Patent ductus arteriosus (PDA) and response to late surfactant treatment in premature infants

To determine the clinical/echocardiography (ECHO) phenotype of patients with hypoxic respiratory failure (HRF) and response to late surfactant, according to patent ductus arteriosus (PDA) status. This retrospective study included infants ≤26+6 weeks gestation who received ≥1 surfactant dose after 6 postnatal days and where PDA status was available by ECHO. Response to surfactant was appraised based on change in respiratory severity score over 48 h. The relationship between PDA status and response to surfactant was evaluated via univariate analysis. We studied late surfactant (n = 71 doses) administration in 35 preterm infants born at a mean weight and GA at birth were 595 g (508, 696) and 23.3 (22.7, 25) weeks, respectively of whom 16 (46%) had a diagnosis of PDA. Positive response to late surfactant treatment was independently associated with absence of PDA [OR 26 (2, 334), p = 0.01] whereas presence of PDA was independently associated with negative response [OR 12 (1.1, 126), p = 0.04]. In neonates ≤26+6 weeks gestation, with HRF, response to surfactant after postnatal day 6 is influenced by PDA status. Future trials should consider PDA status which may enhance diagnostic precision and refine patient selection for late surfactant treatment.


INTRODUCTION
Although the survival rate of preterm infants continues to rise, both morbidity and mortality remain high [1].The introduction of surfactant positively modulated the outcomes of infants with respiratory distress syndrome (RDS) [2], specifically reducing both morbidity and mortality [3,4].Surfactant treatment leads to improved lung compliance and decreased need for oxygen and mechanical ventilation [5].Post surfactant slump, or respiratory failure in the second postnatal week due to progressive atelectasis, was first described in 1994 [6].The typical course is characterized by increasing oxygen requirements around day 9-15 with a radiological appearance consistent with surfactant deficiency.Late surfactant deficiency or inactivation may be a source of morbidity in up to 20% of premature infants [7].Observational data from Katz et al., demonstrated that late surfactant administration (>day 6), to infants who despite optimization of mechanical ventilation, had an FiO2 > 0.7 for more than 6-8 hours, led to improvement in respiratory severity score in 70% of patients [7].However, the true utilization rate of late surfactant administration remains unknown and evidence of clinical impact is conflicting.In the TOLSURF trial, infants born <28 weeks gestational age (GA) were randomized to calfactant or placebo [8].No difference in bronchopulmonary dysplasia (BPD) or time to extubation were reported, although need for home respiratory support at 1 year of age was decreased.There were, however, major confounders in the use of surfactant in the TOLSURF trial; specifically, all randomized patients also received inhaled nitric oxide and, unlike the observational study by Katz et al. [7], late surfactant was administered irrespective of the delivered FiO 2 (often less than 0.4) and without any radiologic evidence of "presumed surfactant deactivation."In the trial by Hascoët et.al., infants <33 weeks were randomized to either poractant alfa surfactant or placebo [9].As in the TOLSURF trial, there were no differences in BPD incidence or time to extubation, although surfactant treated patients had fewer hospitalizations for respiratory problems.Finally, although subject to a randomized clinical trial the prevalence of this intervention in contemporary neonatal practice across the world is unclear.
A hemodynamically significant patent ductus arteriosus (hsPDA) may be clinically indistinguishable from late surfactant deficiency; thus, diagnostic imprecision may contribute to the variance in response [10].Prospective echocardiography evaluation of the hemodynamic effects of surfactant administration in the first postnatal hour was followed by an increased size of the PDA and altered Qp:Qs [11,12].Therefore, phenotypic characterization of late surfactant responsiveness according to PDA status, is a priority.The primary aim of this study was to characterize surfactant response in patients with a PDA vs no PDA.We hypothesized that the presence of a PDA is associated with lower likelihood of positive response to late surfactant.

METHODS
This was a retrospective cohort study of premature infants admitted to the University of Iowa Stead Family Children's Hospital Neonatal Intensive Care Unit (NICU) between September 2018 and July 2020.The study was approved by the Institutional Review Board.Clinical and echocardiography data were collected from the electronic medical record (Epic 2021) and Neonatal Hemodynamics program database.

