Association of full premedication on tracheal intubation outcomes in the neonatal intensive care unit: an observational cohort study

Evaluate the association of short-term tracheal intubation (TI) outcomes with premedication in the NICU. Observational single-center cohort study comparing TIs with full premedication (opiate analgesia and vagolytic and paralytic), partial premedication, and no premedication. The primary outcome is adverse TI associated events (TIAEs) in intubations with full premedication compared to those with partial or no premedication. Secondary outcomes included change in heart rate and first attempt TI success. 352 encounters in 253 infants (median gestation 28 weeks, birth weight 1100 g) were analyzed. TI with full premedication was associated with fewer TIAEs aOR 0.26 (95%CI 0.1–0.6) compared with no premedication, and higher first attempt success aOR 2.7 (95%CI 1.3–4.5) compared with partial premedication after adjusting for patient and provider characteristics. The use of full premedication for neonatal TI, including an opiate, vagolytic, and paralytic, is associated with fewer adverse events compared with no and partial premedication.

Intubation premedication, including analgesics, vagolytics, and paralytics, has been shown to improve TI success and reduce adverse events [2, 4-6, 11, 12]. The vagolytic atropine mitigates vagally induced bradycardia, reduces oral secretions, and may minimize hypoxemia during TI when paired with paralysis [6,11]. Analgesics such as opioids are used to reduce the discomfort of intubation. Morphine is a commonly used opiate for pain control in the neonatal population. However, the rapid onset and short duration of the synthetic opiate fentanyl make it a better choice for TI [6,11]. Using a paralytic may contribute to a more controlled environment for intubation and optimize the position and view of the airway landmarks [3,4,6]. The ideal paralytic is one with quick onset and short duration of action, improving the outcome of intubation without eliminating a neonate's spontaneous ventilatory drive for a prolonged time [6,11,13].
While premedication has been recommended for non-emergent neonatal TI [11], there remains considerable practice variation among Neonatal Intensive Care Units (NICUs) [2-6, 8, 14-18]. In a recent manuscript from the National Emergency Airway Registry for Neonates (NEAR4NEOS), Ozawa et al. found significantly fewer TI attempts and improved first attempt success for intubations performed with opiate sedation and a paralytic compared with intubations performed without medications [4]. However, they did not specifically evaluate the use of atropine in combination with opiate sedation and paralysis.
We conducted an observational cohort study to evaluate the association between premedication and short-term TI outcomes. We aimed to compare TI using an opiate analgesic, vagolytic and paralytic (full premedication) with TI using a partial combination of premedication or no medications. We hypothesized that intubations with full premedication would have fewer TIAEs and higher first attempt success rates than intubations with partial or no premedication.

Setting and design
This observational cohort study was performed at a single academic NICU using prospectively collected data from NEAR4NEOS, a multicenter collaborative with the goal of improving neonatal intubation safety [19,20]. The University of Washington Medical Center (UWMC) is a 46-bed, level IV NICU with a delivery service of approximately 1900 deliveries each year. The UWMC has participated as a clinical site within the NEAR4NEOS collaborative since 2016. The NEAR4NEOS data collection form captures patient, practice, provider, and TI outcome data for delivery room and NICU intubations as described in standard operational definitions [19,20]. Data forms are filled out immediately following each intubation by the provider(s) performing the intubation. For accuracy, research assistants audit all data forms and input data into a secure Research Electronic Data Capture (REDCap). This study was determined exempt from signed informed consent by the Seattle Children's Institutional Review Board (IRB # 14922) with the UWMC NICU included as a participating site.

Data collection and operational definitions
Data were collected from all in-unit TI encounters between June 2017 and December 2021. The NEAR4NEOS defines an intubation encounter as one advanced airway management event and an intubation course as one method or approach to securing the airway (e.g., oral or nasal) [19,20]. A single TI encounter may have multiple courses, and some infants in the cohort had multiple TI encounters within the data collection period. We included only the first course of each TI encounter as data from subsequent courses may not be independent of each other [4]. We included the medications administered prior to the first TI course. We excluded TIs performed in the delivery room or in the setting of unstable hemodynamics, such as ongoing Cardiopulmonary Resuscitation (CPR), as premedication is not indicated during those circumstances.

