Respiratory Severity Score during the first three hours of life as a predictor for CPAP failure and need for late surfactant administration

doi:10.21203/rs.3.rs-2093192/v1

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Respiratory Severity Score during the first three hours of life as a predictor for CPAP failure and need for late surfactant administration

https://doi.org/10.21203/rs.3.rs-2093192/v1

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Background

Preterm infants often develop CPAP failure. These infants miss the advantages of early rescue surfactant therapy. In this study, we evaluate the utility of Respiratory Severity Score (RSS) during the first three hours of life (HOL) as a predictor for CPAP failure.

Methods

We conducted a post-hoc analysis of patients who received usual care in the AERO-02 clinical trial. Univariate and multivariable logistic regression were used to assess whether the RSS summary measures were associated with the odds of surfactant administration.

Results

Study involved 146 infants. Sixty-four infants (45%) received surfactant within the first 72 hours. Administration of surfactant was associated with the mean RSS (p < 0.01) and the linear trend (p < 0.01).

Conclusion

We demonstrated that RSS during the first three HOL can predict CPAP failure and need for surfactant administration. Optimal RSS cutoffs for early rescue surfactant therapy need to be determined in large cohort studies.

Respiratory Distress Syndrome

Surfactant

Early Rescue Surfactant

CPAP failure

Respiratory Severity Score

Respiratory distress syndrome (RDS) is frequently seen in preterm infants in the neonatal intensive care unit (NICU). RDS can lead to respiratory failure, pneumothorax, chronic lung disease and even death. (1) Non-invasive respiratory support such as Continuous Positive Airway Pressure (CPAP) to stabilize the lower airways and prevent the collapse of alveoli, and subsequent selective surfactant administration is considered the standard of care. (2, 3) Therapy with exogenous surfactant is the cornerstone in the management of RDS. (4–6)

The ideal time for surfactant administration has been debated. (7) A meta-analysis of multiple large clinical trials by Bahadue and Soll found that early rescue surfactant treatment resulted in decreased risk of pneumothorax and a decreased risk of neonatal mortality and chronic lung disease compared to late rescue surfactant treatment. (8) Based on this data current guidelines for RDS management recommend early rescue surfactant administration within 2–3 hours after birth. (2, 3). Despite these recommendations a significant portion of preterm infants receive surfactant as late rescue treatment. (9) These infants unfortunately miss the advantages of early surfactant therapy. Therefore, it is desirable to identify infants who eventually develop CPAP failure and require surfactant treatment in the early course of the disease to administer surfactant within the first 2–3 hours of life.

Current clinical criteria for surfactant administration aside from clinical and chest X-ray (CXR) findings are based on the fraction of oxygen (FiO2) level needed to maintain a goal oxygen saturation of 90–94%. The most recent European RDS guideline recommends FiO2 of 30% for instillation of surfactant in premature infants with a clinical diagnosis of RDS.(3) Many institutions still use different cutoffs ranging from 30–50% based on FiO2 cutoffs used in surfactant clinical trials. (10, 11).

Using FiO2 as its sole criteria can be misleading as FiO2 is affected by the level of mean airway pressure (MAP). Respiratory Severity Score (RSS), the product of FiO2 x MAP, is a non-invasive index to assess pulmonary status. (12) RSS has been used in studies to evaluate the prediction of BPD, extubation readiness, and as a measure of disease severity but has not been studied as a criterion for surfactant administration. (13–16)

In this study, we evaluate the utility of the RSS, during the first 3 hours of life (HOL) as a predictor for CPAP failure and need for surfactant administration in preterm infants during the first 72 HOL.