Eligibility criteria
Neonates were eligible for the study if they were born at < 27 weeks' gestation, had at least one dose of surfactant on or after postnatal day 7, and had a complete TnECHO within 24-48 hours following surfactant administration.Neonates with structural heart disease and those who died within 48 h of receiving their qualifying dose of surfactant were excluded.Clinical characteristics.Information were collected on the following: (i) neonatal demographics including gestational age, gender, birth weight, race, and ethnicity; (ii) maternal data and pregnancy history including maternal age, gravidity, parity, multiple gestation, history of preeclampsia, gestational diabetes, intrauterine fetal demise, intrauterine growth retardation (IUGR), chorioamnionitis, and antenatal steroids; (iii) delivery room course including mode of delivery, need for delivery intervention, resuscitation and complications, APGAR scores at 1, 5 and 10 min, and mode of ventilation upon admission; (iv) surfactant administration including type, dose, postnatal age (days) at timing of dose, and total number of doses given on or after postnatal day 7.
Surfactant response.Patient ventilation characteristics including fraction of inspired oxygen (FiO 2 ) and mean airway pressure were recorded at 0, 1, 4, 12, 24, and 48 hours after the administration of each surfactant dose.Respiratory severity score (RSS) was calculated (mean airway pressure x FiO 2 ) at each of these time points [13].The response to each individual dose of surfactant was categorized according to the magnitude of change in RSS over the subsequent 48 hours as positive [≥15% decrease], negative [≥15% increase], or non-response [<15% change].For individual patients that received multiple surfactant doses, patients were classified according to the most predominant response (for example, if 4 doses were administered and 3 out of 4 showed positive response, then the patient would be classified as a surfactant responder).Systolic, and diastolic blood pressures, heart rate, and hemoglobin were recorded at each of these time points over 48 hours after administration.All cardiorespiratory data were collected by data abstractors (MB, AC) who were blinded to PDA status.
Echocardiography assessment.Comprehensive targeted neonatal echocardiography (TnECHO) evaluation was completed according to a standardized imaging protocol by fully accredited neonatologists with hemodynamic expertise [14].Sedation is not routinely provided during the TnECHO evaluations.Studies were performed using the Vivid E90 cardiovascular ultrasound system (GE Medical Systems, Milwaukee, WI, USA) with a 12-MHz high-frequency phased-array transducer probe.Standard two-dimensional, M-mode, color Doppler, pulsed wave (PW) Doppler, and continuous wave (CW) Doppler images were obtained.Analyses of left heart volume loading, left (LV) and right (RV) ventricle systolic function, shunt physiology, pulmonary hemodynamics, and cardiac output, were performed.All echocardiography analyses were performed using a dedicated workstation (EchoPAC version BT10; GE Medical Systems, Milwaukee, WI, USA) by a single trained investigator (RG) who was blinded to the clinical information to minimize bias.Echocardiographic images and measurements were performed according to published methodology [15].Three consecutive cardiac cycles were evaluated and averaged for each measurement.Echocardiograms completed within 24 hours of each dose of surfactant were analyzed.
Group allocation.Patients were classified as either PDA [≥1 mm] or NO PDA [<1 mm].We chose an arbitrary threshold of 1 mm based on prior data which showed that patients with a trivial sized PDA have a comparable echocardiography profile, in terms of markers of shunt volume, to patients with "NO PDA".The Iowa PDA score was also calculated to provide an objective measure of shunt severity and hemodynamic significance [16].Elements of the PDA score included mitral valve E-wave velocity, IVRT, pulmonary vein D-wave velocity, LA:Ao, LVO, and the presence of diastolic flow reversal in the descending aorta, celiac artery, or middle cerebral artery (Supplementary Table 1).Points of 0, 1, or 2 are given based on these measured elements.The sum of points is added to the size of the PDA (in millimeters) divided by the patient's weight to calculate the final PDA score.A score of ≥6 signifies a presumed hsPDA.
Approach to PDA care.Comprehensive TnECHO screening is performed on all infants born less than 27 weeks' gestation between 12-18 postnatal hours.If a small PDA or a PDA with low volume shunt is identified, the neonate is observed, and repeat TnECHO is obtained between day 5-7 or sooner if clinically indicated.If a PDA with a moderate to high volume shunt is diagnosed, the infant is treated with intravenous acetaminophen 15 mg/ kg q6hr for a total of 7 days maximum.If the PDA remains hemodynamically significant after postnatal day 7, infants may receive up to 2 courses of indomethacin (0.2 mg/kg q12hr for 3 doses) after which they are referred for definitive closure (surgery or percutaneous device closure).
Approach to respiratory management including surfactant use.We have a standardized unit policy regarding respiratory care in the first postnatal month which is the usual time of late surfactant administration.Firstintention High Frequency Jet Ventilation (LifePulse 204, Bunnell Incorporated, Salt Lake City, Utah, USA) is standard of care for all preterm infants born less than 27 weeks GA according to a previously reported approach [17].The first dose of endotracheal surfactant [poractant 2.5 ml/kg divided in two aliquots] is given prophylactically, within 1-2 hours of birth, to all intubated infants born <26 weeks GA.Late surfactant is considered after postnatal day 4-7 when the infant is requiring more than 50% oxygen and there is clinical suspicion of surfactant inactivation or dysfunction from atelectotrauma, pulmonary hemorrhage, sepsis, pneumonia, or maturation associated "surfactant slump" and chest radiograph evidence of diffuse atelectasis, ground glass appearance, or air bronchograms.Late surfactant treatment is standardized with poractant at a dose of 1.25 mg/kg divided in two aliquots.Surfactant is administered by gentle hand bagging using peak inspiratory pressure (PIP) not to exceed 20 cm [17.Calfactant is typically used for premature infants who are unresponsive to two doses of poractant, or in premature infants with concern for surfactant inactivation or dysfunction.Calfactant is given in a dose of 3 ml/kg divided into two aliquots.Following surfactant administration, blood gases are monitored 15 minutes post surfactant and then at 1-3-hour intervals depending on the clinical condition of the patient.Routine chest radiographs are obtained at 1-and 4-hours post surfactant to avoid hyperinflation.Ventilator settings are adjusted to maintain arterial carbon dioxide between 40-55 mmHg in the first 7 postnatal days.Intravenous dexamethasone and furosemide are not routinely administered in the first postnatal month.In addition, intravenous sedatives or pulmonary vasodilators are not concurrently administered with surfactant.

