial expression, and arm position) and assigns a score as follows: 0–2 points = no pain; 3–4 points = mild-moderate pain; >4 points = severe pain. We targeted an adequate pain control, tolerating a mild pain level during laryngoscopy (NIPS score < 4). Sedation was assessed using the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) at the beginning of the procedure, and again at 30–60 minutes and 120 minutes. This scale evaluates both behavioral parameters (e.g., facial expression) and vital signs to assign a score, as follows: deep sedation: -10 to -5; light sedation: -5 to -2 ( 32 ). We aimed to achieve a mild sedation level (N-PASS score − 5 to -2) to maintain the integrity of respiratory drive. After LISA had been performed we collected data about efficacy and safety of dexmedetomidine, such as the occurrence of apnea/desaturation +/-bradycardia with or without intubation in the first 72 hours after the procedure, the number of laryngoscopy attempts, the quality of intubation condition at laryngoscopy using the Goldberg score (divided into four categories: excellent- score < 3-, good- score 4-6-, poor score 7-9-, or inadequate- score 10–12)( 33 ), the time taken to perform LISA (defined as the time from the first laryngoscopy to the withdrawal of the catheter from the mouth), and the trend of cardiorespiratory parameters from baseline to 1, 3, 5, 15, 30, 60, and 120 minutes after the first drug injection. Other adverse events were also collected, including pneumothorax or selective surfactant administration, as well as the incidence of adverse effects related to dexmedetomidine administration (typically cardiovascular events such as persistent bradycardia less then 100 bpm and hypotension defined as blood pressure < third centile for age). Outcomes were assessed at discharge, including mortality, bronchopulmonary dysplasia (defined as the need for oxygen administration and/or respiratory support at 36 weeks postmenstrual age), intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity. Statistical analysis Descriptive statistics were reported as absolute numbers (percentages) for categorical variables, and as median (I quartile – III quartile) for continuous variables. Wilcoxon’s rank sum test was used for continuous variables and the Pearson Chi-square test, or the Fisher’s exact test when appropriate (n 20% cells) were used for categorical variables to compare patient characteristics and LISA procedure-related variables between infants with gestational age 26–31 + 6 and gestational age 32–36 + 6. The NIPS and Golberg scores were dichotomized using thresholds of 4 and 6, respectively; for both scales, scores less than or equal to the cutoff indicating good clinical condition. The proportion of patients classified as being in good condition according to each scale was calculated, with 95% confidence intervals estimated using the exact binomial method. Mixed linear models were used to assess the changes in NPASS score, saturation, and heart rate over time. A two-sided p-value of < 0.05 was considered significant. To account for multiple testing, a Benjamini-Hochberg False Discovery Rate (FDR) correction was applied across "Efficacy and safety of dexmedetomidine premedication" analyses separately( 34 ) An FDR-corrected p-value (termed “q-value”) threshold of < 0.05 was used to define statistical significance. All analyses were performed using R system version 4.3.2( 35 ). Ethics The Ethics Committee of Ospedale Ca’ Foncello, Treviso, Italy, approved this observational study (number 920/CE MARCA). No additional consent was required, as the implementation of the protocol was considered standard care. All adverse events were collected. RESULTS Population Between May 2021 and July 2024, 82 patients born between 26 +0 and 36 +6 weeks' gestation were treated with surfactant for RDS. Three of them were not eligible for the LISA technique because they were aged less than 26 weeks and intubated in delivery room. 79 underwent the LISA procedure, and 32 were not eligible for dexmedetomidine administration due to hemodynamic instability. Forty-seven patients were managed according to the protocol and received premedication with dexmedetomidine before the procedure. Patients who were not eligible for dexmedetomidine (due to hemodynamic instability) received alternative premedication (Figure 1). The characteristics of the population are described in Table 1. Table 1. Population characteristics. Comparison of infants with gestational age 26+0-31+6 and gestational age 32+0-36+6. Overall N = 47 1 26-31 +6 weeks gestation N = 30 1 32-36 +6 weeks gestation N = 17 1 p-value 2 Gestational age at birth (weeks) 29+6 (28+5, 33+1) 29+2 (28+2, 29+5) 33+6 (33+0-34+5) < 0.001 Birth weight (grams) 1421 (1069, 2074) 1130 (1005, 1362) 2180 (2046, 2340) 0.9 Apgar score at 5 minutes 9.00 (8.00, 9.00) 8.00 (8.00, 9.00) 9.00 (8.00, 10.00) 0.085 FiO 2 before LISA procedure 0.35 (0.30, 0.45) 0.35 (0.30, 0.50) 0.35 (0.30-0.44) 0.6 Ventilation mode before LISA procedure nCPAP nPPV 11 (23%) 36 (77%) 4 (13%) 26 (87%) 7 (41%) 10 (59%) 0.069 Age at LISA procedure (hours) 3.00 (2.50, 6.00) 2.80 (2.00, 4.00) 7.50 (4.00, 15) < 0.001 1 n (%); Median (Q1, Q3) 2 Fisher’s exact test; Pearson’s Chi-squared test; Wilcoxon rank sum test Before LISA, 11 patients were treated with nasal CPAP, and 36 patients received non-invasive ventilation support, both delivered through nasal masks or prongs. The median FiO 2 before the LISA procedure was 0.35 (I-III quartiles: 0.30–0.45), and the median time (hours) to perform LISA was 3 hours (I-III quartiles: 2.5–6). Patients born at 26–31 +6 weeks' gestation received surfactant at a median time of 2.8 hours (I-III quartiles: 2–4). Efficacy and safety of the analgo-sedation According to the protocol, 1 mcg/kg of dexmedetomidine was administered intravenously slowly before the procedure. The efficacy and safety of dexmedetomidine premedication are described in Table 2. Table 2. Efficacy and safety of dexmedetomidine premedication. Overall N = 47 1 26-31 +6 weeks gestation N = 30 1 32-36 +6 weeks gestation N = 17 1 q-value 2,3 Laryngoscopy attempts 1 attempt n. (%) 1.00 (1.00, 2.00) 31 (66) 1.00 (1.00, 2.00) 1.00 (1.00, 2.00) 0.6 Goldberg score (Intubation conditions) Excellent intubation conditions (score < 3) n, % Good intubation conditions (score 4-6) n, % Poor intubation condition (score 7-9) n, % Inadequate intubation condition (score 10-12) n, % 5.00 (3.00, 6.00) 12 (25,5%) 30 (63,8%) 5 (10,7%) 0 (0%) 4.00 (3.00, 5.00) 6.00 (4.00, 6.00) 0.088 LISA procedure duration (minutes) 3.00 (2.00, 5.00) 3.00 (2.00, 4.00) 3.00 (2.00, 5.00) 0.6 Intubation after LISA (72 hours) Yes No 6 (13%) 41 (87%) 5 (17%) 25 (83%) 1 (6%) 16 (94%) 0.8 Time from LISA to intubation *patients with Intubation after LISA 2.00 (2.00, 16.00) 2.00 (2.00, 16.00) 2.00 (2.00, 2.00) > 0.9 Apnea Yes No 6 (13%) 41 (87%) 6 (20%) 24 (80%) 0 (0%) 17 (100%) 0.6 Hypotension Yes No 3 (6.4%) 44 (93.6%) 2 (6.7%) 28 (93.3%) 1 (5.9%) 16 (94.1%) > 0.9 Excessive sedation (NPASS score 0.9 1 n (%); Median (Q1, Q3) 2 Fisher’s exact test; Pearson’s Chi-squared test; Wilcoxon rank sum test 3 False discovery rate correction for multiple testing The median of Goldberg scale value at intubation was 5 (I-III quartiles: 3–6). The 90% of newborns had scores < 6 classified as adequate intubation conditions. The median number of intubation attempts was 1 (I-III quartiles: 1–1). The NIPS pain score (median, I-III quartiles) was assessed before the procedure (1.5, 1–3), during laryngoscopy (3, 2–3), and surfactant administration (2, 1–3), as well as after the procedure (1, 0–3). Pain scores at these evaluated times showed no pain before and after the procedure, mild pain during the procedure. Before the procedure 89% of newborns had NIPS score < 4 and 76 % during laryngoscopy, indicating an adequate pain control even during the most invasive part of the procedure (Figure 2). Sedation was evaluated using the N-PASS score (median, I-III quartiles) at the beginning of the procedure (1, 1–2), 30 minutes after the procedure (0, -2–2), 60 minutes after the procedure (0, -2–2.5), and 120 minutes after the procedure (0, 0–1.5). A light sedation (N-PASS -2 to -5) was achieved in 10/43 newborns (23%) before the procedure lasting till 60 minutes after the procedure. Three patients (7%) were deeply sedated before the procedure (N-PASS < -6) and this effect lasted till 120 minutes after the procedure. The evolution of N-PASS distribution over time is shown in Figure 3 as a linear predictive model. Six patients (13%) presented apnea and desaturation/bradycardia in the first 24 hours after the procedure, of them 3 were intubated as described above. The other 3 patients were assisted successfully with NIV. Six patients (13%) requested intubation within the first 72 hours after the procedure. Of these, four patients were intubated in the first 2 hours after the procedure: three for recurrent apnea/desaturation +/- bradycardia (all aged less than 32 weeks) and one for a worsening of RDS (33+0). Two other patients were intubated later: one aged 30 + 6 weeks’ gestation at 16 hours for pulmonary hypertension and one aged 28 + 2 weeks gestation at 36 hours for a worsening of RDS. Three patients developed hypotension (6.4%) in the first hours after the procedure: one extremely preterm baby (less then 28 weeks), one born from C-section after maternal blood losses and one with pulmonary hypertension. In the first two cases no pharmacological therapy was needed. No pneumothorax or selective surfactant administration was reported. Regarding vital signs in the first two hours after the procedure, the predictive evolution of oxygen saturation and heart rate from baseline is described in Figure 4A and 4B. As expected, desaturation and bradycardia increased during the maneuver from minute 1 to 5 compared to baseline, related to the obstruction to the airways while laryngoscopy was performed and surfactant administered. Outcome at discharge Fourteen patients (30%) were diagnosed with BPD (13 aged between 26 and 31+6 weeks’ gestation). Three patients (6.4%) had minor grade IVH (less than 2), 3 patients (6.4%) had medical NEC and 11 patients (23%) had late onset sepsis. There were no deaths, no PVL. The median length of stay was 51 days (30-62). DISCUSSION To the best of our knowledge, this is the first observational prospective study testing the use of dexmedetomidine for analgesia and sedation for LISA procedure. We found that the administration of dexmedetomidine was associated with an adequate pain control during laryngoscopy and good intubation conditions (evaluated by the Goldberg score). However, mild sedation was not consistently achieved during the procedure. Sedation scores closer to mild sedation were observed mostly after the procedure, lasting up to 60–120 minutes. Notably, excessive sedation (N-PASS < -6) occurred in 7% of patients (3 cases), with 2 of these infants extremely preterm. This suggests a higher sensitivity to dexmedetomidine in this subgroup, warranting consideration of lower dosing strategies for preterm neonates." We chose dexmedetomidine to perform LISA procedure for its specific characteristics. It is a selective alpha-2 adrenergic receptor agonist that provides both sedative and analgesic effects with minimal respiratory depression ( 24 – 26 , 36 ). Moreover, it is a promising drug as it may offer neuroprotective benefits as demonstrated in preclinical studies ( 25 , 26 ). Continuous intravenous route/infusion has already been used in mechanically ventilated newborns, post-surgical patients, and those undergoing hypothermia treatment ( 27 , 37 – 40 ). For procedural sedation, intranasal administration has been used safely for performing MRI scans ( 41 , 42 ). The results of our study indicate that while an IV bolus of 1 mcg/kg provided adequate pain control during the procedure, however the desired sedative effect (N-PASS score between − 2 and − 5) was not consistently achieved and sedation scores close to mild sedation persisted for a while period after the procedure. Despite this limitation, good conditions for laryngoscopy and a limited number of attempts were observed. LISA procedure is typically performed within the first hours of life in newborns with RDS, requiring an ideal drug with a rapid onset and offset of both pain control and sedation. Our findings suggest that dexmedetomidine may not be the optimal agent for this rapid procedure due to its delayed and mild sedative effect. Regarding the safety profile of dexmedetomidine in our population, analyzing the evolution of vital signs, desaturation and bradycardia were observed in the first minutes of the LISA maneuver. These events were likely related to the procedure itself rather than to the drug administration. As Herting et al. highlighted ( 43 ), desaturation and bradycardia are commonly observed during LISA procedure, as direct laryngoscopy causes hypoxemia and bradycardia; moreover CPAP is poorly transmitted during LISA ( 11 , 12 , 44 , 45 ).In addition, surfactant instillation itself might have negative consequences on hemodynamics ( 44 ). These effects could potentially be mitigated by careful laryngoscopy, atropine premedication, and slow administration of surfactant. In our protocol, we did not use atropine, but our findings suggest considering its use to prevent bradycardia during laryngoscopy. Within the first 72 hours after the procedure, six patients required intubation (13%), 5 of them aged less than 31 weeks’ gestation. Four patients were intubated within the first 2 hours after the procedure. Recurrent apnea and desaturation were noted in 3 newborns aged less than 32 weeks, which may be related to the immaturity/prematurity; however we cannot exclude that this may be due to dexmedetomidine effects. In the other patient, intubated in the first hours, we observed a worsening of RDS. The last two patients were intubated respectively at 16 and 36 hours of life for pulmonary hypertension and a worsening of RDS. There is no direct correlation between dexmedetomidine infusion and pulmonary hypertension described in pediatric patients( 46 ) and so we assume that in the last three cases, intubation was due to a failure of the LISA procedure itself. Six patients presented apnea/desaturation and bradycardia (13%), all aged less than 32 weeks. Three of them were intubated and the other three were assisted with NIPPV. Considering other cardiovascular effects of dexmedetomidine described in literature ( 47 ), hypotension was observed in three patients (6.4%). In two cases, it occurred within the first hours after administration and was managed with supportive therapy (IV fluids). One of these two newborns was born for maternal blood losses, so hypotension may not be related to dexmedetomidine infusion but to fluid depletion. The third case developed hypotension at 16 hours of life in the context of evolving pulmonary hypertension and required inotropes therapy. We did not report persistent bradycardia in the first 24 hours after the procedure. Our findings on safety align with the retrospective study by Nissimov et al.( 28 ), which reported a LISA success rate of 89.2% and no serious adverse events. They noted an incidence of 27% of apnea/desaturation ± bradycardia in the first 24 hours, that is a higher than ours (13%), Regarding intubation rates we noted in 13% of patients and this was similar to the Israeli report (10.8%). The reported rates of apnea/desaturation with other tested drugs for LISA are higher. A prospective observational trial testing ketamine and atropine reported desaturations in 52% of newborns ( 48 ). In an RCT comparing propofol with no premedication, the incidence of desaturations was 90% and 70%, respectively ( 17 ). Another RCT comparing fentanyl with no sedation reported more than 40% of desaturations in the fentanyl group ( 21 ). Our findings are consistent with those of Nissimov et al. and suggest that dexmedetomidine affects respiratory drive to a lesser extent. Moreover, as in Israeli court, we supported patients with NIPPV, which may also be effective in desaturations control ( 28 ). Our results align with recent reviews indicating that the major side effects of dexmedetomidine are cardiovascular, such as bradycardia and hypotension. These effects, as reported in other studies, were generally self-limiting and did not require therapeutic intervention, but only the administration of fluids or supportive care, beyond the withdrawal of the drug itself ( 24 – 26 ). We observed that more premature infants presented more adverse events such as intubations, apneas or excessive sedation, suggesting the importance of adhering to correct neonatal dosage ranges, especially in this vulnerable and sensitive population. Nissimov et al. ( 28 ) reported an incidence of 16.2% of mild hypothermia, suggesting that dexmedetomidine may affect thermoregulation. This parameter was not detected in our study, however the daily controls of temperature reported by the nurses did not disclosure problems. Premedication for the LISA procedure remains a subject of ongoing debate. To our knowledge, different drugs have been tested in retrospective and observational studies, including ketamine, fentanyl, and propofol. Only one RCT has been conducted by a Danish group comparing propofol and no sedation, and one comparing the use of fentanyl with no sedation in a low-income country ( 16 – 19 , 21 , 48 ). All this trials together with recent systematic reviews encompassing more than 30 studies conclude that sedation reduces discomfort and pain but increases the risk of desaturation/apnea and the failure to maintain spontaneous breathing ( 22 , 23 ). These reviews underscore the need for a more standardized approach to sedation during LISA, as significant variability exists across centers in the use of both pharmacological and non-pharmacological techniques ( 7 , 49 – 52 ). Several promising RCT trials about premedication for LISA procedure are now ongoing: one compares propofol versus placebo ( 20 ), one the use of ketamine versus fentanyl ( 53 ), one ketamine versus placebo ( 54 ), and fentanyl along with atropine versus placebo ( 55 ). These studies will provide further information about the best strategy for premedication before the LISA procedure. Limitations The limitations of this study include the absence of a control group, as we normally perform LISA with premedication. Furthermore, the sample size is limited, and the youngest gestational ages (less than 26 weeks) were not included. Moreover, the assessment of sedation and pain with scales may not always be reliable; we used NIPS and NPASS scores, which involve face evaluation, and this may sometimes be difficult to assess during laryngoscopy. Conclusion Intravenous dexmedetomidine is a safe drug for performing LISA procedure and provides effective pain control and good intubation conditions. However, mild sedation was not consistently achieved during the procedure. Premedication with dexmedetomidine does not seem ideal for the LISA procedure, as a drug with a more rapid onset is required. While awaiting more robust evidence from ongoing trials, an individualized approach that considers pharmacological and non-pharmacological strategies has to be warranted. Abbreviations RDS (Respiratory Distress Syndrome), LISA (Less Invasive Surfactant Administration), CPAP (Continuous Positive Airway Pressure), FiO2 (Fraction of Inspired Oxygen), PEEP (Positive end-expiratory pressure), NIPPV (Non-Invasive Positive Pressure Ventilation), NICU (Neonatal Intensive Care Unit). Declarations ETHICAL APPROVAL: This study was approved by the RESEARCH ETHICS BOARD APPROVAL of the Ca’ Foncello Hospital (Observational study, number 920/CE Marca) CONSENT OF PUBBLICATION: Not applicable. DATA AVAIABILITY: Data are available from the authors upon reasonable request COMPETING INTERESTS: The authors declare that they have no competing interests. FUNDING: Not founded AUTHORS’CONTRIBUTIONS PL conceived the study design and has given final approval of the actual version, BG made substantial contribution to the conception, design of the study protocol and prepared electronic data sheets, collected data. FT, SG, SV collected data CAMP and DG performed the statistical analysis. All authors read and approved the final manuscript. ACKNOWLEDGEMENTS Not applicable. References Sweet DG, Carnielli VP, Greisen G, Hallman M, Klebermass-Schrehof K, Ozek E, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. Neonatology. 2023 Mar 1;120(1):3–23. Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Vol. 2016, Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd; 2016. Fischer HS, Bührer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: A meta-analysis. Vol. 132, Pediatrics. American Academy of Pediatrics; 2013. Early CPAP versus Surfactant in Extremely Preterm Infants. New England Journal of Medicine. 2010 May 27;362(21):1970–9. Aldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: A systematic review and meta-analysis. Vol. 102, Archives of Disease in Childhood: Fetal and Neonatal Edition. BMJ Publishing Group; 2017. p. F17–23. Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasiveventilation strategies withmortality and bronchopulmonarydysplasiaamong preterm infants: A systematic review and meta-analysis. In: JAMA - Journal of the American Medical Association. American Medical Association; 2016. p. 611–24. Härtel C, Kribs A, Göpel W, Dargaville P, Herting E. Less Invasive Surfactant Administration for Preterm Infants - State of the Art. Neonatology. S. Karger AG; 2024. Lista G, Bresesti I, Fabbri L. Is Less Invasive Surfactant Administration Necessary or only Helpful or Just a Fashion? Vol. 35, American Journal of Perinatology. Thieme Medical Publishers, Inc.; 2018. p. 530–3. Gortner L, Schüller SS, Herting E. Review demonstrates that less invasive surfactant administration in preterm neonates leads to fewer complications. Vol. 107, Acta Paediatrica, International Journal of Paediatrics. Blackwell Publishing Ltd; 2018. p. 736–43. Kribs A, Roll C, Göpel W, Wieg C, Groneck P, Laux R, et al. Nonintubated surfactant application vs conventional therapy in extremely preterm infants: A randomized clinical trial. JAMA Pediatr. 2015 Aug 1;169(8):723–30. Kumar P, Denson SE, Mancuso TJ, Papile LA, Stark AR, Adamkin DH, et al. Clinical report - Premedication for nonemergency endotracheal intubation in the neonate. Pediatrics. 2010 Mar;125(3):608–15. Prevention and Management of Procedural Pain in the Neonate: An Update. Pediatrics. 2016 Feb 1;137(2):e20154271. Klotz D, Porcaro U, Fleck T, Fuchs H. European perspective on less invasive surfactant administration—a survey. Eur J Pediatr. 2017 Feb 1;176(2):147–54. Kurepa D, Perveen S, Lipener Y, Kakkilaya V. The use of less invasive surfactant administration (LISA) in the United States with review of the literature. Journal of Perinatology. 2019 Mar 1;39(3):426–32. Pichler K, Kuehne B, Dekker J, Stummer S, Giordano V, Berger A, et al. Assessment of Comfort during Less Invasive Surfactant Administration in Very Preterm Infants: A Multicenter Study. Neonatology. 2023 Aug 1;120(4):473–81. Descamps CS, Chevallier M, Ego A, Pin I, Epiard C, Debillon T. Propofol for sedation during less invasive surfactant administration in preterm infants. Vol. 102, Archives of Disease in Childhood: Fetal and Neonatal Edition. BMJ Publishing Group; 2017. p. F465. Dekker J, Lopriore E, Rijken M, Rijntjes-Jacobs E, Smits-Wintjens V, Te Pas A. Sedation during Minimal Invasive Surfactant Therapy in Preterm Infants. Neonatology. 