Novel scoring tool of hypoxemic respiratory failure and pulmonary hypertension for defining severity of persistent pulmonary hypertension of newborn

doi:10.21203/rs.3.rs-2967860/v1

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Novel scoring tool of hypoxemic respiratory failure and pulmonary hypertension for defining severity of persistent pulmonary hypertension of newborn

https://doi.org/10.21203/rs.3.rs-2967860/v1

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published 25 Aug, 2023

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Objective:

To create and obtain preliminary validity data for a hypoxemic respiratory failure/pulmonary hypertension (HRF/PH) score for classifying persistent pulmonary hypertension of the newborn (PPHN).

Study Design:

Retrospective chart review of 83 neonates admitted to a Children’s hospital from 2016–2021 with PPHN, gestational age ≥ 34 weeks, and echocardiograms in the first week. We assessed correlation between HRF/PH score and short-term outcomes using linear and logistic regressions.

Results:

HRF/PH scores ranged 2–12 (mean 8.5), and were classified mild (0–5), moderate (6–10) and severe (11–15), with 6%, 77% and 17% infants in respective categories. HRF/PH score category correlated with invasive ventilation, nitric oxide, high frequency ventilation, vasoactive infusions, extracorporeal life support and death. HRF/PH score category did not correlate with duration of support or length of stay.

Conclusion:

The HRF/PH score offers a promising representation of disease severity for PPHN and can be a potential tool to assess outcomes in clinical trials.

Health sciences/Medical research/Outcomes research

Health sciences/Risk factors

At birth, an 8–10 fold increase in pulmonary blood flow and drop in pulmonary vascular resistance (PVR) facilitates the establishment of lungs as the organ for gas exchange. This transition from placenta to lung is mediated by several factors including endogenous nitric oxide, prostaglandins, phosphodiesterase 5, and natriuretic peptides [1, 2]. When PVR fails to decrease because of pathology within the lungs or vasculature, increased afterload on the right ventricle drives right-to-left shunting through fetal shunts and worsening hypoxemia. Hypoxemic respiratory failure (HRF) ensues, with resultant hypoxemia, hypercarbia, and increased metabolic demand contributing to development of persistent pulmonary hypertension of the newborn (PPHN) [3]. HRF and PPHN may be conservatively managed with lung recruitment (with ventilation and surfactant, if indicated), oxygen supplementation, inhaled nitric oxide (iNO), and in some cases extracorporeal life support (ECLS).

Given the great variability in underlying pathology causing PPHN, randomized controlled trials (RCTs) seeking to optimize treatments have differed in the defined inclusion criteria of infants. RCTs for treatments such as iNO [4–8], milrinone [9] and surfactant [10] have traditionally used oxygenation index (OI) as an inclusion criterion. Occasionally, some of these trials have added presence of PPHN by echocardiography as a dichotomous variable and an additional criterion for inclusion [4]. Severity of hypoxemia and pulmonary hypertension contribute to the pathophysiology of HRF and PPHN [11]. However, to our knowledge, there are no RCTs that have assessed the severity of HRF and pulmonary hypertension as combined inclusion criteria or as the primary outcome. Most of these trials have evaluated death or cannulation for ECLS as primary outcomes. Given the low frequency of death/ECLS in PPHN (with the exception of congenital diaphragmatic hernia – CDH), studies that are planned with this outcome require a large sample size. Creation and validation of a score that combines assessment of severity of hypoxemia [12] and pulmonary hypertension [13] may offer alternate criteria for inclusion and/or primary outcome in trials evaluating HRF/PH [14]. Use of oxygen saturation by pulse oximetry (SpO₂) instead of arterial partial pressure of oxygen (PaO₂), reduces the need for an indwelling arterial line and enables assessment of preductal and postductal oxygenation in a continuous and non-invasive manner.

In this study, we aimed to create and assess an HRF/PH score to characterize the severity of PPHN without need for invasive arterial access. In a collaborative effort with neonatologists, pediatric cardiologists, and pediatric intensivists at our institution, we developed a score that incorporates level of hypoxemia and echocardiographic findings of PH and evaluated this score in a retrospective review of infants with PPHN.

