Abstract
Objective:
To evaluate the association between desaturation <60% (severe desaturation) during intubation and total number of intubation attempts in the first week of life in very low birth weight (VLBW) infants with adverse long-term outcomes including bronchopulmonary dysplasia (BPD) and severe periventricular/intraventricular hemorrhage grade 3 or 4 (PIVH).
Study Design:
A retrospective chart review was performed on VLBW infants intubated in the neonatal intensive care unit during the first week of life between January 2017 and July 2020. Descriptive tables were generated for two outcomes including BPD and PIVH. Multivariable logistic regression was then performed for each outcome including significant predictors that differed between groups with a p-value of <0.2.
Results:
A total of 146 patients were included. Patients with BPD or PIVH had a lower GA and birth weight. Patients with BPD had a greater number of intubation attempts in the first week of life (4 vs. 3, p<0.001). Patients with PIVH were more likely to experience severe desaturation during intubation (71% vs. 39%, p-value 0.019). In multivariable logistic regression controlling for confounding variables the odds developing BPD were higher for patients with increased number of intubation attempts in the first week of life (OR=1.29, CI 1.03-1.62, P=0.029). Post-hoc analyses revealed increased odds of developing BPD with increased number of intubation encounters in the first week of life (OR=2.20, CI 1.04-4.82, P=0.043). When including intubation encounters in the model, desaturation <60% during intubation in the first week of life was associated with increased odds of developing BPD (OR=2.35, CI 1.02-5.63, P=0.048).
Conclusion:
The odds of developing BPD for VLBW infants were higher with increased intubation attempts, intubation encounters, and desaturation during intubation in the first week of life. Further research is needed to determine mechanisms of the relationship between complicated intubations and the development of BPD.
Keywords: Neonatal Endotracheal Intubation, Intubation Complications, Adverse Events, Patient Safety, Bronchopulmonary Dysplasia, Periventricular-Intraventricular Hemorrhage, Very Low Birth Weight Infants
Background:
Intubation is a common procedure in the neonatal intensive care unit, performed for respiratory failure, administration of surfactant, apnea, or other indications. Recent studies have shown a high prevalence of complications and adverse events occurring during neonatal intubation. In a study examining video-recordings of delivery room resuscitation, clinical deterioration was present in 49% of intubation attempts, as evidenced by a 10% decrease in baseline oxygen saturation or heart rate.1 In another prospective study of adverse events in 178 patients, 39% of patients experienced an adverse event with 44% experiencing hypoxemia (<60%) during the intubation.2 Increased number of attempts increased the odds of an adverse event.2 At the same center, a quality improvement initiative to reduce adverse events was successful using a standardized checklist, pre-medication algorithm, and a computerized provider order entry set.3 Foglia et al showed in a multi-center registry that 18% of intubations had some form of adverse event, with 48% of intubations having a severe desaturation (>20% decrease from baseline). The same registry showed that infants who required more than 3 attempts by a non-resident provider had an increased risk of experiencing an adverse event or a severe oxygen desaturation.6 Ultimately all of these studies show a significant risk of complications or adverse events during neonatal intubation. Several studies have identified mitigating factors, but no studies yet have examined long-term outcomes of these adverse events during neonatal intubation.
Several studies have examined number of intubation attempts and long-term outcomes. Wallenstein et al showed that failed endotracheal intubation in the first 10 minutes of life in infants <1000g was associated with an increased risk of death or neurodevelopmental impairment.7 The mechanism of these associations are not known but may include an increased use of chest compressions or epinephrine in infants who have multiple attempts at intubation. Another hypothesis stated by the authors was a possible predisposition of infants who are at risk of death or neurodevelopmental impairment to be difficult to intubate on the first attempt. However, in this study the groups were similar in all baseline characteristics which makes this less likely. In a study of infants <1500 grams who were intubated in the delivery room, infants with severe intraventricular hemorrhage (IVH) had a higher number of intubation attempts compared to those with mild or no IVH, and in infants <750g with severe IVH there were an increased number of intubation attempts within the first four days of life.8 The authors hypothesized that this may be due to physiologic changes associated with intubation, such as an acute increase in intracranial pressure, especially without pre-medication in the delivery room.