2016 Jun 1;109(4):308–13. Dekker J, Lopriore E, Van Zanten HA, Tan RNGB, Hooper SB, Pas ABT. Sedation during minimal invasive surfactant therapy: A randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019 Jul 1;104(4):F378–83. Brotelande C, Milési C, Combes C, Durand S, Badr M, Cambonie G. Premedication with ketamine or propofol for less invasive surfactant administration (LISA): observational study in the delivery room. Eur J Pediatr. 2021 Sep 1;180(9):3053–8. Chevallier M, Durrmeyer X, Ego A, Debillon T, Beuchee A, Bourgoin L, et al. Propofol versus placebo (with rescue with ketamine) before less invasive surfactant administration: Study protocol for a multicenter, double-blind, placebo controlled trial (PROLISA). BMC Pediatr. 2020 May 8;20(1). Sk H, Saha B, Mukherjee S, Hazra A. Premedication with Fentanyl for Less Invasive Surfactant Application (LISA): A Randomized Controlled Trial. J Trop Pediatr. 2022 Apr 1;68(2). Tribolet S, Hennuy N, Snyers D, Lefèbvre C, Rigo V. Analgosedation before Less-Invasive Surfactant Administration: A Systematic Review. Vol. 119, Neonatology. S. Karger AG; 2022. p. 137–50. Moschino L, Ramaswamy VV, Reiss IKM, Baraldi E, Roehr CC, Simons SHP. Sedation for less invasive surfactant administration in preterm infants: a systematic review and meta-analysis. Vol. 93, Pediatric Research. Springer Nature; 2023. p. 471–91. Mantecón-Fernández L, Lareu-Vidal S, González-López C, Solís-Sánchez G, Suárez-Rodríguez M. Dexmedetomidine: An Alternative to Pain Treatment in Neonatology. Vol. 10, Children. MDPI; 2023. Portelli K, Kandraju H, Ryu M, Shah PS. Efficacy and safety of dexmedetomidine for analgesia and sedation in neonates: a systematic review. Vol. 44, Journal of Perinatology. Springer Nature; 2024. p. 164–72. Curtis S, Kilpatrick R, Billimoria ZC, Zimmerman K, Tolia V, Clark R, et al. Use of Dexmedetomidine and Opioids in Hospitalized Preterm Infants. JAMA Netw Open. 2023 Nov 3;6(11):E2341033. McDonald D, Palsgraf H, Shah P. Dexmedetomidine – An emerging option for sedation in neonatal patients. Vol. 42, Journal of Perinatology. Springer Nature; 2022. p. 845–55. Nissimov S, Kohn A, Keidar R, Livne A, Shemer M, Gover A, et al. Dexmedetomidine for Less Invasive Surfactant Administration: A Pilot Study. Pediatric Drugs. 2024; Aziz K, Lee HC, Escobedo MB, Hoover A V., Kamath-Rayne BD, Kapadia VS, et al. Part 5: Neonatal Resuscitation: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16 2):S524–50. ATC: App Neofarm- SIN, Italian Society of Neonatology. Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw [Internet]. 1993 Sep 1 [cited 2025 Mar 11];12(6):59–66. Available from: https://europepmc.org/article/med/8413140 Hummel P, Lawlor-Klean P, Weiss MG. Validity and reliability of the N-PASS assessment tool with acute pain. Journal of Perinatology. 2010 Jul;30(7):474–8. Tran DTT, Newton EK, Mount VAH, Lee JS, Mansour C, Wells GA, et al. Rocuronium vs. succinylcholine for rapid sequence intubation: a Cochrane systematic review. Anaesthesia [Internet]. 2017 Jun 1 [cited 2025 Mar 11];72(6):765–77. Available from: https://pubmed.ncbi.nlm.nih.gov/28654173/ Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society: Series B (Methodological) [Internet]. 1995 Jan 1 [cited 2025 Apr 11];57(1):289–300. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.2517-6161.1995.tb02031.x R: The R Project for Statistical Computing [Internet]. [cited 2025 Apr 11]. Available from: https://www.r-project.org/ Chrysostomou C, Schulman SR, Herrera Castellanos M, Cofer BE, Mitra S, Da Rocha MG, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. Journal of Pediatrics. 2014;164(2). Dersch-Mills DA, Banasch HL, Yusuf K, Howlett A. Dexmedetomidine Use in a Tertiary Care NICU: A Descriptive Study. Annals of Pharmacotherapy. 2019 May 1;53(5):464–70. McAdams RM, Pak D, Lalovic B, Phillips B, Shen DD. Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia. Anesthesiol Res Pract. 2020;2020. Sellas MN, Kyllonen KC, Lepak MR, Rodriguez RJ. Dexmedetomidine for the management of postoperative pain and sedation in newborns. Journal of Pediatric Pharmacology and Therapeutics. 2019 May 1;24(3):227–33. Morton SU, Labrecque M, Moline M, Hansen A, Leeman K. Reducing benzodiazepine exposure by instituting a guideline for dexmedetomidine usage in the NICU. Pediatrics. 2021 Nov 1;148(5). Bua J, Massaro M, Cossovel F, Monasta L, Brovedani P, Cozzi G, et al. Intranasal dexmedetomidine, as midazolam-sparing drug, for MRI in preterm neonates. Paediatr Anaesth [Internet]. 2018 Aug 1 [cited 2025 Mar 11];28(8):747–8. Available from: https://pubmed.ncbi.nlm.nih.gov/30144232/ Snyers D, Tribolet S, Rigo V. Intranasal Analgosedation for Infants in the Neonatal Intensive Care Unit: A Systematic Review. Vol. 119, Neonatology. S. Karger AG; 2022. p. 273–84. Herting E, Härtel C, Göpel W. Less invasive surfactant administration (LISA): Chances and limitations. Vol. 104, Archives of Disease in Childhood: Fetal and Neonatal Edition. BMJ Publishing Group; 2019. p. F655–9. De Luca D, de Winter JP. Less invasive surfactant administration: all that glitters is not gold. Vol. 179, European Journal of Pediatrics. Springer; 2020. p. 1295–6. Jourdain G, De Tersant M, Dell’Orto V, Conti G, De Luca D. Continuous positive airway pressure delivery during less invasive surfactant administration: A physiologic study. Journal of Perinatology. 2018 Mar 1;38(3):271–7. Friesen RH, Nichols CS, Twite MD, Cardwell KA, Pan Z, Pietra B, et al. The hemodynamic response to dexmedetomidine loading dose in children with and without pulmonary hypertension. Anesth Analg. 2013 Oct;117(4):953–9. Tervonen M, Cajanus J, Kallio M, Huhtamäki H, Pokka T, Peltoniemi O. Adverse cardiovascular events are common during dexmedetomidine administration in neonates and infants during intensive care. Acta Paediatrica, International Journal of Paediatrics. 2023 Nov 1;112(11):2338–45. Bourgoin L, Caeymaex L, Decobert F, Jung C, Danan C, Durrmeyer X. Administering atropine and ketamine before less invasive surfactant administration resulted in low pain scores in a prospective study of premature neonates. Acta Paediatrica, International Journal of Paediatrics. 2018 Jul 1;107(7):1184–90. Durrmeyer X, Walter-Nicolet E, Chollat C, Chabernaud JL, Barois J, Chary Tardy AC, et al. Premedication before laryngoscopy in neonates: Evidence-based statement from the French society of neonatology (SFN). Vol. 10, Frontiers in Pediatrics. Frontiers Media SA; 2023. Muehlbacher T, Boos V, Geiger LB, Rüegger CM, Grass B. Analgosedation for less-invasive surfactant administration: Variations in practice. Pediatr Pulmonol. 2024 Mar 1;59(3):750–7. Shetty S, Tolentino D, Lau C, Duffy D, Greenough A. Changes in practice of less-invasive surfactant administration (LISA) in United Kingdom neonatal units. Acta Paediatrica, International Journal of Paediatrics. 2024 Feb 1; Peterson J, Den Boer MC, Roehr CC. To Sedate or Not to Sedate for Less Invasive Surfactant Administration: An Ethical Approach. Vol. 118, Neonatology. S. Karger AG; 2021. p. 639–46. Study Details | Premedication for Less Invasive Surfactant Administration | ClinicalTrials.gov [Internet]. [cited 2025 Mar 11]. Available from: https://clinicaltrials.gov/study/NCT03735563?cond=Premedication&term=Less%20invasive%20surfactant%20administration&rank=1 Study Details | The Use of Sedation Drugs in the Procedure of Administering Surfactant Without Intubation (LISA/MIST) | ClinicalTrials.gov [Internet]. [cited 2025 Mar 11]. Available from: https://clinicaltrials.gov/study/NCT04409665 Study Details | Premedication for Less Invasive Surfactant Administration Study (PRELISA) | ClinicalTrials.gov [Internet]. [cited 2025 Mar 11]. Available from: https://clinicaltrials.gov/study/NCT05065424?cond=rds&term=Less%20invasive%20surfactant%20administration&intr=premedication&rank=2 Cite Share Download PDF Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Italian Journal of Pediatrics → Version 1 posted Editorial decision: Major revision 29 Jul, 2025 Reviewers agreed at journal 19 May, 2025 Reviewers invited by journal 05 May, 2025 Editor assigned by journal 15 Apr, 2025 First submitted to journal 14 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6438065","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":452218560,"identity":"751f9456-a396-46cb-8075-dffd2c015412","order_by":0,"name":"Beatrice Galeazzo","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-5613-9138","institution":"Neonatal Intensive Care Unit, Azienda ULSS2-Marca Trevigiana, Ca'Foncello Hospital, Treviso","correspondingAuthor":true,"prefix":"","firstName":"Beatrice","middleName":"","lastName":"Galeazzo","suffix":""},{"id":452218561,"identity":"0d0f9c44-2b8e-47fc-8489-be6874148b6a","order_by":1,"name":"Tormena Francesca","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, Azienda ULSS2-Marca Trevigiana, Ca'Foncello Hospital, Treviso","correspondingAuthor":false,"prefix":"","firstName":"Tormena","middleName":"","lastName":"Francesca","suffix":""},{"id":452218562,"identity":"7bf6ee69-e47e-42d2-a02b-8893decadcf5","order_by":2,"name":"Papappicco Cinzia Anna Maria","email":"","orcid":"","institution":"Unit of Biostatistics, Epidemiology and Public Health, University of Padova","correspondingAuthor":false,"prefix":"","firstName":"Papappicco","middleName":"Cinzia Anna","lastName":"Maria","suffix":""},{"id":452218563,"identity":"fe415349-637a-4e51-aff5-0599a762a43f","order_by":3,"name":"Gomirato Serena","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, Azienda ULSS2-Marca Trevigiana, Ca'Foncello Hospital, Treviso","correspondingAuthor":false,"prefix":"","firstName":"Gomirato","middleName":"","lastName":"Serena","suffix":""},{"id":452218564,"identity":"2fb9eb0a-3d22-4e9d-8d92-d1a0a7995b28","order_by":4,"name":"Vendramin Silvia","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, Azienda ULSS2-Marca Trevigiana, Ca'Foncello Hospital, Treviso","correspondingAuthor":false,"prefix":"","firstName":"Vendramin","middleName":"","lastName":"Silvia","suffix":""},{"id":452218565,"identity":"3742db61-fe7e-4af6-9816-cbb5b47fd846","order_by":5,"name":"Gregori Dario","email":"","orcid":"","institution":"Unit of Biostatistics, Epidemiology and Public Health, University of Padova","correspondingAuthor":false,"prefix":"","firstName":"Gregori","middleName":"","lastName":"Dario","suffix":""},{"id":452218566,"identity":"2177a141-ff92-4b69-ba1a-f496f6e4d384","order_by":6,"name":"Lago Paola","email":"","orcid":"","institution":"Neonatal Intensive Care Unit, Azienda ULSS2-Marca Trevigiana, Ca' Foncello Hospital, Treviso","correspondingAuthor":false,"prefix":"","firstName":"Lago","middleName":"","lastName":"Paola","suffix":""}],"badges":[],"createdAt":"2025-04-13 08:23:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6438065/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6438065/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13052-026-02202-z","type":"published","date":"2026-02-04T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82559247,"identity":"f1da2dd8-7b57-464c-9801-096796033840","added_by":"auto","created_at":"2025-05-13 01:25:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":104966,"visible":true,"origin":"","legend":"\u003cp\u003eFlow-chart of the population\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6438065/v1/eb0ebf32554fef5bf89adeaa.png"},{"id":82559246,"identity":"833a7f14-9954-46d0-b3a1-19ed955edfc0","added_by":"auto","created_at":"2025-05-13 01:25:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63341,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of infants with adequate pain control (NIPS score ≤4) at different phases of the LISA procedure. Points represent the estimated percentage of infants classified as being in good clinical condition, with 95% confidence intervals calculated using the exact binomial method.