Adverse tracheal intubation associated events
The NEAR4NEOS defines TIAEs as any unwanted outcome or event that occurred because of the intubation or observed during or after the intubation [3,4,19,20] (see Supplementary Table 1). Vital sign data collected by the intubating team includes the highest pulse oximetry and heart rate reading immediately before the first TI attempt and the lowest pulse oximetry and heart rate reading during the course. Severe oxygen desaturation was captured separately from TIAE and defined as ≥20% decrease from the highest oxygen saturation (SpO 2 ) during the intubation course [4]. The heart rate difference was defined as the absolute change in heart rate during the first TI course.

Premedication
During the study period, the UWMC NICU underwent practice changes to enhance the use of premedication for non-emergent TI. Practice changes included creating an intubation medication order set with fentanyl, atropine, and the shorter acting rocuronium premedication. Fentanyl was selected over morphine based on the faster onset of action compared with slower acting morphine in the context of intubation. Due to concerns for the rare side effect of rigid chest with fentanyl in intubations without a paralytic, some providers prefer morphine as an analgesic, and final choice of premedication was at the discretion of the intubating provider. For this study, "full premedication" was defined as opiate analgesia (morphine or fentanyl) with a vagolytic (atropine) and paralytic (rocuronium or vecuronium). "Partial premedication" was defined as opiate and/or vagolytic, and/or paralytic. Intubations performed without premedication (no vagolytic, opiate, or paralytic) were defined as "no premedication".

Outcomes
The primary outcome is the incidence of adverse tracheal intubation associated events (TIAE). Secondary outcomes included change in heart rate during the intubation course, severe oxygen desaturation, and intubation success (first attempt success and number of intubation attempts).

Statistical analysis
We evaluated the primary and secondary outcomes across three premedication groups: full premedication, partial premedication, and no premedication, as defined above. Using SAS® OnDemand for Academics (Cary, NC: SAS Institute Inc.), we generated descriptive statistics, including median and interquartile range (IQR) for nonparametric variables. Patient characteristics and intubation practice measures were compared across three groups. Continuous variables such as age, weight, and heart rate were analyzed between groups using one-way Analysis of Variance with post-hoc comparisons using the Tukey's honestly significant difference (HSD). The Kruskal-Wallis test was used for nonparametric variables. Categorical variables such as patient, practice, provider characteristics, and TIAEs were compared between groups using Chi-square testing. A multivariable logistic regression model was used to adjust for confounding variables known to impact intubation success and safety, such as age at intubation, weight at intubation <1.5 kg, comorbidities (history of a difficult airway, acute or chronic respiratory failure), intubation indication (frequent apnea or bradycardia, elective procedure, or reintubation after unplanned extubation, surfactant delivery), and the device used (direct or video laryngoscopy). After visual confirmation of heteroscedasticity of residuals when performing multivariable linear regression to evaluate heart rate difference during intubation across three groups, it was decided to perform the analyses using quantile regression adjusting for similar covariates as listed above. All statistical tests were two-sided, a p value of <0.05 was considered statistically significant.

Cohort characteristics
In total, 352 intubation encounters in 253 infants were analyzed (Fig. 1). The median gestational age was 28 weeks (IQR 25-32), and the median birth weight was 1.1 kg (IQR 0.7-1.9). Detailed description of the full, partial and no premedication groups may be found in Table 1. A total of 206 encounters included opiate analgesia (n = 116, 56% morphine, n = 90, 44% fentanyl). After the introduction of the standardized medication order set, 8 (8%) intubations with an opiate used morphine while 89 (92%) used fentanyl. Of the 82 TIs with a paralytic, 23 (28%) included vecuronium and 59 (72%) rocuronium. After order set introduction, all intubations using a paralytic were performed with rocuronium. A total of 212 or 89% of encounters using any premedication used the vagolytic atropine specifically as a premedication (Fig. 1).
Neonates in the group receiving full premedication were more commonly older (≥28 days at intubation) and larger at the time of intubation. In contrast, intubations performed on the day of birth were more likely to use no medications (Table 1). Before an elective procedure (e.g., Magnetic Resonance Imaging (MRI) or retinopathy of prematurity (ROP) surgery), full premedication was used significantly more often than partial or no premedication (full n = 12, 15%, partial n = 4, 3%, and no premedication n = 0, p < 0.0001). There were no significant differences in the provider intubating on the first attempt between groups (Table 1). Severe oxygen desaturation is defined as 20% or more absolute change from the highest oxygen saturation during the intubation course.