Studies have shown that infants who require reintubation after extubation failure have increased rates of BPD and longer duration of mechanical ventilation9, 10. Jensen et al found that cumulative duration of mechanical ventilation was more predictive of BPD compared to the need for multiple courses alone11. Similarly, another study found that initial extubation of premature infants at a later age (greater than one week old) was associated with higher rates of BPD than infants extubated at less than three days old regardless of whether infants in the early extubation group needed reintubation12. These studies confirm a relationship between need for mechanical ventilation and BPD, but no studies have yet determined if more individual intubation attempts or desaturation during intubation affect the rate of BPD. Bronchopulmonary dysplasia is a complex disease process with many etiologies, including some factors which may be associated with intubation-related complications. This study aims to determine whether intubation complications in the first week of life are associated with subsequent BPD.
Methods:
This is a single-center retrospective cohort study evaluating baseline characteristics and outcomes between very low birth weight (VLBW) infants who experienced a severe desaturation in the neonatal intensive care unit (NICU) during intubation in the first week of life and those who did not. This study was approved by the University Hospitals Institutional Review Board. The study took place in an 82-bed level IV academic NICU divided between intensive and transitional care units. Nearly all intubations are performed by neonatal-perinatal medicine fellows or attendings, neonatal nurse practitioners, or pediatric residents; and occasionally by respiratory therapists or pediatric subspecialists. Patients were selected initially by their inclusion in the institutional quality database, which identifies patients intubated in the NICU and does not include delivery room intubations alone15. The quality data are collected prospectively at the time of intubation. Desaturation during intubation is recorded as a check box for “desaturation <60%” and typically recorded by the bedside nurse on the quality improvement form and reviewed by the medical team at the conclusion of the intubation encounter. Any discrepancies between quality improvement form and documentation in the electronic medical record (EMR) are discussed with the medical team at the time of entry into the quality database. Patients were further selected for birth weight less than 1500 grams and intubation taking place within the first 7 days of life. Premedications are typically used for all non-emergent intubations in this NICU including atropine, fentanyl, and rocuronium. Documentation of emergent intubations and entry into the quality database is encouraged but is not as reliably completed.
Primary predictive variables were whether a desaturation <60% occurred during any intubation in the first week of life and total number of intubation attempts in the first week of life. Attempts are defined as each entry of the laryngoscope blade into the mouth to attempt an intubation, regardless of whether a tube was passed or not. Intubation encounters are defined as any discrete episode of intubation including all attempts. Additional data on complications were collected including bradycardia (heart rate of <60 beats per minute for ≥5 seconds), airway trauma, difficulty with bag-mask ventilation, emesis, chest wall rigidity, pneumothorax, chest compressions, and code medications; modified from studies by Hatch et al.2 Nearly all patients who experienced these adverse events also had a desaturation <60%. Primary outcome measures included death or bronchopulmonary dysplasia as evidenced by oxygen requirement at 36 weeks corrected gestation; or grade 3-4 periventricular-intraventricular hemorrhage. If the PIVH was diagnosed prior to any intubation attempt in the NICU those subjects were removed from the analysis. Variables were collected from Vermont Oxford Network data from this institution, quality data collected in the intubation database, and electronic medical record (EMR) review.
Due to availability of data on the predictive variable of desaturation <60%, only patients who had been entered into the database on intubation-related quality data were included in this study. This excluded patients who were only intubated in the delivery room or who had an emergent intubation in the NICU without quality data entered. With a set sample size of 146, a power of 0.8, and a baseline rate of BPD of about 50% in this population, we would be able to detect a difference of 25% in the rate of BPD between groups.
Statistical Analysis:
Baseline characteristics and primary predictors were compared between patients who had death or BPD and patients who did not, and patients who had severe PIVH and patients who did not using Wilcoxon rank sum test, Pearson’s Chi-squared test, or Fisher’s exact test as applicable. Significant characteristics that differed between groups were entered into a multivariable logistic regression model for each outcome based on a p-value of <0.2 and clinical significance. P-value of less than 0.05 and odds ratio 95% confidence interval not including 1 was considered statistically significant for the analysis. All the analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC) and R software, version 4.0.0.