Outcomes
The primary outcome was response (positive, negative, or non-response) to surfactant according to net change in RSS within 48 hours of surfactant administration.Secondary outcomes included PDA score, and type/ number of doses of late surfactant.

Statistical analysis
As the relationship between PDA and late surfactant responsiveness is not known a sample size of convenience was chosen; specifically, we included all patients who received late surfactant during the defined study time-period.Univariate analysis was performed to compare demographic and outcome data between "PDA" vs "NO PDA" groups.In addition, one-way ANOVA was performed to evaluate time-dependent changes in RSS and mean airway pressure according to each individual surfactant dose (i.e., each dose was classified as a positive, negative, or non-response).Changes in RSS over time were evaluated in each sub-group.A multivariate logistic regression was built to investigate factors associated with positive (model 1) or negative (model 2) response to late surfactant.Variables with a p value < 0.1 on univariate analysis were included in the model.An odds ratio with 95% confidence interval were used and results were considered significant if p < 0.05.An ROC curve was generated for a PDA score of 6, which is the standard threshold for adjudication of hemodynamic significance, as a predictor of both positive (vs non-responders and negative responders) and negative (vs non-responders and positive responders) response to late surfactant.

RESULTS
A total of 91 patients were screened for eligibility.Of these, 35 patients received at least one dose of late surfactant and satisfied other eligibility criteria (Figure 1).Baseline antenatal and neonatal characteristics are outlined in Table 1.The mean weight and GA at birth were 595 g (508, 696) and 23.3 (22.7, 25) weeks, respectively.Most patients were inborn (n = 33, 94%), male (n = 20, 57%), and received postnatal hydrocortisone during NICU admission (n = 34, 97%).Of the 35 patients who received late surfactant, 45% (n = 16) had an echocardiography diagnosis of PDA.
"Individual surfactant dose response" Among 35 eligible patients, a total of 71 surfactant doses were given on or after postnatal day 7.Of the 71 doses, positive, negative, and no response were noted in 27 (38%), 16 (23%), and 28 (39%) doses, respectively (Table 2).Changes in RSS over time are demonstrated in each subgroup (Fig. 2).Among those with a positive response, 92% (n = 25) of cases had a status of "NO PDA" at the time of surfactant administration.Conversely, among those with negative response 69% (n = 11) had a status of "PDA".Among those with non-response, 54 % (n = 15) had "NO PDA" and 46% (n = 13) had "PDA" status, respectively.In addition, mean PDA score was highest [8.8 (2.2, 10.4), p < 0.001] among patients with a negative response to surfactant.The average postnatal age of surfactant administration for positive, negative, and nonresponse were 22 ± 11, 18 ± 10 and 15 ± 6 days, respectively (p = 0.03).Infants with a positive response received a higher cumulative surfactant dosage (p < 0.05).