Primary outcome
Adverse TI associated events (TIAEs) occurred in 32% of all encounters. Non-severe and severe adverse events were noted in 91 (26%) and 23 (7%) of encounters, respectively. While the nonsevere TIAE of "dysrhythmia" includes tachycardia, bradycardia with heart rate <60 bpm and other arrhythmias, 98% (40/41) of the cohort with "dysrhythmia" during TI had bradycardia <60 bpm ( Table 2). In the univariate analysis, infants intubated with full premedication had fewer TIAEs (p < 0.001), including dysrhythmia (p < 0.0001) when compared to those intubated with no premedication (Table 2 and Fig. 2). When adjusting for confounding factors in the multivariable logistic regression model, the adjusted odds of any adverse TIAE was significantly lower for those neonates intubated with full premedication compared to infants who received no premedication (aOR 0.26 (95% CI 0.1-0.6), p = 0.001) (Fig. 3a). Study power for our primary outcome was assessed post-hoc and found to be 94.5% for the comparison between full and no premedication groups and 71.1% for the analysis between full and partial premedication.

Secondary outcomes
Change in heart rate during intubation. The median highest heart rate at the start of the intubation was 159 bpm (IQR: 140, 170) for those infants receiving no premedication, 170 bpm (IQR: 156, 181) for partial, and 179 bpm (IQR: 168,190) for the full premedication groups. The median lowest heart rate during intubation was 96 bpm (IQR: 55,130) for no premedication, 140 bpm (IQR: 106,154) for partial, and 158 bpm (IQR: 140, 173) for full premedication groups. The median heart rate decreased 12% from baseline at the start of intubation for the full premedication group compared with 18% Fig. 3 Multivariate analysis of primary and secondary outcomes comparing three premedication groups. Adjusted Odds Ratios (aOR) comparing full premedication with no premedication and partial premedication groups for any adverse TIAE (a), severe bradycardia 1 (b), first attempt intubation success (c), and severe oxygen desaturation 2 (d). 1 Defined as heart rate <60 bpm during intubation as described in TIAE "dysrhythmia", 2 Severe Oxygen Desaturation is defined as ≥20% decrease from highest recorded SpO 2 during intubation.
decrease from baseline for the partial and 40% decrease in heart rate from baseline for neonates intubated without premedication (see Supplementary Fig. 1). This result was validated using quantile regression against the median. Overall, there were fewer instances of mild or severe change in heart rate (lowest heart rate during intubation <100 bpm or <60 bpm, respectively) during intubation with full compared to no premedication in both the univariate and multivariate models ( Table 2 and Fig. 3b). Within the full premedication group, only 7 (10%) TI encounters had greater than 40% decrease in heart rate from the highest heart rate recorded during the TI course, compared with 34 (23%) in the partial and 44 (43%) in the no premedication group (full vs. partial: p = 0.03, full vs. none: p < 0.0001).
First attempt intubation success was greater for intubations using full premedication compared to partial premedication on univariate analysis (n = 40, 49% vs. n = 47, 30%, p = 0.003) and multivariate analysis adjusting for factors such as age and weight at intubation, history of a difficult airway and intubation indication (frequent apnea or bradycardia, elective procedure, or reintubation after unplanned extubation, surfactant delivery), as well as the device used (direct or video laryngoscopy) (aOR 2.7 (95% CI 1.3-4.5), p = 0.004) (Fig. 3c). There was no difference in first attempt success comparing the group of infants intubated with full compared with the no premedication group (aOR 1.7) (95% CI 0.8-3.3, p = 0.15).
Oxygen saturation and severe oxygen desaturation. The median pre-intubation oxygen saturation was 100% (IQR 97,100) for all encounters. Severe oxygen desaturation episodes occurred in 47% of total encounters. There was no difference with respect to severe oxygen desaturation during intubation between groups (full vs. partial: p = 0.37, full vs. none: p = 0.23) (Table 2, Fig. 2). There was a significant difference in the multivariate analysis with nearly two times the occurrence of severe oxygen desaturation for intubations performed with partial premedication vs. no premedication (aOR 1.9 (95% CI 1.1-3.4), p = 0.03) (Fig. 3d).