Data source

We conducted a post-hoc analysis of patients with a clinical diagnosis of RDS who received usual care in the AERO-02 trial. AERO-02 clinical trial is the largest multicenter, prospective, randomized controlled trial to compare aerosolized Calfactant (Infasurf; ONY Biotech, Amherst, NY) to usual care in newborns with early mild to moderate respiratory distress syndrome in 22 level III or IV NICUs in the United States. That study showed a decreased need for intubation and need for surfactant instillation by 50% in infants with RDS. (17)

Study population

Newborns who were non-intubated, had not previously received surfactant, were > 1 hour but < 12 hours of age, and were with suspected or confirmed RDS requiring therapeutic administration of nasal respiratory support by continuous positive airway pressure (CPAP), high-flow nasal cannula, or noninvasive positive pressure ventilation (NIPPV) were eligible for inclusion in the AERO-02 trial. Exclusion criteria were a congenital anomaly limiting care or requiring surgery; hypotension with metabolic acidosis (a base deficit > 10 mEq/L); hypoxemia (O2 saturation < 88%)or hypercapnia (arterial partial pressure of carbon dioxide [PaCO2] > = 60 mm Hg) unresponsiveness to intervention; grade 3 or 4 intraventricular brain hemorrhage; or acute hypoxic encephalopathy, defined as disturbed neurologic function, including abnormal tone and/or reflexes for gestational age, after a suspected perinatal hypoxic- ischemic event, as evidenced by a 5-minute Apgar score < 5 and/or umbilical cord acidosis (pH < 7.0 and/or based deficit > = 16 mmol/L).

There was a total of 231 eligible subjects that received usual care in the AERO-02 trial. The usual care group was managed according to standard local NICU protocols. Infants were intubated and given liquid surfactant for persistent or worsening respiratory distress, at providers’ discretion. Subjects who were intubated and/or received surfactant during the first 3 hours of life and patients whose RSS could not be calculated (due to lack of documentation on MAP) from available data and those infants on low flow or high flow nasal cannula were excluded for this post-hoc analysis.

Procedures and statistical analysis

Maternal demographic and neonatal characteristics were summarized using the range, mean and standard deviation (SD), or median with the interquartile range for continuous variables; categorical factors were summarized with frequencies and percentages. Hourly respiratory support data had been collected from birth up to 96 hours of life for each subject. Hourly respiratory parameters (mode of respiratory support, respiratory support settings, FiO2) were obtained from the database.

Respiratory severity score (RSS) was calculated as FiO2 × PEEP for those on CPAP and as FiO2 × MAP for subjects on NIPPV. RSS values at HOL 1–3 for each patient were expressed as their overall mean (average RSS from HOL 1–3) and a linear trend (half the difference between last and first RSS; [HOL3 − HOL1]/2). These two summary measures of RSS were used in models relating RSS to the primary outcome of the need for surfactant within the first 72 hours of life to RSS. Univariate and multivariable logistic regression was used to assess whether any of the RSS summary measures were associated with the odds of surfactant administration within 72 HOL after, accounting for potential maternal or neonatal characteristics.

Average RSS for the first 3 hours was grouped into five non-overlapping intervals, with length of 0.25 units for each: 1.00 -< 1.25, 1.25 -< 1.50, 1.50 -< 1.75, 1.75 -< 2.00, 2.00 and above. Binomial logistic regression was used to compute relative odds of surfactant administration and whether subjects were ventilated, on CPAP, or had died day 7 for each interval, with the first serving as the referent category.

Kaplan-Meier methods and Cox regression models were used to estimate the time to surfactant administration for each category relative to the same referent. Analyses were performed using R (v.4.1.1) with the associated survival package. Statistical significance was defined as p < 0.05 with no adjustment for multiplicity in this hypothesis-generating study.

The final study cohort consisted of 146 infants. Overall gestational age (GA) ranged from 23.4–40.3 weeks. Median GA and birthweights were 32.9 weeks and 1.86 Kg, respectively. Over half the sample (58%) was male, 75% were singleton births, and 32% were born by vaginal deliveries. Nearly three-quarters of the sample (74%) were exposed to antenatal steroids. Almost all infants (139/146; 95%) were on CPAP during the first three HOL and the remaining seven subjects were on NIPPV during the same time span. Characteristics of the study cohorts are presented in Table 1.