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6438065/v1/6439ad74e42a65ba43ee91c5.png"},{"id":82559249,"identity":"eb9f5579-7a91-4685-95a7-d2f0664a798d","added_by":"auto","created_at":"2025-05-13 01:25:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":40389,"visible":true,"origin":"","legend":"\u003cp\u003ePredictive model-based trends of NPASS score. The x-axis indicates time in minutes after the start of the LISA procedure. The y-axis shows the estimated values over time predicted by mixed linear models for NPASS score The continuous black line illustrates the model-predicted mean value of each variable over time. The grey area represents the 95% confidence interval for the predicted values.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6438065/v1/9dc00dc2240b0f01ee43adec.png"},{"id":82559259,"identity":"0a855bd5-f0ad-4708-a8d4-b27352a24dbd","added_by":"auto","created_at":"2025-05-13 01:25:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":108965,"visible":true,"origin":"","legend":"\u003cp\u003ePredictive model-based trends of and oxygen saturation (A) and heart rate (B) over time. The x-axis indicates time in minutes after the start of the LISA procedure. The y-axis shows the estimated values over time predicted by mixed linear models of oxygen saturation (A) and heart rate (B) The continuous black line illustrates the model-predicted mean value of each variable over time. The grey area represents the 95% confidence interval for the predicted values.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6438065/v1/a7a940251cdd48d5e570fa90.png"},{"id":102233971,"identity":"da7f4881-46b9-4bbd-ba16-3e06e880ba20","added_by":"auto","created_at":"2026-02-09 16:01:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":914696,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6438065/v1/6fd9bd6c-eed4-4afe-a165-380e9ec38a2e.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eDexmedetomidine for Lisa Procedure: a Single Center Experience\u003c/p\u003e","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eRespiratory distress syndrome (RDS) is the most common respiratory problem in preterm newborns(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The combination of exogenous surfactant administration and non-invasive ventilation is the most effective approach to manage RDS (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmong the various techniques for surfactant delivery, the European Consensus Guidelines on RDS management, recommend Less Invasive Surfactant Administration (LISA) as the preferred method for spontaneously breathing newborns on CPAP with worsening RDS (FiO₂ \u0026gt; 0.30 on CPAP pressure\u0026thinsp;\u0026ge;\u0026thinsp;6 cmH₂O)(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This technique reduces the need for invasive mechanical ventilation during the first 72 hours, lowers the incidence of major outcomes and decreases the risk of death or BPD among survivors (\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eLISA involves the use of a semirigid catheter inserted through the trachea via direct laryngoscopy to administer surfactant while the infant maintains spontaneous breathing and the vocal cords sustain auto-PEEP (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhile a premedication for non-urgent direct laryngoscopy is strongly recommended (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), there is no consensus on sedation for LISA procedure.\u003c/p\u003e \u003cp\u003eSurveys revealed that neonatologists in Europe (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and in the USA (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) don't use sedation for LISA, but they apply non-pharmacological measures such as intra-oral sucrose and swaddling. These measures seem to be effective in achieving comfort in almost 60% of preterm newborns (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eVarious drugs, including Propofol, Fentanyl, and Ketamine, have been evaluated in time, but evidences are low (\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTwo recent systematic review concluded that the use of sedative drugs for LISA in preterm neonates increases the risk of desaturation and the need for NIPPV, although better comfort scores have been observed (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWith the widespread use of this technique, it is essential to establish a more standardized approach to sedation for LISA.\u003c/p\u003e \u003cp\u003eAn ideal drug for this context should have a fast onset, short duration of action, rapid offset, and provide good sedation and analgesia with minimal impact on respiratory drive.\u003c/p\u003e \u003cp\u003eIn the last decades, dexmedetomidine has become increasingly popular in neonatal and pediatric populations. It is an α2-adrenergic agonist that acts on the brainstem by inhibiting norepinephrine release, activating the receptors in the locus coeruleus and decreasing the release of substance P in the dorsal horn of the spinal cord. This leads to its sedative, anxiolytic and analgesic effects without impacting respiratory drive. It is an attractive agent to achieve procedural sedation and pain control in spontaneously breathing newborns (e.g., neuroimaging MRI)(\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecently, a single-center study was published that tested dexmedetomidine for the LISA procedure (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). It concluded that this drug is not associated with severe adverse events and that the rate of LISA success was favorable. However, this is a retrospective study, and pain control and sedation were not assessed.\u003c/p\u003e \u003cp\u003eWith this study we aim to evaluate: 1) the effectiveness of dexmedetomidine for analgesia and sedation during the LISA procedure; 2) the safety of this drug in preterm infants in a pilot study.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Population\u003c/h2\u003e \u003cp\u003eWe conducted a prospective observational study in the tertiary NICU of Ca\u0026rsquo; Foncello Hospital, Treviso, Italy, from May 2021 to July 2024 to assess our new protocol for the LISA procedure.\u003c/p\u003e \u003cp\u003eWe enrolled preterm newborns, with gestational ages ranging from 26\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e to 36\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks (divided in two groups 26\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-31\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e and 32\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-36\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks), who were hospitalized in our NICU, diagnosed with RDS and required surfactant therapy.\u003c/p\u003e \u003cp\u003eThe exclusion criteria were: need for emergency intubation in the delivery room, major congenital malformations (such as cardiopathies), chromosomal abnormalities, fetal hydrops, hypercapnia (CO₂ \u0026gt; 65 mmHg), pneumothorax, and hemodynamic compromise.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDescription of the Procedure\u003c/h3\u003e\n\u003cp\u003eEligible infants were stabilized in the delivery room according to the ILCOR 2020 guidelines (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). If necessary, CPAP or non-invasive ventilation was applied and continued in Neonatal Intensive Care Unit (NICU).\u003c/p\u003e \u003cp\u003eIn accordance with the European guidelines for the management of RDS, LISA procedure was performed early in the course of the disease when the infants showed worsening symptoms, dyspnea, and required FiO₂ \u0026gt; 0.30 on CPAP with a pressure of at least 6 cmH₂O (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). A semirigid catheter for surfactant endotracheal instillation was inserted via the mouth in spontaneously breathing infants. Direct laryngoscopy was performed, and the probe was inserted beyond the vocal cords to the required depth. Once the probe was correctly positioned, surfactant (Poractant alfa, Curosurf, CHIESI Farmaceutici, Parma, Italy) was slowly infused over 2\u0026ndash;3 minutes at an initial dose of 200 mg/kg. At the end of the administration, the catheter was immediately removed. The newborn remained continuously on NIPPV or CPAP delivered throughout nasal mask or prongs during the procedure. All operators were skilled in performing the LISA procedure.\u003c/p\u003e \u003cp\u003eBefore performing LISA, dexmedetomidine was administered at a dose of 1 mcg/kg intravenously in 10 minutes according to the guidelines published in the Neofarm-SIN App by the Italian Society of Neonatology (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). We performed LISA after newborns were adequately sedated .\u003c/p\u003e \u003cp\u003eIn each infant, non-pharmacological comfort techniques were applied, including the administration of 24% oral sucrose in the cheek pouch/tongue with a pacifier for at least 2 minutes before the procedure, and swaddling the infant to keep them contained.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eWe collected the following population characteristics: sex, gestational age, birth weight, Apgar score, type of respiratory support before LISA, fraction of inspired oxygen before LISA and hours of life at the time of the procedure.\u003c/p\u003e \u003cp\u003ePain during the procedure was assessed using the Neonatal Infant Pain Scale (NIPS) (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) which was evaluated before, during, and after LISA procedure. This score considers various parameters (such as crying, facial expression, and arm position) and assigns a score as follows: 0\u0026ndash;2 points\u0026thinsp;=\u0026thinsp;no pain; 3\u0026ndash;4 points\u0026thinsp;=\u0026thinsp;mild-moderate pain; \u0026gt;4 points\u0026thinsp;=\u0026thinsp;severe pain. We targeted an adequate pain control, tolerating a mild pain level during laryngoscopy (NIPS score\u0026thinsp;\u0026lt;\u0026thinsp;4).\u003c/p\u003e \u003cp\u003eSedation was assessed using the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) at the beginning of the procedure, and again at 30\u0026ndash;60 minutes and 120 minutes. This scale evaluates both behavioral parameters (e.g., facial expression) and vital signs to assign a score, as follows: deep sedation: -10 to -5; light sedation: -5 to -2 (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). We aimed to achieve a mild sedation level (N-PASS score \u0026minus;\u0026thinsp;5 to -2) to maintain the integrity of respiratory drive.\u003c/p\u003e \u003cp\u003eAfter LISA had been performed we collected data about efficacy and safety of dexmedetomidine, such as the occurrence of apnea/desaturation +/-bradycardia with or without intubation in the first 72 hours after the procedure, the number of laryngoscopy attempts, the quality of intubation condition at laryngoscopy using the Goldberg score (divided into four categories: excellent- score\u0026thinsp;\u0026lt;\u0026thinsp;3-, good- score 4-6-, poor score 7-9-, or inadequate- score 10\u0026ndash;12)(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), the time taken to perform LISA (defined as the time from the first laryngoscopy to the withdrawal of the catheter from the mouth), and the trend of cardiorespiratory parameters from baseline to 1, 3, 5, 15, 30, 60, and 120 minutes after the first drug injection.