DISCUSSION
In our single-center observational cohort study, we found that neonates receiving an opiate, vagolytic, and paralytic premedication before intubation were less likely to suffer an adverse TI associated event compared with those receiving either a partial combination of premedication or no premedication. This improvement in TIAEs is especially relevant as neonatal TI remains a challenging technical skill, particularly for learners. In addition, the use of full premedication may create a more controlled environment for intubation ensuring patient comfort while minimizing bradycardia and desaturation [3,4,6].
Despite recommendations in the neonatal intubation literature, much variability persists regarding premedication usage in the NICU [11,16,21]. Sarkar et al. surveyed NICU fellowship program directors in 2006 and found that 44% of 78 programs responding used sedation for non-emergent TI while only 18% routinely used paralysis; 9 respondents co-administered atropine with opiate analgesia or sedative (e.g., benzodiazepine) and a paralytic [17]. More recently, Muniraman et al. surveyed 693 neonatologists, 23% of the practicing members of the AAP Perinatal Section in 2015, and found that still only one-third of neonatologists across all levels of unit [22] reported frequent use of intubation premedication with only 20% of respondents reporting use of a combination of analgesia, muscle relaxant and vagolytic agents [16]. The specific evaluation of atropine in the context of intubation outcomes in this analysis adds a clinically relevant perspective surrounding the role of atropine in relation to adverse outcomes such as hypoxemia and bradycardia during tracheal intubation.
Our primary outcome was the incidence of adverse TIAEs between premedication groups. We found the group of infants intubated with full premedication to have significantly fewer adverse TI associated events even in the adjusted model compared to those who received both partial and no premedication. We did not find a difference in the incidence of adverse TIAEs comparing the partial premedication group with the no premedication group. This is in comparison to results in Ozawa et al. indicating a higher occurrence of adverse TIAEs for intubations in the sedation only group compared with no medication [4]. Interestingly, similar to their study, we also identified higher odds of severe oxygen desaturation in the partial premedication groups compared to no premedication. These findings may be clinically relevant, particularly when premedication is considered for patients undergoing intubation for surfactant therapy with planned immediate extubation (INSURE) [16,23] or the thin catheter based less invasive surfactant administration (LISA) [24].
Patients intubated for INSURE remain at risk for adverse events associated with laryngoscopy and endotracheal tube placement. However, they are not good candidates for premedication with a paralytic as they must maintain spontaneous breathing immediately following extubation. Patients undergoing LISA may benefit from analgesia given the need for laryngoscopy and instrumentation in the form of a thin intratracheal catheter. Currently, there is no consensus regarding standard premedication for INSURE or LISA. A small, controlled trial by Sk et al. randomized 34 preterm infants to either receive IV fentanyl or placebo prior to LISA and found a higher level of comfort (significant decrease in premature infant pain scores) for infants receiving fentanyl compared with placebo. These investigators reported fewer attempts at catheter placement. There was an increased incidence of desaturation and bradycardia during the procedure for the fentanyl group compared with placebo, however, these outcomes did not reach statistical significance [24]. A retrospective study of moderately preterm infants receiving surfactant with INSURE using a number of premedications including theophylline, morphine and pentobarbital did not report desaturation or bradycardia during intubation as an outcome [25].
While our study results showed no difference in TIAEs between the partial and no premedication groups there was significantly more hypoxemia during intubation with partial premedication. These results add to the literature evaluating the use of partial premedication for intubation. While we support use of premedication for INSURE and LISA to maintain patient comfort during awake intubation, we advise providers to use caution from the standpoint of adverse intubation events [24,26]. Furthermore, as units explore the use of high-flow nasal cannula or other forms of supplemental oxygen therapy as a method of prolonging the time to desaturation during neonatal TI, future studies should objectively characterize the benefits of partial premedication (e.g., improved comfort) while minimizing the risks of adverse intubation events within this context [27].