Table 1
Characteristics of the study sample. Sample size is n = 146 unless noted.
Mode of delivery, n (%)
C-section	100 (68.5)
Antenatal steroids, n (%)
None	31 (21.2)
< 12h	30 (20.5)
> 12h	78 (53.4)
No data	7 (4.8)
Sex
Female	61 (41.8)
Multiplicity
Singleton	110 (75.3)
Gestational age (weeks)
Median [IQR]	32.9 [30.7, 34.4]
Birthweight (Kg)
Median [IQR]	1.86 [1.9, 2.43]
5-min APGAR score [a]
Median [IQR]	8 [7, 9]
Surfactant given, n (%)
No	81 (55.5)
Yes	65 (44.5)
Age (hrs) when surfactant given
Median (IQR)	6 [4–15]
Pneumothorax at 3 days, n (%)
Yes	4 (2.7)
Respiratory support at 3 days
No support/ discharged	55 (37.7)
Nasal cannula w/wo O2	16 (11)
Nasal CPAP	64 (43.8)
Mechanical Ventilation	11 (7.5)
Respiratory support at 7 days [b]
No support/ discharged	85 (58.6)
Nasal cannula w/wo O2	15 (10.3)
Nasal CPAP	39 (26.9)
Mechanical Ventilation	6 (4.1)
BPD at 28 days, n (%)
Yes	5 (3.4)
Status at 28 days, n (%)
Alive	145 (99.3)
Deceased	1 (0.7)
Length of stay, days
Median [IQR]	25 [13, 29]
[a] 1 missing value; n = 145
[b] One patient was deceased on Day 6 and was excluded: n = 145

RSS during HOL 1–3 ranged between 1.05–5.50 and centered around 1.8 ± 0.7 (mean ± SD) at each time point. RSS summary measures for the study sample are depicted in Table 2. The four most common patterns of RSS are presented in Fig. 1. 61% (89/146) of infants had RSS that remained constant over all three time periods. None experienced a steady increase over time, and only 3% steadily decreased over time. 10% (15/146) initially held constant (HOL 1 to HOL 2) and then reduced at the end (HOL 2 to HOL 3), 10% (15/146) initially increased then stayed steady at the end while another 9% (13/146) had RSS initially decrease and then held constant at the end.

Table 2
Description of RSS summary measures HOL 1–3.
RSS summary measure	Mean (SD)
HOL 1	1.81 (0.70)
HOL 2	1.81 (0.70)
HOL 3	1.77 (0.71)
Overall mean (n = 146)	1.80 (0.66)
Linear trend (slope) (per 1 HOL)
Increasing (n = 24)	0.28 (0.29)
Decreasing (n = 32)	-0.31 (0.25)
Flat (n = 90)	0 (0)

Sixty-five infants (45%) received liquid surfactant and 64/65 received it within the first 72 hours (median 6 hours, IQR 4–15) (Table 1). Four infants (2.7%) developed pneumothorax. Six infants (4.1%) required mechanical ventilation at 7 days of life. Five infants (3.4) developed chronic lung disease defined as defined as any respiratory support at 28 days of age. There was one death (0.7%) by age of 28 days.

There was an overall non-linear association (p = 0.01) between GA and the need for surfactant administration within the specified time frame. Infants born at 28 weeks gestation have estimated odds of needing surfactant within 72 hours, that are more than three times the odds of that same response for an infant born at 33 weeks (OR = 3.12; 95% CI: 1.32–7.14, p = 0.01). There was no association between need for surfactant within the first 72 hours and mode of delivery, antenatal steroids, sex, multiplicity, 5-minute Apgar score, or birth weight (p > 0.25). (Table 3)