\u003c/p\u003e \u003cp\u003eOther adverse events were also collected, including pneumothorax or selective surfactant administration, as well as the incidence of adverse effects related to dexmedetomidine administration (typically cardiovascular events such as persistent bradycardia less then 100 bpm and hypotension defined as blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;third centile for age).\u003c/p\u003e \u003cp\u003eOutcomes were assessed at discharge, including mortality, bronchopulmonary dysplasia (defined as the need for oxygen administration and/or respiratory support at 36 weeks postmenstrual age), intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were reported as absolute numbers (percentages) for categorical variables, and as median (I quartile \u0026ndash; III quartile) for continuous variables. Wilcoxon\u0026rsquo;s rank sum test was used for continuous variables and the Pearson Chi-square test, or the Fisher\u0026rsquo;s exact test when appropriate (n\u0026thinsp;\u0026lt;\u0026thinsp;5 in \u0026gt;\u0026thinsp;20% cells) were used for categorical variables to compare patient characteristics and LISA procedure-related variables between infants with gestational age 26\u0026ndash;31\u0026thinsp;+\u0026thinsp;6 and gestational age 32\u0026ndash;36\u0026thinsp;+\u0026thinsp;6. The NIPS and Golberg scores were dichotomized using thresholds of 4 and 6, respectively; for both scales, scores less than or equal to the cutoff indicating good clinical condition. The proportion of patients classified as being in good condition according to each scale was calculated, with 95% confidence intervals estimated using the exact binomial method. Mixed linear models were used to assess the changes in NPASS score, saturation, and heart rate over time. A two-sided p-value of \u0026lt;\u0026thinsp;0.05 was considered significant. To account for multiple testing, a Benjamini-Hochberg False Discovery Rate (FDR) correction was applied across \"Efficacy and safety of dexmedetomidine premedication\" analyses separately(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) An FDR-corrected p-value (termed \u0026ldquo;q-value\u0026rdquo;) threshold of \u0026lt;\u0026thinsp;0.05 was used to define statistical significance. All analyses were performed using R system version 4.3.2(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e The Ethics Committee of Ospedale Ca\u0026rsquo; Foncello, Treviso, Italy, approved this observational study (number 920/CE MARCA). No additional consent was required, as the implementation of the protocol was considered standard care. All adverse events were collected.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e\u003cbr\u003eBetween May 2021 and July 2024, 82 patients born between 26\u003csup\u003e+0\u003c/sup\u003e and 36\u003csup\u003e+6\u003c/sup\u003e weeks\u0026apos; gestation were treated with surfactant for RDS. Three of them were not eligible for the LISA technique because they were aged less than 26 weeks and intubated in delivery room. 79 underwent the LISA procedure, and 32 were not eligible for dexmedetomidine administration due to hemodynamic instability. Forty-seven patients were managed according to the protocol and received premedication with dexmedetomidine before the procedure. Patients who were not eligible for dexmedetomidine (due to hemodynamic instability) received alternative premedication (Figure 1).\u003c/p\u003e\n\u003cp\u003eThe characteristics of the population are described in Table 1.\u003c/p\u003e\n\u003cp\u003eTable 1. Population characteristics. Comparison of infants with gestational age 26+0-31+6 and gestational age 32+0-36+6.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003cp\u003eN = 47\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e26-31\u003csup\u003e+6\u0026nbsp;\u003c/sup\u003eweeks gestation\u003c/p\u003e\n \u003cp\u003eN = 30\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e32-36\u003csup\u003e+6\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eweeks gestation\u003c/p\u003e\n \u003cp\u003eN = 17\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ep-value\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eGestational age at birth (weeks)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e29+6\u003c/p\u003e\n \u003cp\u003e(28+5, 33+1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e29+2\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(28+2, 29+5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e33+6\u003c/p\u003e\n \u003cp\u003e(33+0-34+5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eBirth weight (grams)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1421\u003c/p\u003e\n \u003cp\u003e(1069, 2074)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1130\u003c/p\u003e\n \u003cp\u003e(1005, 1362)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e2180\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2046, 2340)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Female \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26 (55%)\u003c/p\u003e\n \u003cp\u003e21 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15(50%)\u003c/p\u003e\n \u003cp\u003e15(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (65%)\u003c/p\u003e\n \u003cp\u003e6 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eMode of Delivery\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;C-section n (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Vaginal delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36 (77%)\u003c/p\u003e\n \u003cp\u003e11 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23 (77%)\u003c/p\u003e\n \u003cp\u003e7 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (76%)\u003c/p\u003e\n \u003cp\u003e4 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026gt; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eApgar score at 5 minutes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e9.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(8.00, 9.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e8.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(8.00, 9.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e9.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(8.00, 10.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e before LISA procedure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003cp\u003e(0.30, 0.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003cp\u003e(0.30, 0.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003cp\u003e(0.30-0.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eVentilation mode before LISA procedure\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;nCPAP\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;nPPV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (23%)\u003c/p\u003e\n \u003cp\u003e36 (77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (13%)\u003c/p\u003e\n \u003cp\u003e26 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (41%)\u003c/p\u003e\n \u003cp\u003e10 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eAge at LISA procedure (hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e3.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2.50, 6.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.80\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2.00, 4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e7.50\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(4.00, 15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\" width=\"666\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e n (%); Median (Q1, Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003e Fisher\u0026rsquo;s exact test; Pearson\u0026rsquo;s Chi-squared test; Wilcoxon rank sum test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBefore LISA, 11 patients were treated with nasal CPAP, and 36 patients received non-invasive ventilation support, both delivered through nasal masks or prongs. The median FiO\u003csub\u003e2\u003c/sub\u003e before the LISA procedure was 0.35 (I-III quartiles: 0.30\u0026ndash;0.45), and the median time (hours) to perform LISA was 3 hours (I-III quartiles: 2.5\u0026ndash;6). Patients born at 26\u0026ndash;31\u003csup\u003e+6\u0026nbsp;\u003c/sup\u003eweeks\u0026apos; gestation received surfactant at a median time of 2.8 hours (I-III quartiles: 2\u0026ndash;4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy and safety of the analgo-sedation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the protocol, 1 mcg/kg of dexmedetomidine was administered intravenously slowly before the procedure. The efficacy and safety of dexmedetomidine premedication are described in Table 2.\u003c/p\u003e\n\u003cp\u003eTable 2. Efficacy and safety of dexmedetomidine premedication.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003e\u003cs\u003e\u0026nbsp;\u003c/s\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003cp\u003eN = 47\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e26-31\u003csup\u003e+6\u0026nbsp;\u003c/sup\u003eweeks gestation\u003c/p\u003e\n \u003cp\u003eN = 30\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e32-36\u003csup\u003e+6\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eweeks\u0026nbsp;\u003c/p\u003e\n \u003cp\u003egestation\u003c/p\u003e\n \u003cp\u003eN = 17\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003eq-value\u003csup\u003e2,3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eLaryngoscopy attempts\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 attempt n. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.00, 2.00)\u003c/p\u003e\n \u003cp\u003e31 (66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.00, 2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.00, 2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eGoldberg score (Intubation conditions)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eExcellent intubation conditions (score \u0026lt; 3) n, %\u003c/p\u003e\n \u003cp\u003eGood intubation conditions (score 4-6) n, %\u003c/p\u003e\n \u003cp\u003ePoor intubation condition (score 7-9) n, %\u003c/p\u003e\n \u003cp\u003eInadequate intubation condition (score 10-12) n, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e5.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(3.00, 6.00)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (25,5%)\u003c/p\u003e\n \u003cp\u003e30 (63,8%)\u003c/p\u003e\n \u003cp\u003e5 (10,7%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e4.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(3.00, 5.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e6.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(4.00, 6.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eLISA procedure duration (minutes)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003cp\u003e(2.00, 5.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003cp\u003e(2.00, 4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003cp\u003e(2.00, 5.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eIntubation after LISA (72 hours)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (13%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;41 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (17%)\u003c/p\u003e\n \u003cp\u003e25 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003cp\u003e16 (94%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eTime from LISA to intubation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e*patients with Intubation after LISA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e2.00 (2.00, 16.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e2.00 (2.00, 16.