DISCUSSION
In this retrospective cohort study of infants born before 27 weeks' gestation, which provides preliminary data, PDA status at the time of surfactant administration after 6 days was associated with  respiratory response; specifically, infants with "NO PDA" were more likely to have a positive response to surfactant whereas infants with "PDA" status were more likely to have a negative response.In addition, calculating the magnitude of shunt volume using the Iowa PDA Score further aided characterization of respiratory response.A PDA score of greater than or equal to 6 was strongly associated with negative response to surfactant with an ROC of 0.78, with moderate-high sensitivity and specificity.
Although this is a small study, from a single center, it is hypothesis generating and important to report for two main reasons.First, for clinician who work in centers where this practice is used, as hsPDA may be clinically indistinguishable from late surfactant deficiency, these data highlight the importance of enhanced phenotypic profiling due to the potential of harm when late surfactant is used in a non-judicious manner.Second, these data also shed new light on the lack of treatment benefit seen in the TOLOSURF trial as patients with cardiac lung disease (e.g., hsPDA, post-capillary phenotype) were not excluded.Extremely premature infants are born during the canalicular period of lung development when Type II alveolar cells are not yet fully developed [17].Towards the end of this period, respiration becomes possible as Type I pneumocytes begin to populate the lung and thin-walled terminal saccules develop thus leading to the potential for gas exchange by 22 weeks' gestation.In addition to surfactant deficiency at birth, the ongoing need for mechanical ventilation required by many extremely low birthweight infants may cause further surfactant dysfunction.Merrill et al. analyzed surfactant samples and found that in chronically ventilated infants, 75% showed surfactant dysfunction [18].Additionally, they demonstrated that infection further decreased surfactant associated proteins.Thus, a deterioration in respiratory status beyond postnatal day 7 may be related to surfactant dysfunction  secondary to sepsis or continued mechanical ventilation.Currently, there continues to be controversy regarding the benefits of late surfactant therapy.Katz investigated use of late surfactant in preterm infants with a birthweight of <1000 g (GA 25.6 ± 1.9 weeks) who developed presumed 'postsurfactant slump" after postnatal day 6 day and were given an additional dose of surfactant if they had a sustained FiO 2 of greater than 0.7 despite the implementation of high frequency ventilation [7].They showed that 20% of infants with RDS at birth developed a post surfactant slump; of these, 70% patients who received additional surfactant after postnatal day 6 had improvement in respiratory function.In contrast to these findings, the results of both the TOLSURF and Hascoët trials showed no difference in the incidence of BPD or time to extubation [8,9].There were, however, major differences in the patient populations that are noteworthy.First, in each of these trials the oxygen threshold for late surfactant administration was much lower which may have diluted the specific population who may have benefitted.Second, there was a higher number of more immature patients (<1000 grams), who are biologically more likely to develop late surfactant inactivation or dysfunction, in the Katz study.Third, patients in the TOLSURF trial had empiric co-administration of inhaled nitric oxide which may have a negative impact on Qp: Qs in patients with hemodynamically significant PDAs.The increased likelihood of negative response to late surfactant in patients with a highvolume PDA shunt in our cohort reinforces this supposition.During fetal development, the ductus arteriosus is a vital part of the fetal circulation as it allows blood flow to bypass the lungs and be directed systemically [19].The adaptive changes in transductal pressure gradient after birth lead to an increase in left to right flow through the ductus.The consequential increase in pulmonary blood flow may trigger release of vasodilatory substances including nitric oxide, bradykinin, and prostacyclin [20].The increased levels of bradykinin, along with decreased prostaglandins and increased arterial oxygen concentration are key determinants of PDA closure.Architectural differences in the PDA and increased levels of prostaglandins among other proinflammatory cytokines may delay the spontaneous closure of the ductus [19].Echocardiography is the gold standard for diagnosing hsPDA due to the limitations of routine clinical signs [21].A prior study by Kindler evaluated the reliability of clinical PDA score to predict a hemodynamically significant PDA in the first postnatal week, but it has only a sensitivity and specificity of 84% and 80% on postnatal day 4 [22].Prior studies have also shown that clinical signs, such as the presence or absence of a murmur, are poor predictors of the PDA status, especially during the first postnatal week [23,24].In addition, the clinical presentations of hsPDA and surfactant deficiency are often indiscernible, with respiratory deterioration being the central feature of each condition.Similarly, both RDS and pulmonary edema secondary to a hsPDA may present with comparable findings on chest x-ray.Therefore, echocardiography is an important tool to aid differentiation of these two conditions.
The interplay between surfactant therapy and the effect on the premature cardiovascular system is complex.Surfactant has an important modulator effect on neonatal hemodynamics and PDA physiology in the preterm infant; specifically, surfactant administration has been shown to decrease pulmonary vascular resistance, increase pulmonary blood flow, and improve right ventricular function [12].Additionally, a study done by Sehgal et al. demonstrated that when surfactant was administered to premature infants within 30 minutes of birth there was increase in size of the PDA and an increased Qp:Qs ratio on echocardiography [11].In premature infants, a hsPDA can lead to pulmonary overcirculation and subsequent pulmonary edema and which may lead to respiratory decompensation [25].Our data suggests a beneficial role of late surfactant when administered in a targeted manner but also highlights the potential patient harm when administered in a non-judicious manner which may explain, at least in part, the poor efficacy in randomized trials.A PDA score >5 (moderate-high volume shunt) has a sensitivity and specificity of 0.74 to predict a deterioration in respiratory status following surfactant administration.On the contrary, patients who had a positive response to surfactant were less likely to have a PDA present at the time of administration.Administration of late surfactant to patients with an undiagnosed but hemodynamically Fig. 3 Receiver operating characteristic (ROC) curve for PDA score as a predictor of positive and negative response to late surfactant.An ROC curve was generated which shows that a PDA score of >5 has a sensitivity and specificity of 64% to predict a positive response to late surfactant and 74% to predict a negative response to late surfactant administration.PDA score was calculated based on the parameters shown in Supplementary Table 1.
significant PDA may cause respiratory decompensation and negative response through its secondary effects on lowering pulmonary vascular resistance leading to an increased systemic pulmonary pressure gradient.The consequences of the increased left to right ductal shunting and augmentation in pulmonary blood flow include pulmonary venous and left atrial hypertension.In premature infants with inherent impaired LV compliance and diastolic heart failure with preserved ejection fraction, these changes may have a deleterious effect on fragile pulmonary vasculature and may lead to pulmonary edema and in some cases pulmonary hemorrhage.Therefore, in patients with respiratory deterioration beyond the transitional period, thought due to presumed secondary surfactant inactivation, echocardiography exclusion of a hemodynamically significant PDA is important to identify which patients are most likely to benefit from late surfactant therapy.