Table 3
Association between demographic and clinical variables to needing surfactant within the first 72 hours. Crude and adjusted odds ratios (aOR) relate each row variable to odds of needing surfactant within the first 72 hours.
Variable	OR (95%CI)	p-value	aOR (95% CI)	p-value
Mode of delivery
C-section	1
Vaginal	0.86 (0.42, 1.74)	0.68
Maternal steroids
None	1
< 12h	0.72 (0.26, 1.96)	0.52
> 12h	0.69 (0.3, 1.59)	0.38
No data	0.38 (0.05, 2.04)	0.28
Sex
Female	1
Male	0.97 (0.5, 189)	0.93
Multiplicity
Singleton	1
Multiple	0.65 (0.29, 1.41)	0.28
5-min Apgar score [a]	1.05 (0.75, 1.48)	0.79
Gestational age
28 vs 33wks	3.12 (1.32, 7.14)	0.01	3.11 (1.25, 7.72)	0.01
36 vs 33 wks	1.67 (0.93, 3.00)	0.09	1.64 (0.85, 3.15)	0.14
Birth weight per 500g	0.92 (0.73, 1.16)	0.50
RSS
Overall mean per 0.5 units	1.45 (1.12, 1.93)	0.01	1.55 (1.14, 2.19)	< 0.01
Linear trend (slope) per 0.5 units	4.64 (1.79, 15.6)	0.01	5.88 (2.09, 20.9)	< 0.01
[a] One missing value, based on n = 145

Administration of surfactant within 72 hours was associated with the mean RSS computed over the first 1–3 hours of life (p < 0.01) and with the average (linear) change in RSS over that same period (p < 0.01). A 0.5 unit increase in the mean RSS was associated with a 45% increase in the odds of needing surfactant (OR = 1.45;95% CI: 1.12– 1.93), and each 0.5 unit increase for the linear trend in RSS per 1 HOL (during the first three HOL) was associated with a 4.6-fold increase in the odds (OR = 4.64; 95% CI: 1.79–15.6). (Table 3)

These associations remained statistically significant after adjusting for GA which appears to produce slightly stronger effects for the overall mean RSS and linear trend in RSS with respect to the odds of needing surfactant (Table 3). A Receiver-Operating-Characteristic (ROC) analysis) (Fig. 2) found the area under the curve equal to 0.74 (95% CI: 0.65–0.80), suggesting the multivariable model has reasonable ability to discriminate those who need surfactant from those who do not.

Average RSS for the first 3 HOL was grouped into five non-overlapping intervals, with a length of 0.25 units, and the timing for surfactant administration are depicted in Table 4 and Fig. 3. The proportion of infants receiving surfactant was higher with higher RSS scores. Subjects in RSS > 1.5 groups were more likely to receive surfactant. Subjects in these groups received surfactant at an earlier time point. However, a higher proportion of subjects in RSS < 1.5 groups required higher respiratory support (mechanical ventilation, CPAP, or death) on day 7 (Table 4 and Fig. 4). These differences were not statistically significant on binomial logistic regression analysis (Table 5).

Table 4
Respiratory outcomes according to RSS subgroups during the first 3 hours.
Average RSS for first 3 hours	# Patients n (%)	Mean gestational age (weeks)	Need for surfactant administration in first 72 hours n (%)	Median time to administration of surfactant (hours)†	Pneumothorax at 3 days n (%)	CPAP or ventilated at 3 days n (%)	CPAP, ventilated, or death at 7 days n (%)	BPD at 28 days n (%)
1.00 - < 1.25	18	32.1	6 (33)	9	0	8 (44)	7 (39)	0
1.25 - < 1.50	36*	31.8	8 (22)	18	0	23 (64)	15 (42)	0
1.50 - < 1.75	33	33.0	16 (48)	8.5	0	16 (48)	10 (30)	0
1.75 - < 2.00	20	33.4	13 (65)	6.6	2 (10)	9 (45)	3 (15)	2 (10)
2.00 and above	39	32.7	21 (54)	5	2 (5)	19 (49)	11(28)	3 (8)

* Includes 1 neonate who later died on DOL 6

† Among those n who received surfactant within 72 hours

Table 5: Association between level of average RSS and and surfactant administration within 72 hours or being CPAP, ventilated ordeath at day 7. Odds ratios and p-values only concern comparisons against the first category.