This study received IRB exemption status (ID: 1668854-3).

Study Population

A retrospective chart review was performed of newborn infants (0–7 days of postnatal age) admitted to a level IV academic neonatal intensive care unit (NICU) from January 2016 to December 2021. Inclusion criteria included a documented diagnosis of PPHN by ICD 9 or 10 codes, gestational age ≥ 34 weeks, and echocardiogram in the first 7 days after birth. The range of 2016–2021 was chosen based on annual estimates to target 100 total patients to fit the scope and feasibility of retrospective study geared towards obtaining preliminary score validity data. Those with CDH, Trisomy 21, and hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia were included. Exclusion criteria included congenital heart disease other than atrial septal defect/patent foreman ovale (ASD/PFO), patent ductus arteriosus (PDA), or ventricular septal defect (VSD) < 2 mm.

Data Collection and Hypoxic Respiratory Failure/Pulmonary Hypertension Score

Prenatal, perinatal, and postnatal demographic data were collected to assess potential risk factors that contributed to PPHN for each newborn infant. Data related to the earliest complete transthoracic echocardiogram for each infant were reviewed to develop the HRF/PH score, which was divided into an oxygenation (HRF) score and an echocardiogram (PH) score (Fig. 1). The oxygenation score was assigned to each neonate based on the respiratory support and oxygenation at the time of the echocardiogram. Those receiving either nasal cannula or high flow nasal cannula (HFNC) scored 0 or 1, with a score of 1 indicating a flow rate ≥ 2 liters per minute, or a fraction of inspired oxygen (FiO₂) at 0.3 or greater. Those who required higher levels of oxygenation support with continuous positive airway pressure (CPAP), nasal intermittent (non-invasive) positive pressure ventilation (NIPPV), or invasive mechanical ventilation (IMV) received a score greater than 1. If an arterial gas was available within four hours of the echocardiogram, the OI (FiO₂*100*Mean airway pressure/PaO₂) was calculated. Without an arterial line, the oxygen saturation index (OSI = FiO₂*100*Mean airway pressure/SpO₂) was calculated using preductal oxygen saturation (SpO₂), which was preferentially measured on the right upper limb > left upper limb > lower limb. Increasing values of OI or OSI in these patients corresponded to a higher oxygenation score, with an OSI < 5 or OI < 10 indicating an oxygenation score of 2 and increasing incrementally (Fig. 1A).

The PH component of the HRF/PH score analyzed the first complete echocardiogram for the interventricular septum (IVS) position, tricuspid annular plane systolic excursion (TAPSE), estimated right ventricular systolic pressure (RVsP), and presence of right ventricular dysfunction. If the echocardiogram report available in the chart did not contain all of these components, the echocardiogram was reviewed by a single pediatric cardiologist (SS) on the research team to provide the missing data and validate measurements. IVS position has been correlated to degree of right ventricular pressures [15]. Specifically, with increasing right ventricular pressures, the short axis geometry of the left ventricle is distorted and leads to progressive flattening of the IVS during systole. As such, the IVS position was scored from 0–3 based on its position in the parasternal short axis. TAPSE, which was measured from a standard apical 4 chamber window and graded from 0–3 based on the numerical measurement, quantifies the systolic excursion of the tricuspid annulus in the longitudinal direction of the right ventricular free wall and represents right ventricular longitudinal function. The RVsP was calculated and graded from 0–3 based on the peak tricuspid regurgitation jet velocity and use of the simplified Bernoulli equation: RVsP = 4(v)², where v is the peak velocity of the tricuspid valve regurgitant jet measured in meters/second. The tricuspid jet was determined either in the parasternal short axis or the apical 4 chamber - whichever image provided the most complete Doppler waveform. If the RVsP was unable to be determined by the tricuspid regurgitant jet due to the lack of valve insufficiency, the IVS position score was multiplied by 2. Right ventricular dysfunction was assigned a score of either present or absent based on the interpretation and experience of the imaging-trained pediatric cardiologist assessing all echocardiograms for the study. PH score was then assigned to each newborn from these components (Fig. 1B). The oxygenation (HRF) and echocardiogram (PH) scores were totaled for a cumulative HRF/PH score (Fig. 1C). The HRF/PH score ranged 0–15 with higher score indicating increased severity.