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e2.00 (2.00, 2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e\u0026gt; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eApnea\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (13%)\u003c/p\u003e\n \u003cp\u003e41 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (20%)\u003c/p\u003e\n \u003cp\u003e24 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e17 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eHypotension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (6.4%)\u003c/p\u003e\n \u003cp\u003e44 (93.6%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (6.7%)\u003c/p\u003e\n \u003cp\u003e28 (93.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (5.9%)\u003c/p\u003e\n \u003cp\u003e16 (94.1%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e\u0026gt; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 43.3713%;\"\u003e\n \u003cp\u003eExcessive sedation (NPASS score \u003cu\u003e\u0026lt;\u003c/u\u003e -6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.369%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (6.4%)\u003c/p\u003e\n \u003cp\u003e44 (93.6%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1993%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (6.7%)\u003c/p\u003e\n \u003cp\u003e28 (93.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1915%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (5.9%)\u003c/p\u003e\n \u003cp\u003e16 (94.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7918%;\"\u003e\n \u003cp\u003e\u0026gt; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e n (%); Median (Q1, Q3)\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003e Fisher\u0026rsquo;s exact test; Pearson\u0026rsquo;s Chi-squared test; Wilcoxon rank sum test\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003e False discovery rate correction for multiple testing\u003c/p\u003e\n\u003cp\u003eThe median of Goldberg scale value at intubation was 5 (I-III quartiles: 3\u0026ndash;6). The 90% of newborns had scores \u0026lt; 6 classified as adequate intubation conditions. The median number of intubation attempts was 1 (I-III quartiles: 1\u0026ndash;1).\u003c/p\u003e\n\u003cp\u003eThe NIPS pain score (median, I-III quartiles) was assessed before the procedure (1.5, 1\u0026ndash;3), during laryngoscopy (3, 2\u0026ndash;3), and surfactant administration (2, 1\u0026ndash;3), as well as after the procedure (1, 0\u0026ndash;3). Pain scores at these evaluated times showed no pain before and after the procedure, mild pain during the procedure. Before the procedure 89% of newborns had NIPS score \u0026lt; 4 and 76 % during laryngoscopy, indicating an adequate pain control even during the most invasive part of the procedure (Figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSedation was evaluated using the N-PASS score (median,\u0026nbsp;I-III quartiles) at the beginning of the procedure (1, 1\u0026ndash;2), 30 minutes after the procedure (0, -2\u0026ndash;2), 60 minutes after the procedure (0, -2\u0026ndash;2.5), and 120 minutes after the procedure (0, 0\u0026ndash;1.5). A light sedation (N-PASS -2 to -5) was achieved in 10/43 newborns (23%) before the procedure lasting till 60 minutes after the procedure. Three patients (7%) were deeply sedated before the procedure (N-PASS \u0026lt; -6) and this effect lasted till 120 minutes after the procedure.\u003c/p\u003e\n\u003cp\u003eThe evolution of N-PASS distribution over time is shown in Figure 3 as a linear predictive model.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSix patients (13%) presented apnea and desaturation/bradycardia in the first 24 hours after the procedure, of them 3 were intubated as described above. The other 3 patients were assisted successfully with NIV.\u003c/p\u003e\n\u003cp\u003eSix patients (13%) requested intubation within the first 72 hours after the procedure. Of these, four patients were intubated in the first 2 hours after the procedure: three for recurrent apnea/desaturation +/- bradycardia (all aged less than 32 weeks) and one for a worsening of RDS (33+0). Two other patients were intubated later: one aged 30\u003csup\u003e+ 6\u003c/sup\u003e weeks\u0026rsquo; gestation at 16 hours for pulmonary hypertension and one aged 28 \u003csup\u003e+ 2\u003c/sup\u003e weeks gestation at 36 hours for a worsening of RDS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThree patients developed hypotension (6.4%) in the first hours after the procedure: one extremely preterm baby (less then 28 weeks), one born from C-section after maternal blood losses and one with pulmonary hypertension. In the first two cases no pharmacological therapy was needed.\u003c/p\u003e\n\u003cp\u003eNo pneumothorax or selective surfactant administration was reported.\u003c/p\u003e\n\u003cp\u003eRegarding vital signs in the first two hours after the procedure, the predictive evolution of oxygen saturation and heart rate from baseline is described in Figure 4A and 4B. As expected, desaturation and bradycardia increased during the maneuver from minute 1 to 5 compared to baseline, related to the obstruction to the airways while laryngoscopy was performed and surfactant administered.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome at discharge\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFourteen patients (30%) were diagnosed with BPD (13 aged between 26 and 31+6 weeks\u0026rsquo; gestation). Three patients (6.4%) had minor grade IVH (less than 2), 3 patients (6.4%) had medical NEC and 11 patients (23%) had late onset sepsis. There were no deaths, no PVL. The median length of stay was 51 days (30-62).\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge, this is the first observational prospective study testing the use of dexmedetomidine for analgesia and sedation for LISA procedure.\u003c/p\u003e \u003cp\u003eWe found that the administration of dexmedetomidine was associated with an adequate pain control during laryngoscopy and good intubation conditions (evaluated by the Goldberg score).\u003c/p\u003e \u003cp\u003eHowever, mild sedation was not consistently achieved during the procedure. Sedation scores closer to mild sedation were observed mostly after the procedure, lasting up to 60\u0026ndash;120 minutes.\u003c/p\u003e \u003cp\u003eNotably, excessive sedation (N-PASS \u0026lt; -6) occurred in 7% of patients (3 cases), with 2 of these infants extremely preterm. This suggests a higher sensitivity to dexmedetomidine in this subgroup, warranting consideration of lower dosing strategies for preterm neonates.\"\u003c/p\u003e \u003cp\u003eWe chose dexmedetomidine to perform LISA procedure for its specific characteristics. It is a selective alpha-2 adrenergic receptor agonist that provides both sedative and analgesic effects with minimal respiratory depression (\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Moreover, it is a promising drug as it may offer neuroprotective benefits as demonstrated in preclinical studies (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Continuous intravenous route/infusion has already been used in mechanically ventilated newborns, post-surgical patients, and those undergoing hypothermia treatment (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). For procedural sedation, intranasal administration has been used safely for performing MRI scans (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe results of our study indicate that while an IV bolus of 1 mcg/kg provided adequate pain control during the procedure, however the desired sedative effect (N-PASS score between \u0026minus;\u0026thinsp;2 and \u0026minus;\u0026thinsp;5) was not consistently achieved and sedation scores close to mild sedation persisted for a while period after the procedure. Despite this limitation, good conditions for laryngoscopy and a limited number of attempts were observed.\u003c/p\u003e \u003cp\u003eLISA procedure is typically performed within the first hours of life in newborns with RDS, requiring an ideal drug with a rapid onset and offset of both pain control and sedation. Our findings suggest that dexmedetomidine may not be the optimal agent for this rapid procedure due to its delayed and mild sedative effect.\u003c/p\u003e \u003cp\u003eRegarding the safety profile of dexmedetomidine in our population, analyzing the evolution of vital signs, desaturation and bradycardia were observed in the first minutes of the LISA maneuver. These events were likely related to the procedure itself rather than to the drug administration. As Herting et al. highlighted (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e), desaturation and bradycardia are commonly observed during LISA procedure, as direct laryngoscopy causes hypoxemia and bradycardia; moreover CPAP is poorly transmitted during LISA (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e).In addition, surfactant instillation itself might have negative consequences on hemodynamics (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). These effects could potentially be mitigated by careful laryngoscopy, atropine premedication, and slow administration of surfactant. In our protocol, we did not use atropine, but our findings suggest considering its use to prevent bradycardia during laryngoscopy.\u003c/p\u003e \u003cp\u003eWithin the first 72 hours after the procedure, six patients required intubation (13%), 5 of them aged less than 31 weeks\u0026rsquo; gestation. Four patients were intubated within the first 2 hours after the procedure. Recurrent apnea and desaturation were noted in 3 newborns aged less than 32 weeks, which may be related to the immaturity/prematurity; however we cannot exclude that this may be due to dexmedetomidine effects. In the other patient, intubated in the first hours, we observed a worsening of RDS. The last two patients were intubated respectively at 16 and 36 hours of life for pulmonary hypertension and a worsening of RDS. There is no direct correlation between dexmedetomidine infusion and pulmonary hypertension described in pediatric patients(\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e) and so we assume that in the last three cases, intubation was due to a failure of the LISA procedure itself.\u003c/p\u003e \u003cp\u003eSix patients presented apnea/desaturation and bradycardia (13%), all aged less than 32 weeks. Three of them were intubated and the other three were assisted with NIPPV.\u003c/p\u003e \u003cp\u003eConsidering other cardiovascular effects of dexmedetomidine described in literature (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), hypotension was observed in three patients (6.4%). In two cases, it occurred within the first hours after administration and was managed with supportive therapy (IV fluids). One of these two newborns was born for maternal blood losses, so hypotension may not be related to dexmedetomidine infusion but to fluid depletion. The third case developed hypotension at 16 hours of life in the context of evolving pulmonary hypertension and required inotropes therapy. We did not report persistent bradycardia in the first 24 hours after the procedure.\u003c/p\u003e \u003cp\u003eOur findings on safety align with the retrospective study by Nissimov et al.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), which reported a LISA success rate of 89.2% and no serious adverse events. They noted an incidence of 27% of apnea/desaturation\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;bradycardia in the first 24 hours, that is a higher than ours (13%), Regarding intubation rates we noted in 13% of patients and this was similar to the Israeli report (10.8%).