Average RSS for first 3 hours	# Patients n (%)	Surfactant within first 72 hours OR (95% CI)	p-value	CPAP, Ventilated or death at day 7 OR (95% CI)	p-value
1.00 - < 1.25	18	--ref--		--ref--
1.25 - < 1.50	36	0.57 (0.16, 2.07)	0.38	1.12 (0.36, 3.68)	0.84
1.50 - < 1.75	33	1.88 (0.58, 6.54)	0.29	0.68 (0.20, 2.32)	0.53
1.75 - < 2.00	20	3.71 (1.00, 15.1)	0.04	0.28 (0.05, 1.23)	0.09
2.00 and above	39	2.33 (0.75, 7.90)	0.14	0.62 (0.19, 2.05)	0.42

Average RSS for the first 3 HOL was grouped into five non-overlapping intervals (each with length of 0.25 units) and the timing for surfactant administration described in Table 4 and Fig. 3. The proportion of infants receiving surfactant differed (p = 0.008) among the five groups defined by RSS and showed increasing odds of needing surfactant with increasing RSS. Each 0.5 unit increase in mean RSS is associated with a 45% increase in the odds of requiring surfactant within 72 hours (OR = 1.45; 95% CI: 1.12–1.93, p = 0.007). (Table 5). Subjects with RSS ≥ 1.5 also appeared to receive surfactant sooner. The proportion of infants that required higher respiratory support (mechanical ventilation or CPAP) or that died by Day 7 did not differ among the five levels of RSS (p = 0.26) and showed no evidence of any trend (p = 0.11). (Table 5).

Early recognition of RDS and early rescue surfactant administration is important so that complications such as respiratory failure, pneumothorax and prolonged need for respiratory support can be prevented. In this study we evaluated the utility of RSS as a marker during the first three HOL to predict infants who develop CPAP failure and require surfactant. Our findings demonstrate that RSS during the first three HOL can be used as a predictor to identify infants who need late surfactant administration.

A substantial number of preterm infants with RDS who are initially stabilized on CPAP ultimately develop CPAP failure and require exogenous surfactant at a less than ideal time.(9, 18–24). A recent national, population-based cohort study in Sweden revealed that late surfactant treatment (> 2 hours after birth) was provided for 39% of preterm infants born before 32 weeks. Nearly half (45%) of 32–36 week infants and quarter of 28–31 week infants received surfactant after 6 hours from the birth. Another population study done in the Australian New Zealand Neonatal Network, revealed that 25% of the infants born at 25–32 weeks developed CPAP failure. Incidence of CPAP failure remained close to 50% for infants at 25 to 27 weeks’ gestation and decreased steadily with each week of additional gestation thereafter. However, given there are more moderate preterm infants born compared to the number of extreme preterm infants, moderate preterm infants born at 28–32 weeks made a substantially greater numerical contribution to the CPAP failure group. Of infants who developed CPAP failure, intubation occurred at a median of 4.4 hours (interquartile range [IQR] 2.3–12.0 hours) in the 25 to 28 week gestation range, and at 5.9 (2.8–20.0) hours at 29 to 32 weeks.