Results:
A total of 146 patients from January 2017 through July 2020 met criteria for this study based on available data in the quality database, birth weight <1500g, and intubation occurring within the first 7 days of life.
75/146 (51.4%) of patients experienced death or BPD. The patients who had BPD had a median gestational age at birth of 27 weeks compared to 29 weeks (p<0.001) and median birth weight of 850g compared to 1190g (p<0.001). 15 patients had severe PIVH compared to 131 patients who did not. Three patients were removed from the analysis due to PIVH diagnosis occurring prior to any intubation encounter in the NICU. Patients who had severe PIVH had a lower GA at birth (25 vs. 28 weeks, p=0.001) and lower BW (756g vs. 1050g, p=0.04). (Table 1).
Table 1:
Descriptive Characteristics
| Bronchopulmonary Dysplasia or Death | Severe Periventricular-Intraventricular Hemorrhage3 | ||||||
|---|---|---|---|---|---|---|---|
| Overall (N=146)1 | No (N=71)1 | Yes (N=75)1 | P-value2 | No (N=131)1 | Yes (N=12)1 | P-value2 | |
| Baseline Characteristics | |||||||
| Gestational Age at Birth (weeks) | 28 (26, 29.43) | 29 (27.71, 30) | 27 (25.29, 28.43) | <0.001* | 28.29 (26.50, 29.71) | 25.14 (24.96, 27.64) | 0.006* |
| Birth Weight (g) | 1,040 (782, 1,260) | 1,190 (1,000, 1,315) | 850 (675, 1,110) | <0.001* | 1,050 (820, 1,265) | 785 (740, 1,188) | 0.195 |
| Male Sex | 73 (50%) | 33 (46%) | 40 (53%) | 0.408 | 61 (47%) | 11 (92%) | 0.003* |
| Maternal Race | 0.019* | 0.278 | |||||
| Black or African American | 78 (53%) | 45 (63%) | 33 (44%) | 66 (50%) | 9 (75%) | ||
| White | 66 (45%) | 25 (35%) | 41 (55%) | 63 (48%) | 3 (25%) | ||
| Asian | 1 (0.7%) | 0 (0%) | 1 (1.3%) | 1 (0.8%) | 0 (0%) | ||
| Other | 1 (0.7%) | 1 (1.4%) | 0 (0%) | 1 (0.8%) | 0 (0%) | ||
| Maternal Ethnicity | 0.120 | >0.999 | |||||
| Not Hispanic | 141 (97%) | 71 (100%) | 70 (93%) | 126 (96%) | 12 (100%) | ||
| Hispanic | 4 (2.7%) | 0 (0%) | 4 (5.3%) | 4 (3.1%) | 0 (0%) | ||
| Unknown | 1 (0.7%) | 0 (0%) | 1 (1.3%) | 1 (0.8%) | 0 (0%) | ||
| Intubated in Delivery Room | 43 (29%) | 12 (17%) | 31 (41%) | 0.001* | 37 (28%) | 4 (33%) | 0.743 |
| Place of Delivery: Outborn | 7 (4.8%) | 4 (5.6%) | 3 (4.0%) | 0.713 | 6 (4.6%) | 1 (8.3%) | 0.466 |
| Patient deceased | 13 (8.9%) | 0 (0%) | 13 (17%) | <0.001* | 12 (9.2%) | 1 (8.3%) | >0.999 |
| Prenatal Care | 140 (96%) | 67 (94%) | 73 (97%) | 0.432 | 127 (97%) | 10 (83%) | 0.080 |
| Antenatal Steroids | 140 (96%) | 68 (96%) | 72 (96%) | >0.999 | 126 (96%) | 11 (92%) | 0.415 |
| Antenatal Magnesium Sulfate | 127 (87%) | 60 (85%) | 67 (89%) | 0.386 | 114 (87%) | 10 (83%) | 0.662 |
| Chorioamnionitis | 50 (34%) | 23 (32%) | 27 (36%) | 0.646 | 42 (32%) | 6 (50%) | 0.218 |
| Maternal Hypertension | 67 (46%) | 34 (48%) | 33 (44%) | 0.638 | 61 (47%) | 5 (42%) | 0.745 |