Our secondary outcomes included the change in heart rate during intubation and first attempt success between premedication groups. We found the partial and full premedication groups to have significantly less heart rate change during intubation than no premedication. This finding is in line with previous studies of intubation safety and adverse events [2,6,18,26]. Bradycardia during intubation may be due to vagal stimulation from laryngoscopy and endotracheal tube placement, as well as from hypoxemia [26]; atropine mitigates this vagally induced bradycardia. Since atropine was used in nearly all intubations in the full premedication group and 83% of the partial premedication group, it was not surprising that we saw no difference in mild or severe bradycardia between full and partial premedication groups.
Even transient episodes of bradycardia may be clinically significant in that fluctuations in perfusion may be associated with changes in cerebral perfusion pressure that could contribute to the development or worsening of intraventricular hemorrhage [6,8,10]. Theoretically, the use of full premedication, including a paralytic, could potentially mitigate these changes in cerebral hemodynamics occurring during intubation, such as fluctuations in the partial pressure of carbon dioxide (pCO 2 ), bradycardia, and hypoxemia [10,13]. In our dataset, all infants with greater than 40% decrease from their highest recorded heart rate had a low heart rate during TI encounter of less than 100 bpm. Compared with partial and no premedication groups, we found significantly fewer infants in the full premedication group with this substantial decrease in heart rate (>40% from highest recorded) during intubation. Future studies should evaluate the relationship between these transient vital sign changes and timing or incidence of intraventricular hemorrhage particularly in smaller infants with dysmature cerebral autoregulation.
While the neonatal literature broadly supports premedication for neonatal TI, there is little guidance surrounding premedication including a paralytic specifically for the population of very low birth weight (VLBW) infants [2,28,29]. Krick et al. evaluated the impact of premedication with and without paralysis on intubation outcomes for infants ≤1500 g and found that intubation with paralysis was associated with fewer intubation attempts and fewer TIAEs compared to premedication without paralysis [2]. It is notable that while the population evaluated for this analysis skewed towards the moderately preterm (median gestational age 28 weeks and birthweight 1.1 kg), the UWMC NICU does not have specific intubation premedication guidelines for VLBW or extremely low birthweight (ELBW) infants. Provider hesitation, particularly for paralytic use, is understandable given the lack of safety data and concern for adverse events. Future studies should focus on both short-and long-term effects of premedication in this unique and vulnerable population of smaller babies.
Finally, we found higher first attempt success rates for neonates intubated with full premedication compared with partial premedication, but no difference in first attempt success between those receiving full and no premedication. Most infants in the partial premedication group received an opiate without paralytic, a scenario that may increase the likelihood of physiologic instability during laryngoscopy without the benefit of the paralytic to optimize the position and view of the glottic structures [4]. Although there was a trend towards higher first attempt success between the full and no premedication groups, this was not statistically significant in this retrospective sample.
This study is limited by its data collection at a single center, retrospective approach, and relatively small number of participants. An independent audit of data collection forms was performed by a study team member, however given that the intubating team collected and recorded the data, items such as TIAE, highest and lowest heart rate may have been recorded with variable accuracy. Using data from continuous electronic cardiorespiratory monitoring systems may reduce this potential for inconsistency in the future. Only the first TI course data were analyzed in this study which increases the risk of missing TIAEs occurring in subsequent TI courses within the same encounter. Future studies should employ techniques such as propensity score matching to reduce bias due to confounding, specifically in an observational cohort study with unbalanced treatment groups. Furthermore, as units move to utilize new tools and medication to improve the safety of neonatal intubation, it will be important to explore the role of practice changes to minimize variability in sampling.

CONCLUSION
We conclude that intubations with full premedication, including a vagolytic, opiate analgesic, and paralytic, are associated with fewer adverse TI events and increased first attempt success compared to intubations with a partial combination of premedication; even when adjusting for confounding variables. Compared to intubations without premedication, we found less change in heart rate during intubation with full premedication, a finding attributed to the addition of atropine to this analysis. The use of a regimen including vagolytic, analgesic, and paralytic should be considered as unit guidelines for neonatal intubation are developed.

DATA AVAILABILITY
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.