CPAP failure and late surfactant administration is associated with significant adverse outcomes. According to population-based study from Sweden late surfactant administration was associated with higher odds of pneumothorax, severe intraventricular hemorrhage, receipt of postnatal corticosteroids, and longer duration of assisted ventilation. (9) These findings were similar to findings from population study by the Australian New Zealand Neonatal Network where CPAP failure was associated with death, bronchopulmonary dysplasia, pneumothorax, intraventricular hemorrhage, and prolonged hospitalization. (18)

Given the higher risks associated with CPAP failure it is important to identify predictors of CPAP failure early in the course of RDS. A number of risk factors for CPAP failure have been investigated in previous research. Predictors for CPAP failures include lower antenatal steroid exposure, birth by cesarian section without labor, male sex, lower birth weight, lower GA, multiple gestation, need for positive pressure ventilation at delivery, lower 5 minute APGAR score, higher FiO2 in the first 1–2 hours (FiO2 > 0.25 or > 0.3), severe RDS on chest x ray, elevated alveolar-arterial oxygen tension gradient and lower arterial/alveolar

PO2 ratio. (18–24)

RSS is a non-invasive measure to assess respiratory status. RSS correlates well with oxygenation index. (25). RSS provides an easy, quick, objective, and non-invasive way to assess the respiratory status using clinical data available at the bedside. RSS has been used to evaluate the prediction of BPD, extubation readiness, and as a measure of disease severity. (14–16) Utility of RSS as a predictor for CPAP failure has not previously been investigated. Since RSS is a useful marker of respiratory disease severity and account for both FiO2 and mean airway pressure (or CPAP level), we propose that RSS would be an effective marker to determine patients at risk of CPAP failure and would benefit from early rescue surfactant treatment. In the current cohort, more than half (54%) infants with average RSS > 1.5 during first 3 hours of life developed CPAP failure and required late surfactant. Optimal RSS cutoffs with high sensitivity and specificity need to be established using large cohort studies.

Since the traditional method of surfactant administration requires an invasive procedure, laryngoscopy and endotracheal intubation, clinicians have been cautious in administering surfactant in the past. Endotracheal intubation is associated with adverse effects such as hypoxia, bradycardia, alterations in blood pressure and potential airway injury. (26) Minimally invasive surfactant administration techniques such as thin catheter surfactant administration (LISA/MIST), surfactant administration through laryngeal or supraglottic airways (SALSA) and aerosolized surfactant, has made surfactant administration safer yet as efficacious when compared to traditional surfactant administration through an endotracheal tube. (17, 27–31) This calls for the early identification of those patient who will eventually fail CPAP and require late surfactant. We think RSS can be an important predictor to identify such infants for early rescue surfactant therapy through the various methods of minimally invasive surfactant administration.

To our knowledge, this is the first report correlating RSS to CPAP failure and need for late surfactant administration. The study was done using prospectively collected data which is another strength of this study. There are several limitations to this study. The cohort size was small. Subjects from a clinical trial might not be representative of general preterm infant population due to selection bias. The decision to intubate and administer liquid surfactant was not defined by the study and left up to the clinical provider. A significant portion of the study cohort were moderate to late preterm infants where the utility of surfactant administration has not been well studied. However, moderate to late preterm infants account for nearly the half of the infants needing surfactant, so this report is relevant for a large proportion of the infants encountered and treated in clinical practice. (32) It is possible that some infants may have had etiologies other than RDS for their respiratory distress because confirmatory chest X ray was not required by the study protocol, however > 70% of infants had an early chest radiograph, consistent with RDS.

This study demonstrates a novel marker using RSS as a predictor for CPAP failure and need for late surfactant administration. As use of minimally invasive surfactant administration techniques become more prevalent, it is desirable to identify patients who would benefit from early rescue surfactant treatment. Optimal RSS cutoffs for early rescue surfactant therapy need to be determined in large cohort studies.

Funding source: none

Financial disclosure: Scott Guthrie serves as a consultant for ONY Biotech.

Acknowledgment: All AERO-02 study investigators, Dr. James Cummings, Melissa Brown, Corey Commaroto, ONY Biotech Inc.

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There is NO conflict of interest to disclose.

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Respiratory Severity Score during the first three hours of life as a predictor for CPAP failure and need for late surfactant administration

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