Limitations
There are several important limitations which need clarification.First, this was a small observational retrospective study, which raises questions about the power of the sample size.Our sample size prohibits extensive adjustment for unaccounted differences in baseline characteristics.Nevertheless, it is hypothesis generating and the findings require validation in a larger sample size.Second, the non-standardized timing of the echocardiogram in relationship to surfactant administration is an important consideration.In particular, characterization of the specific physiologic effects of surfactant both in the PDA and NO PDA group would be beneficial to differentiate the positive versus negative effects to respiratory wellbeing.Longitudinal pre-and post-interventional echocardiography evaluation of the effects of late surfactant would provide additional mechanistic insights.Third, the timing of the study is an important consideration.Most studies which have characterized the hemodynamic effects of surfactant are exclusively in the transitional period.This is the first to assess the hemodynamics of surfactant outside the transitional period where the physiologic context and hemodynamic milieu are likely to be different; in particular, the magnitude of PDA shunt volume is likely to be greater after prolonged shunt exposure.This study highlights the need to conduct a prospective longitudinal echocardiography evaluation of the hemodynamic consequences in both surfactant responders and non-responders.

CONCLUSION
In neonates with hypoxemic respiratory failure, born at less than 27 weeks' gestation, our preliminary data provide hypothesis generating data which suggest that response to surfactant after postnatal day is associated with PDA status.The absence of PDA was associated with higher rate of positive response to surfactant, whereas the presence of a PDA, and in particular moderate-high volume shunt, was associated with higher rate of negative response.Serial TnECHO may be a useful tool to characterize the physiologic nature of worsening of respiratory status and enhance the selection of patients likely to benefit from late surfactant treatment.Although, the extent of this practice is unclear in the neonatal literature, our data questions the validity of prior trials of late surfactant administration; of note, these data emphasize the importance of enhanced methods of patient selection and the exclusion of patients with a pathologic PDA shunt.

Fig. 1
Fig. 1 Population description.Patients were screened and categorized as positive, negative, or non-response based on their most predominant response.Response to surfactant was determined based on change in respiratory severity score over 48 h following administration as positive [≥15% improvement], negative [≥15% deterioration] or non-response.Patent ductus arteriosus (PDA) status was determined through echocardiography during the 48 hours following surfactant administration.

Fig. 2
Fig. 2 Change in respiratory severity score following surfactant administration.Patients who had a positive, negative, or no response to surfactant were split into three groups.The above figures depict the average respiratory severity score (mean airway pressure x fraction of inspired oxygen) at multiple time points during the 48 hours following surfactant administration (Data were analyzed as one-way ANOVA).

Table 1 .
Surfactant response results based on PDA status.

Table 2 .
Response to individual doses of surfactant.Data are presented as number [frequency (percent)] or mean ± standard deviation.Chi-square analysis and one-way ANOVA were performed for continuous and categorical datasets.PDA patent ductus arteriosus.