| Maternal Diabetes | 18 (12%) | 5 (7.0%) | 13 (17%) | 0.059 | 16 (12%) | 2 (17%) | 0.649 |
| Caesarean Delivery | 44 (30%) | 26 (37%) | 18 (24%) | 0.097 | 38 (29%) | 4 (33%) | 0.748 |
| Multiple Gestation | 30 (21%) | 15 (21%) | 15 (20%) | 0.866 | 27 (21%) | 3 (25%) | 0.716 |
| APGAR score 5 minutes, median (IQR) | 7 (6, 8) | 7 (6.50, 8) | 7 (5, 8) | 0.026* | 7.00 (6.00, 8.00) | 7.00 (4.00, 7.25) | 0.214 |
| Predictor Variables of Interest | |||||||
| Overall (N=146) | No (N=71) | Yes (N=75) | P-value | No (N=129) | Yes (N=14) | P-value | |
| Desaturation < 60% during any intubation in first week of life | 61 (42%) | 24 (34%) | 37 (49%) | 0.057 | 51 (39%) | 8 (67%) | 0.073 |
| Total Intubation Attempts in 1st week of life | 3 (2, 5) | 3 (1, 4) | 4 (2, 5.50) | <0.001* | 3.00 (2.00, 5.00) | 3.00 (2.00, 4.25) | 0.915 |
| Total number of intubation encounters in the first week of life | 1.00 (1.00, 2.00) | 1.00 (1.00, 1.50) | 2.00 (1.00, 2.00) | <0.001 | 1.00 (1.00, 2.00) | 1.50 (1.00, 2.00) | 0.806 |
| Average number of attempts per encounter in the first week of life | 2.00 (1.00, 3.00) | 2.00 (1.00, 3.00) | 2.50 (1.50, 3.00) | 0.186 | 2.00 (1.00, 3.00) | 2.00 (1.88, 2.62) | 0.944 |
Median (IQR); n (%)
Wilcoxon rank sum test; Pearson’s Chi-squared test; Fisher’s exact test
3 patients removed from PIVH analysis due to PIVH occurring prior to intubation encounter
Birth weight was excluded from both logistic regression models due to collinearity with GA at birth. Multivariable logistic regression for BPD included gestational age at birth, APGAR score at 5 minutes, race, maternal diabetes, and mode of delivery in addition to desaturation <60% in any intubation in the first week of life and total number of intubation attempts in the first week of life. Maternal ethnicity was not included due to the small overall number of patients identified as Hispanic. Odds of death or BPD decreased with increased gestational age at birth (OR 0.58, CI 0.45-0.72, p<0.001), and increased with white race (OR 4.91, CI 2.03-12.8, p<0.001), and with increased number of intubation attempts in the first week of life (OR 1.29, CI 1.03-1.62, p=0.029) (Table 2). In order to further evaluate the relationship between intubation attempts and intubation encounters in the development of BPD, two further analyses were completed post-hoc. In a multivariable logistic regression analysis including intubation encounters in the first week of life, additional intubation encounters were associated with increased odds of developing BPD (OR 2.20, CI 1.04-4.82, p=0.043). Additionally, in this model desaturation <60% during intubation in the first week of life was associated with increased odds of developing BPD (OR 2.35, CI 1.02-5.63, p=0.048) (Table 4).