\u003c/p\u003e \u003cp\u003eThe reported rates of apnea/desaturation with other tested drugs for LISA are higher. A prospective observational trial testing ketamine and atropine reported desaturations in 52% of newborns (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). In an RCT comparing propofol with no premedication, the incidence of desaturations was 90% and 70%, respectively (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Another RCT comparing fentanyl with no sedation reported more than 40% of desaturations in the fentanyl group (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur findings are consistent with those of Nissimov et al. and suggest that dexmedetomidine affects respiratory drive to a lesser extent. Moreover, as in Israeli court, we supported patients with NIPPV, which may also be effective in desaturations control (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur results align with recent reviews indicating that the major side effects of dexmedetomidine are cardiovascular, such as bradycardia and hypotension. These effects, as reported in other studies, were generally self-limiting and did not require therapeutic intervention, but only the administration of fluids or supportive care, beyond the withdrawal of the drug itself (\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe observed that more premature infants presented more adverse events such as intubations, apneas or excessive sedation, suggesting the importance of adhering to correct neonatal dosage ranges, especially in this vulnerable and sensitive population.\u003c/p\u003e \u003cp\u003eNissimov et al. (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) reported an incidence of 16.2% of mild hypothermia, suggesting that dexmedetomidine may affect thermoregulation. This parameter was not detected in our study, however the daily controls of temperature reported by the nurses did not disclosure problems.\u003c/p\u003e \u003cp\u003ePremedication for the LISA procedure remains a subject of ongoing debate. To our knowledge, different drugs have been tested in retrospective and observational studies, including ketamine, fentanyl, and propofol. Only one RCT has been conducted by a Danish group comparing propofol and no sedation, and one comparing the use of fentanyl with no sedation in a low-income country (\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). All this trials together with recent systematic reviews encompassing more than 30 studies conclude that sedation reduces discomfort and pain but increases the risk of desaturation/apnea and the failure to maintain spontaneous breathing (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThese reviews underscore the need for a more standardized approach to sedation during LISA, as significant variability exists across centers in the use of both pharmacological and non-pharmacological techniques (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral promising RCT trials about premedication for LISA procedure are now ongoing: one compares propofol versus placebo (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), one the use of ketamine versus fentanyl (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e), one ketamine versus placebo (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e), and fentanyl along with atropine versus placebo (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e). These studies will provide further information about the best strategy for premedication before the LISA procedure.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eThe limitations of this study include the absence of a control group, as we normally perform LISA with premedication. Furthermore, the sample size is limited, and the youngest gestational ages (less than 26 weeks) were not included. Moreover, the assessment of sedation and pain with scales may not always be reliable; we used NIPS and NPASS scores, which involve face evaluation, and this may sometimes be difficult to assess during laryngoscopy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIntravenous dexmedetomidine is a safe drug for performing LISA procedure and provides effective pain control and good intubation conditions. However, mild sedation was not consistently achieved during the procedure. Premedication with dexmedetomidine does not seem ideal for the LISA procedure, as a drug with a more rapid onset is required. While awaiting more robust evidence from ongoing trials, an individualized approach that considers pharmacological and non-pharmacological strategies has to be warranted.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRDS (Respiratory Distress Syndrome), LISA (Less Invasive Surfactant Administration), CPAP (Continuous Positive Airway Pressure), FiO2 (Fraction of Inspired Oxygen), PEEP (Positive end-expiratory pressure), NIPPV (Non-Invasive Positive Pressure Ventilation), NICU (Neonatal Intensive Care Unit).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICAL APPROVAL:\u003c/strong\u003e This study was approved by the RESEARCH ETHICS BOARD APPROVAL of the Ca’ Foncello Hospital (Observational study, number 920/CE Marca)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT OF PUBBLICATION:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAIABILITY:\u003c/strong\u003e Data are available from the authors upon reasonable request\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS:\u003c/strong\u003e The authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING:\u0026nbsp;\u003c/strong\u003eNot founded\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS’CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePL conceived the study design and has given final approval of the actual version, BG made substantial contribution to the conception, design of the study protocol and prepared electronic data sheets, collected data. FT, SG, SV collected data CAMP and DG performed the statistical analysis. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSweet DG, Carnielli VP, Greisen G, Hallman M, Klebermass-Schrehof K, Ozek E, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. Neonatology. 2023 Mar 1;120(1):3\u0026ndash;23.\u003c/li\u003e\n \u003cli\u003eLemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Vol. 2016, Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd; 2016.\u003c/li\u003e\n \u003cli\u003eFischer HS, B\u0026uuml;hrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: A meta-analysis. Vol. 132, Pediatrics. American Academy of Pediatrics; 2013.\u003c/li\u003e\n \u003cli\u003eEarly CPAP versus Surfactant in Extremely Preterm Infants. New England Journal of Medicine. 2010 May 27;362(21):1970\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eAldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: A systematic review and meta-analysis. Vol. 102, Archives of Disease in Childhood: Fetal and Neonatal Edition. BMJ Publishing Group; 2017. p. F17\u0026ndash;23.\u003c/li\u003e\n \u003cli\u003eIsayama T, Iwami H, McDonald S, Beyene J. Association of noninvasiveventilation strategies withmortality and bronchopulmonarydysplasiaamong preterm infants: A systematic review and meta-analysis. In: JAMA - Journal of the American Medical Association. American Medical Association; 2016. p. 611\u0026ndash;24.\u003c/li\u003e\n \u003cli\u003eH\u0026auml;rtel C, Kribs A, G\u0026ouml;pel W, Dargaville P, Herting E. Less Invasive Surfactant Administration for Preterm Infants - State of the Art. Neonatology. S. Karger AG; 2024.\u003c/li\u003e\n \u003cli\u003eLista G, Bresesti I, Fabbri L. Is Less Invasive Surfactant Administration Necessary or only Helpful or Just a Fashion? Vol. 35, American Journal of Perinatology. Thieme Medical Publishers, Inc.; 2018. p. 530\u0026ndash;3.\u003c/li\u003e\n \u003cli\u003eGortner L, Sch\u0026uuml;ller SS, Herting E. Review demonstrates that less invasive surfactant administration in preterm neonates leads to fewer complications. Vol. 107, Acta Paediatrica, International Journal of Paediatrics. Blackwell Publishing Ltd; 2018. p. 736\u0026ndash;43.\u003c/li\u003e\n \u003cli\u003eKribs A, Roll C, G\u0026ouml;pel W, Wieg C, Groneck P, Laux R, et al. Nonintubated surfactant application vs conventional therapy in extremely preterm infants: A randomized clinical trial. JAMA Pediatr. 2015 Aug 1;169(8):723\u0026ndash;30.\u003c/li\u003e\n \u003cli\u003eKumar P, Denson SE, Mancuso TJ, Papile LA, Stark AR, Adamkin DH, et al. Clinical report - Premedication for nonemergency endotracheal intubation in the neonate. Pediatrics. 2010 Mar;125(3):608\u0026ndash;15.\u003c/li\u003e\n \u003cli\u003ePrevention and Management of Procedural Pain in the Neonate: An Update. Pediatrics. 2016 Feb 1;137(2):e20154271.\u003c/li\u003e\n \u003cli\u003eKlotz D, Porcaro U, Fleck T, Fuchs H. European perspective on less invasive surfactant administration\u0026mdash;a survey. Eur J Pediatr. 2017 Feb 1;176(2):147\u0026ndash;54.\u003c/li\u003e\n \u003cli\u003eKurepa D, Perveen S, Lipener Y, Kakkilaya V. The use of less invasive surfactant administration (LISA) in the United States with review of the literature. Journal of Perinatology. 2019 Mar 1;39(3):426\u0026ndash;32.\u003c/li\u003e\n \u003cli\u003ePichler K, Kuehne B, Dekker J, Stummer S, Giordano V, Berger A, et al. Assessment of Comfort during Less Invasive Surfactant Administration in Very Preterm Infants: A Multicenter Study. Neonatology. 2023 Aug 1;120(4):473\u0026ndash;81.\u003c/li\u003e\n \u003cli\u003eDescamps CS, Chevallier M, Ego A, Pin I, Epiard C, Debillon T. Propofol for sedation during less invasive surfactant administration in preterm infants. Vol. 102, Archives of Disease in Childhood: Fetal and Neonatal Edition. BMJ Publishing Group; 2017. p. F465.\u003c/li\u003e\n \u003cli\u003eDekker J, Lopriore E, Rijken M, Rijntjes-Jacobs E, Smits-Wintjens V, Te Pas A. Sedation during Minimal Invasive Surfactant Therapy in Preterm Infants. Neonatology. 2016 Jun 1;109(4):308\u0026ndash;13.\u003c/li\u003e\n \u003cli\u003eDekker J, Lopriore E, Van Zanten HA, Tan RNGB, Hooper SB, Pas ABT. Sedation during minimal invasive surfactant therapy: A randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019 Jul 1;104(4):F378\u0026ndash;83.\u003c/li\u003e\n \u003cli\u003eBrotelande C, Mil\u0026eacute;si C, Combes C, Durand S, Badr M, Cambonie G. Premedication with ketamine or propofol for less invasive surfactant administration (LISA): observational study in the delivery room. Eur J Pediatr. 2021 Sep 1;180(9):3053\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eChevallier M, Durrmeyer X, Ego A, Debillon T, Beuchee A, Bourgoin L, et al. Propofol versus placebo (with rescue with ketamine) before less invasive surfactant administration: Study protocol for a multicenter, double-blind, placebo controlled trial (PROLISA). BMC Pediatr. 2020 May 8;20(1).\u003c/li\u003e\n \u003cli\u003eSk H, Saha B, Mukherjee S, Hazra A. Premedication with Fentanyl for Less Invasive Surfactant Application (LISA): A Randomized Controlled Trial. J Trop Pediatr. 2022 Apr 1;68(2).\u003c/li\u003e\n \u003cli\u003eTribolet S, Hennuy N, Snyers D, Lef\u0026egrave;bvre C, Rigo V. Analgosedation before Less-Invasive Surfactant Administration: A Systematic Review. Vol. 119, Neonatology. S. Karger AG; 2022. p. 137\u0026ndash;50.\u003c/li\u003e\n \u003cli\u003eMoschino L, Ramaswamy VV, Reiss IKM, Baraldi E, Roehr CC, Simons SHP. Sedation for less invasive surfactant administration in preterm infants: a systematic review and meta-analysis. Vol. 93, Pediatric Research. Springer Nature; 2023. p. 471\u0026ndash;91.\u003c/li\u003e\n \u003cli\u003eMantec\u0026oacute;n-Fern\u0026aacute;ndez L, Lareu-Vidal S, Gonz\u0026aacute;lez-L\u0026oacute;pez C, Sol\u0026iacute;s-S\u0026aacute;nchez G, Su\u0026aacute;rez-Rodr\u0026iacute;guez M. Dexmedetomidine: An Alternative to Pain Treatment in Neonatology. Vol. 10, Children. MDPI; 2023.\u003c/li\u003e\n \u003cli\u003ePortelli K, Kandraju H, Ryu M, Shah PS. Efficacy and safety of dexmedetomidine for analgesia and sedation in neonates: a systematic review. Vol. 44, Journal of Perinatology. Springer Nature; 2024. p. 164\u0026ndash;72.