Outcomes

The primary outcome was death/ECLS before discharge. Other outcomes were length of stay (LOS), survival to discharge, and the use and duration of supportive care required through the infant’s hospital course, including IMV, high frequency oscillatory ventilation (HFOV), iNO, need for vasoactive infusions and maximum vasoactive-isotropic score (VIS – equation in supplement).

All data were entered into a REDCap database [16].

Data Analysis

HRF/PH score was divided into 3 categories: mild (0–5), moderate (6–10), and severe (11–15), and outcomes were examined with respect to both total HRF/PH score and score category. Associations of HRF/PF score with continuous and dichotomous outcomes were assessed using linear regression with robust standard errors and exact logistic regression, respectively. Data were summarized with absolute and relative frequencies for dichotomous outcomes and with the median and interquartile range for continuous outcomes. Fisher’s exact test was used for categorical variables with 3 or more levels. P < 0.05 was considered significant. Statistical analysis was performed in Stata/SE (version 17).

One hundred consecutive charts were reviewed, and 13 newborns were excluded – 3 due to presence of congenital heart disease, and 10 due to missing echocardiogram or outcomes data due to transfer from or to other hospitals. 83 newborns were included, of which 64% were male. The mode of delivery was cesarean section in 60% of cases. 16% of patients required suction and stimulation as their most invasive form of post-delivery resuscitation. A majority (84%) required higher levels of resuscitation, such as positive pressure ventilation (PPV) or intubation.

HRF/PH scores ranged from 2–12 with a mean of 8.5. As mentioned previously, patients were stratified to three groups to indicate their level of PPHN severity, based on their HRF/PH score. Based on the three HRF/PH score categories, 6% had mild, 77% had moderate, and 17% had severe PPHN.

Baseline demographic data were grossly similar among HRF/PH severity groups (Table 1). There were no significant differences between groups in terms of gestational age, sex assigned at birth, or delivery method. There was also no significant difference in maternal risk factors between cohorts including prolonged rupture of membranes, group B streptococcal (GBS) positive status, hypertension of pregnancy or gestational diabetes. Conditions known to cause or contribute to PPHN occurred with similar frequency among severity groups, with 36% of total cases having meconium aspiration, and 5% culture-proven sepsis. The moderate and severe PPHN patients had increased percentage of cases with fetal distress during labor, however it was not significant. The severe PPHN cohort had a higher number of infants with lung malformations, including CDH, congenital pulmonary airway malformation, and pulmonary hypoplasia (Table 1).

Table 1

Demographic characteristics by HRF/PH severity category
	Mild (0–5) N = 5	Moderate (6–10) N = 65	Severe (11–15) N = 13	p value
Gestational age, weeks (median, IQR)	37.7 (37-38.4)	39.3 (38-40.4)	37.6 (36.9–39.9)	0.06
Sex (%) Male	1 (20)	43 (66)	9 (69)	0.21
Delivery method C-section	3 (60)	42 (65)	5 (38)	0.22
Prolonged rupture of membranes^a	0	9/55 (16)	2/10 (20)	0.48
Fetal distress during labor	0	33 (51)	4 (31)	> 0.9
GBS positive (maternal)^a	2/2 (50)	19/54 (35)	5/9 (56)	0.59
Maternal hypertensive disease	1 (20)	14 (22)	2 (15)	0.77
Maternal diabetes	2 (40)	11 (17)	2 (15)	0.53
Post-delivery resuscitation Suction/stimulation NIPPV Intubation	2 (40) 3 (60) 0	10 (15) 28 (43) 27 (42)	1 (8) 5 (38) 7 (54)	0.22
Compressions required post-delivery	0	12 (18)	4 (31)	0.23
Non-cardiac birth defect	2 (40)	7 (11)	1 (8)	0.26
Genetic defect	1 (20)	5 (8)	2 (15)	> 0.9
Lung malformation^b	0	2 (3)	3 (23)	0.02
Small for gestational age	0	7 (11)	2 (15)	0.44
Large for gestational age	0	10 (17)	4 (36)	0.10
Mechanism(s) for PPHN^c Meconium aspiration Culture proven sepsis Pneumonia	1 (20) 1 (20) 0	25 (38) 2 (3) 1 (2)	4 (31) 1 (8) 0	> 0.9 > 0.9 > 0.9
Age at echocardiogram (median, IQR)	1 (1–1)	1 (1–2)	1 (1–1)	0.02
^aDenominators are shown when it differs from total column N due to some patients having “unknown” status.
^bLung malformation includes congenital diaphragmatic hernia, sequestration, congenital pulmonary airway malformation, and severe pulmonary hypoplasia.
^cColumn percentage does not equal 100% because infants may have had no identified mechanism, or multiple identified mechanisms.