Table 2:
Multivariable Logistic Regression: Patient and Clinical Factors Associated with Odds of Bronchopulmonary Dysplasia or Death
| Variable | OR1 | 95% CI1 | p-value |
|---|---|---|---|
| Gestational Age at Birth | 0.58 | 0.45, 0.72 | <0.001* |
| APGAR score 5 minutes | 1.03 | 0.98, 1.16 | 0.4 |
| White Race | 4.91 | 2.03, 12.8 | <0.001* |
| Maternal Diabetes | 2.16 | 0.58, 9.29 | 0.3 |
| Cesarean Delivery | 2.33 | 0.94, 6.00 | 0.072 |
| Desaturation <60% in any intubation in first week of life | 1.74 | 0.74, 4.17 | 0.2 |
| Total Intubation Attempts in the first week of life | 1.29 | 1.03, 1.62 | 0.029* |
OR = Odds Ratio, CI = Confidence Interval
Table 4:
Table 2: Multivariable Logistic Regression: Patient and Clinical Factors Associated with Odds of Bronchopulmonary Dysplasia or Death including Intubation Encounters
| Multivariable Logistic Regression results of patient and clinical factors associated with Odds of BPD | |||
|---|---|---|---|
|
| |||
| Characteristic | OR1 | 95% CI1 | p-value |
| Total Gestational Age | 0.60 | 0.46, 0.75 | <0.001* |
| APGAR score 5 minutes | 1.03 | 0.98, 1.19 | 0.5 |
| Intubation encounters in first week of life | 2.20 | 1.04, 4.82 | 0.043* |
| White Race | 5.12 | 2.11, 13.5 | <0.001 |
| Maternal Diabetes | 2.51 | 0.69, 10.5 | 0.2 |
| Caesarean Delivery | 2.27 | 0.93, 5.74 | 0.075 |
| Desaturation < 60% in any intubation in first week of life | 2.35 | 1.02, 5.63 | 0.048* |
OR = Odds Ratio, CI = Confidence Interval
An additional analysis was completed looking at the average number of intubation attempts per intubation encounter in the first week of life. This was not associated with the development of BPD (OR 1.06, CI 0.85-1.42, p=0.7) (Table 5).
Table 5:
Multivariable Logistic Regression: Patient and Clinical Factors Associated with Odds of Bronchopulmonary Dysplasia or Death including Average Number of Intubation Attempts per Encounter
| Variable | OR1 | 95% CI1 | p-value |
|---|---|---|---|
| Total Gestational Age | 0.54 | 0.42, 0.68 | <0.001* |
| APGAR score 5 minutes | 1.03 | 0.98, 1.16 | 0.4 |
| Average number of intubation attempts per encounter in the first week of life | 1.06 | 0.85, 1.42 | 0.7 |
| White Race | 5.59 | 2.34, 14.5 | <0.001* |
| Maternal Diabetes | 2.22 | 0.62, 9.22 | 0.2 |
| Caesarean Delivery | 2.36 | 0.98, 5.91 | 0.059 |
| Desaturation < 60% in any intubation in first week of life | 2.08 | 0.89, 4.98 | 0.094 |
OR = Odds Ratio, CI = Confidence Interval
Multivariable logistic regression for PIVH included gestational age at birth, APGAR score at 5 minutes, sex, desaturation <60% in any intubation in the first week of life and total number of intubation attempts in the first week of life. Odds of PIVH decreased with increased gestational age at birth (OR 0.64, CI 0.44-0.89, p=0.013), and increased with male sex (OR 12.2, CI 2.07-246, p=0.023). Both desaturation <60% (OR 3.51, CI 0.87-16.7, p=0.089) and increased number of intubation attempts (OR 0.81, CI 0.54-1.14, p=0.3) were not statistically significantly associated with increased odds of BPD. (Table 3).
Table 3:
Multivariable Logistic Regression: Patient and Clinical Factors Associated with Odds of Severe Periventricular-Intraventricular Hemorrhage
| Variable | OR1 | 95% CI1 | p-value |
|---|---|---|---|
| Total Gestational Age | 0.64 | 0.44, 0.89 | 0.013* |
| APGAR score 5 minutes | 0.99 | 0.75, 1.06 | >0.9 |
| Male Sex | 12.2 | 2.07, 246 | 0.023* |
| Desaturation < 60% in any intubation in first week of life | 3.51 | 0.87, 16.7 | 0.089 |
| Total Intubation Attempts in 1st week of life | 0.81 | 0.54, 1.14 | 0.3 |
OR = Odds Ratio, CI = Confidence Interval
Discussion:
This single-center retrospective cohort study is the first to specifically examine the associations between complicated intubations in the first week of life and adverse outcomes of prematurity including BPD and severe PIVH. Patients with increased numbers of intubation attempts and intubation encounters in the first week of life had increased odds of death or BPD. In post-hoc analyses including intubation encounters in the model, severe desaturation <60% during intubation in the first week of life was associated with increased odds of developing BPD.