\u003c/li\u003e\n \u003cli\u003eCurtis S, Kilpatrick R, Billimoria ZC, Zimmerman K, Tolia V, Clark R, et al. Use of Dexmedetomidine and Opioids in Hospitalized Preterm Infants. JAMA Netw Open. 2023 Nov 3;6(11):E2341033.\u003c/li\u003e\n \u003cli\u003eMcDonald D, Palsgraf H, Shah P. Dexmedetomidine \u0026ndash; An emerging option for sedation in neonatal patients. Vol. 42, Journal of Perinatology. Springer Nature; 2022. p. 845\u0026ndash;55.\u003c/li\u003e\n \u003cli\u003eNissimov S, Kohn A, Keidar R, Livne A, Shemer M, Gover A, et al. Dexmedetomidine for Less Invasive Surfactant Administration: A Pilot Study. Pediatric Drugs. 2024;\u003c/li\u003e\n \u003cli\u003eAziz K, Lee HC, Escobedo MB, Hoover A V., Kamath-Rayne BD, Kapadia VS, et al. Part 5: Neonatal Resuscitation: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16 2):S524\u0026ndash;50.\u003c/li\u003e\n \u003cli\u003eATC: App Neofarm- SIN, Italian Society of Neonatology.\u003c/li\u003e\n \u003cli\u003eLawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw [Internet]. 1993 Sep 1 [cited 2025 Mar 11];12(6):59\u0026ndash;66. Available from: https://europepmc.org/article/med/8413140\u003c/li\u003e\n \u003cli\u003eHummel P, Lawlor-Klean P, Weiss MG. Validity and reliability of the N-PASS assessment tool with acute pain. Journal of Perinatology. 2010 Jul;30(7):474\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eTran DTT, Newton EK, Mount VAH, Lee JS, Mansour C, Wells GA, et al. Rocuronium vs. succinylcholine for rapid sequence intubation: a Cochrane systematic review. Anaesthesia [Internet]. 2017 Jun 1 [cited 2025 Mar 11];72(6):765\u0026ndash;77. Available from: https://pubmed.ncbi.nlm.nih.gov/28654173/\u003c/li\u003e\n \u003cli\u003eBenjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society: Series B (Methodological) [Internet]. 1995 Jan 1 [cited 2025 Apr 11];57(1):289\u0026ndash;300. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.2517-6161.1995.tb02031.x\u003c/li\u003e\n \u003cli\u003eR: The R Project for Statistical Computing [Internet]. [cited 2025 Apr 11]. Available from: https://www.r-project.org/\u003c/li\u003e\n \u003cli\u003eChrysostomou C, Schulman SR, Herrera Castellanos M, Cofer BE, Mitra S, Da Rocha MG, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. Journal of Pediatrics. 2014;164(2).\u003c/li\u003e\n \u003cli\u003eDersch-Mills DA, Banasch HL, Yusuf K, Howlett A. Dexmedetomidine Use in a Tertiary Care NICU: A Descriptive Study. Annals of Pharmacotherapy. 2019 May 1;53(5):464\u0026ndash;70.\u003c/li\u003e\n \u003cli\u003eMcAdams RM, Pak D, Lalovic B, Phillips B, Shen DD. Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia. Anesthesiol Res Pract. 2020;2020.\u003c/li\u003e\n \u003cli\u003eSellas MN, Kyllonen KC, Lepak MR, Rodriguez RJ. Dexmedetomidine for the management of postoperative pain and sedation in newborns. Journal of Pediatric Pharmacology and Therapeutics. 2019 May 1;24(3):227\u0026ndash;33.\u003c/li\u003e\n \u003cli\u003eMorton SU, Labrecque M, Moline M, Hansen A, Leeman K. Reducing benzodiazepine exposure by instituting a guideline for dexmedetomidine usage in the NICU. Pediatrics. 2021 Nov 1;148(5).\u003c/li\u003e\n \u003cli\u003eBua J, Massaro M, Cossovel F, Monasta L, Brovedani P, Cozzi G, et al. Intranasal dexmedetomidine, as midazolam-sparing drug, for MRI in preterm neonates. Paediatr Anaesth [Internet]. 2018 Aug 1 [cited 2025 Mar 11];28(8):747\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/30144232/\u003c/li\u003e\n \u003cli\u003eSnyers D, Tribolet S, Rigo V. Intranasal Analgosedation for Infants in the Neonatal Intensive Care Unit: A Systematic Review. Vol. 119, Neonatology. S. Karger AG; 2022. p. 273\u0026ndash;84.\u003c/li\u003e\n \u003cli\u003eHerting E, H\u0026auml;rtel C, G\u0026ouml;pel W. Less invasive surfactant administration (LISA): Chances and limitations. Vol. 104, Archives of Disease in Childhood: Fetal and Neonatal Edition. BMJ Publishing Group; 2019. p. F655\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eDe Luca D, de Winter JP. Less invasive surfactant administration: all that glitters is not gold. Vol. 179, European Journal of Pediatrics. Springer; 2020. p. 1295\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eJourdain G, De Tersant M, Dell\u0026rsquo;Orto V, Conti G, De Luca D. Continuous positive airway pressure delivery during less invasive surfactant administration: A physiologic study. Journal of Perinatology. 2018 Mar 1;38(3):271\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eFriesen RH, Nichols CS, Twite MD, Cardwell KA, Pan Z, Pietra B, et al. The hemodynamic response to dexmedetomidine loading dose in children with and without pulmonary hypertension. Anesth Analg. 2013 Oct;117(4):953\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eTervonen M, Cajanus J, Kallio M, Huhtam\u0026auml;ki H, Pokka T, Peltoniemi O. Adverse cardiovascular events are common during dexmedetomidine administration in neonates and infants during intensive care. Acta Paediatrica, International Journal of Paediatrics. 2023 Nov 1;112(11):2338\u0026ndash;45.\u003c/li\u003e\n \u003cli\u003eBourgoin L, Caeymaex L, Decobert F, Jung C, Danan C, Durrmeyer X. Administering atropine and ketamine before less invasive surfactant administration resulted in low pain scores in a prospective study of premature neonates. Acta Paediatrica, International Journal of Paediatrics. 2018 Jul 1;107(7):1184\u0026ndash;90.\u003c/li\u003e\n \u003cli\u003eDurrmeyer X, Walter-Nicolet E, Chollat C, Chabernaud JL, Barois J, Chary Tardy AC, et al. Premedication before laryngoscopy in neonates: Evidence-based statement from the French society of neonatology (SFN). Vol. 10, Frontiers in Pediatrics. Frontiers Media SA; 2023.\u003c/li\u003e\n \u003cli\u003eMuehlbacher T, Boos V, Geiger LB, R\u0026uuml;egger CM, Grass B. Analgosedation for less-invasive surfactant administration: Variations in practice. Pediatr Pulmonol. 2024 Mar 1;59(3):750\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eShetty S, Tolentino D, Lau C, Duffy D, Greenough A. Changes in practice of less-invasive surfactant administration (LISA) in United Kingdom neonatal units. Acta Paediatrica, International Journal of Paediatrics. 2024 Feb 1;\u003c/li\u003e\n \u003cli\u003ePeterson J, Den Boer MC, Roehr CC. To Sedate or Not to Sedate for Less Invasive Surfactant Administration: An Ethical Approach. Vol. 118, Neonatology. S. Karger AG; 2021. p. 639\u0026ndash;46.\u003c/li\u003e\n \u003cli\u003eStudy Details | Premedication for Less Invasive Surfactant Administration | ClinicalTrials.gov [Internet]. [cited 2025 Mar 11]. Available from: https://clinicaltrials.gov/study/NCT03735563?cond=Premedication\u0026amp;term=Less%20invasive%20surfactant%20administration\u0026amp;rank=1\u003c/li\u003e\n \u003cli\u003eStudy Details | The Use of Sedation Drugs in the Procedure of Administering Surfactant Without Intubation (LISA/MIST) | ClinicalTrials.gov [Internet]. [cited 2025 Mar 11]. Available from: https://clinicaltrials.gov/study/NCT04409665\u003c/li\u003e\n \u003cli\u003eStudy Details | Premedication for Less Invasive Surfactant Administration Study (PRELISA) | ClinicalTrials.gov [Internet]. [cited 2025 Mar 11]. Available from: https://clinicaltrials.gov/study/NCT05065424?cond=rds\u0026amp;term=Less%20invasive%20surfactant%20administration\u0026amp;intr=premedication\u0026amp;rank=2\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"RDS, LISA, sedation, dexmedetomidine","lastPublishedDoi":"10.21203/rs.3.rs-6438065/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6438065/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e Respiratory Distress Syndrome (RDS) is the most common respiratory problem of preterm newborns. The preferred way to manage RDS is with Less Invasive Surfactant Administration (LISA), which involves direct laryngoscopy in spontaneously breathing infants. Despite its widespread diffusion, the optimal sedation protocol for LISA remains unclear. Dexmedetomidine, an α2-adrenergic agonist, offers sedative and analgesic properties with minimal respiratory depression. This pilot study evaluates the efficacy and safety of dexmedetomidine for analgesia and sedation during the LISA procedure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e This is a prospective observational study conducted in our tertiary Italian NICU from May 2021 to July 2024. We enrolled preterm neonates aged between 26\u003csup\u003e+0 \u003c/sup\u003eto 36\u003csup\u003e+6\u003c/sup\u003e weeks, diagnosed with RDS who required LISA. Dexmedetomidine (1 mcg/kg) was administered intravenously before LISA. Primary outcomes included pain control assessed by Neonatal Infant Pain Scale (NIPS) score, sedation adequacy assessed by Neonatal Pain, Agitation, and Sedation Scale (N-PASS), and success rate of the procedure. We also assessed the safety of the procedure evaluating adverse events, such as intubation rates, apneas/desaturations, bradycardia, and hypotension. We divided the newborns into two groups based on a cut-off of 32 weeks.\u003c/p\u003e\n\u003cp\u003eResults Forty seven preterm newborns received dexmedetomidine. The median (IQR) gestational age, birth weight (grams) and age (hours) at LISA were respectively 29+6 (28+5, 33+1), 1421 (1069-2074), 3(2.5-6). Pain scores indicated adequate pain control during the procedure (NIPS \u0026lt;4 in 76% during laryngoscopy). Mild sedation (N-PASS -2 to -5) was observed in 23% of patients before the procedure, lasting up to 60 minutes. Excessive sedation (N-PASS \u0026lt; -5) occurred in 7% of babies (3 patients). Laryngoscopy conditions were optimal in 90% of neonates (Goldberg score \u0026lt;6). Apnea/desaturation with/without bradycardia occurred in 13% of newborns. Six patients were intubated (13%) within 72 hours after the procedure. Hypotension was noted in 6.4% of patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e Dexmedetomidine provided effective analgesia and facilitated laryngoscopy but did not consistently achieve mild sedation during LISA. While its safety profile was acceptable, a more rapid-onset sedative may be preferable for this procedure. Further randomized controlled trials are needed to establish an optimal sedation strategy for LISA in preterm newborns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration \u003c/strong\u003eRegister:\u003cstrong\u003e \u003c/strong\u003eClinicalTrials.gov, number ID NCT04820101, enregistered 03-29-2021, https://clinicaltrials.gov/study/NCT04820101?cond=RDS\u0026amp;term=dexmedetomidine\u0026amp;rank=1#study-record-dates\u003c/p\u003e","manuscriptTitle":"Dexmedetomidine for Lisa Procedure: a Single Center Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 01:25:15","doi":"10.21203/rs.3.rs-6438065/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-07-29T10:48:36+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-19T08:02:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-05T16:56:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-15T13:24:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2025-04-14T08:42:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d4b8944f-1cf4-497d-8df3-bdde88bcae34","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:00:25+00:00","versionOfRecord":{"articleIdentity":"rs-6438065","link":"https://doi.org/10.1186/s13052-026-02202-z","journal":{"identity":"italian-journal-of-pediatrics","isVorOnly":false,"title":"Italian Journal of Pediatrics"},"publishedOn":"2026-02-04 15:57:12","publishedOnDateReadable":"February 4th, 2026"},"versionCreatedAt":"2025-05-13 01:25:15","video":"","vorDoi":"10.1186/s13052-026-02202-z","vorDoiUrl":"https://doi.org/10.1186/s13052-026-02202-z","workflowStages":[]},"version":"v1","identity":"rs-6438065","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6438065","identity":"rs-6438065","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}