The relationship between the number of intubation encounters and BPD has been difficult to clarify as severity of underlying lung disease influences both the need for intubation and the development of BPD. This study reinforces the previous findings of Chawla et al and Kidman et al, who reported higher rates of BPD in patients with extubation failure9, 10. The relationship between the intubation procedure and BPD is difficult to study in isolation. Post-hoc analysis was performed to attempt to identify whether an increased number of intubation attempts alone was predictive of BPD as opposed to intubation encounters, and found increased odds of BPD with increased number of intubation encounters in the first week of life. Patients who go on to develop BPD have more severe underlying lung disease, leading to extubation failure and need for reintubation. Additionally, increased intubation encounters are directly correlated with increased duration of mechanical ventilation, which is already known to be associated with the development of BPD11. In this analysis desaturation <60% during any intubation in the first week of life was associated with increased odds of BPD. This may be a marker for severity of lung disease, or this severe hypoxia may initiate an inflammatory cascade contributing to the development of BPD. Further post-hoc analysis evaluated average number of attempts per encounter with BPD and showed no association. However, these findings are likely influenced by the overall small number of intubation attempts per encounter, which makes it difficult to detect a significant difference.
More centers are now evaluating for complications and adverse events during neonatal intubations, including a large multicenter database (NEAR4NEOS)2, 4. These studies have consistently shown that complications and adverse events are common during neonatal intubation.
Several studies have shown mitigation strategies for reducing complications3, 5, 16, 17.
One area of mitigation is selection of the more experienced intubation provider, as intubation by an attending physician has been shown to have a reduced risk of adverse events.16 This has implications for residency training programs and educational efforts for intubation, especially in the light of possible adverse outcomes associated with increased number of intubation attempts and desaturation during intubation. Additionally, the use of paralytic pre-medication and videolaryngoscopy have been shown to reduce adverse events.4, 5
In contrast to the results of this study, other studies have shown that increased number of attempts are associated with increased risk of death or neurodevelopmental impairment,7 along with severe IVH,8 specifically in premature infants. The differences seen in this study may be due to the inclusion criteria of NICU intubation rather than delivery room intubation. These intubations take place in a more controlled environment, typically with pre-medication including paralytic medication. This may reduce the physiologic disturbances associated with intubation that can lead to IVH. Additionally, the overall rate of severe IVH was low in this study. Strategies to implement premedication protocols may be important in reducing this morbidity, however, we cannot conclude this based on the findings of this study alone.
The strengths of this study include the prospectively collected data on desaturation <60% during intubation, which is objectively recorded during the intubation encounter. This threshold was chosen based on the study by Hatch et al,2 and facilitates ease of translating these findings to a wide variety of centers and populations. Additionally, a strength includes evaluating intubations taking place in both the delivery room and in the NICU, accounting for the multiple intubation encounters in the first week of life often experienced by VLBW infants. A major limitation of this study includes lack of inclusion of patients intubated only in the delivery room or emergent situations in the NICU without entry into the quality database. Due to the nature of the predictive variable of desaturation, it was not possible to ascertain whether or not a desaturation <60% occurred in intubations which were not entered into the quality database. This may limit generalizability of these results. Additionally, total duration of mechanical ventilation was not assessed in this study; and would have been helpful in further evaluating the complex relationship between the intubation procedure, need for mechanical ventilation, and development of BPD.
Conclusions:
Adverse events and complications are common during neonatal intubation and are increased in intubations with a higher number of attempts. The long-term effect of these complications has not been well described. This study shows BPD is increased in patients with more intubation attempts, encounters, and desaturation during intubation in the first week of life. It is difficult to determine whether these events initiate a cascade of inflammation leading to BPD or if these events are markers of severe lung disease that directly contributes to development of BPD. More studies are needed to clarify these relationships and provide additional information on the relationship of intubation encounters and adverse long-term outcomes in premature infants.
Key Points.
Neonatal intubations often require multiple attempts.
Neonates frequently desaturate during intubation.
Intubation attempts are positively associated with BPD.
Severe desaturation is positively associated with BPD.
Funding:
NHLBI K24 HL143291, PI: Dr. Anna Maria Hibbs
Study data were collected and managed using Research electronic data capture tools (REDCap) hosted at University Hospitals, funded by Clinical and Translational Science Collaborative (CTSC) grant support (UL1TR002548)
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