Logistic regression (Table 2) demonstrated that a higher PPHN severity category significantly correlated with combined death/ECLS, death before discharge, as well as need for iNO, IMV, HFOV, ECLS, and vasoactive infusions. 100% of cases in the severe PPHN cohort required iNO, IMV, HFOV, and vasoactive infusions, as compared to 20% of cases in the mild cohort requiring iNO and IMV, and zero cases in the mild cohort requiring HFOV or vasoactive infusions. ECLS was used in zero mild, 12% of moderate, and 62% of severe PPHN cases. Finally, death before discharge was significantly increased in higher severity cohorts, with zero percent of mild, 11% of moderate, and 54% of severe PPHN cases

Table 2

Outcomes by HRF/PH severity category
	Mild (0–5) N = 5	Moderate (6–10) N = 65	Severe (11–15) N = 13	p value
Dichotomous outcomes, N (%)
Death/ECLS	0	12 (18)	10 (77)	< 0.0001
Required ECLS	0	8 (12)	8 (62)	< 0.001
Died before discharge	0	7 (11)	7 (54)	< 0.001
Required iNO	1 (20)	50 (77)	13 (100)	< 0.01
Required vasoactive infusions	0	42 (65)	13 (100)	< 0.0001
Required IMV	1 (20)	49 (75)	13 (100)	< 0.01
Required HFOV	0	41 (84)	13 (100)	0.03
Ventilated week or longer^a	0	21/42 (50)	3/6 (50)	0.72
Ventilated 2 weeks or longer^a	0	7/42 (17)	3/6 (50)	0.13
LOS over a week^a	4/5 (80)	53/58 (91)	6/6 (100)	0.31
Continuous outcomes^b, median (IQR)
Duration of iNO, hours^a	8 (8–8)	86 (57–158)	120 (58–242)	0.27
Duration of IMV, days^a	1 (1–1)	6.5 (4–11)	9 (4–16)	0.27
Total length of stay, days^a,b	16 (13–23)	19 (11–33)	32.5 (16–76)	0.95
ICU length of stay, days^a	16 (13–23)	19 (11–33)	32.5 (16–51)	0.93
VIS score	--	14.5 (9-27.5)	25 (15-1745)	0.17
Duration ECLS, hours^a	--	106 (96–162)	152 (86–278)	0.69
iNO: inhaled nitric oxide. ECLS: extracorporeal life support. IMV: invasive mechanical ventilation. HFOV: high frequency oscillatory ventilation. VIS: vasoactive-isotropic score. IQR: interquartile range.
^aExcludes patients that died so denominator shown when relevant.
^bp values are from linear regression comparing outcomes as continuous variables across the score categories.

The total mortality rate was 17%. Of the 14 patients who died, 10 of them had progressive multiorgan failure that appeared to be incited by profound HRF and PH. Of the other 4 patients, 2 died of severe hypoxic ischemic injury with evidence of an in-utero insult and poor neurologic prognosis, 1 suffered spontaneous intestinal perforation and overwhelming sepsis in the setting of pulmonary hypoplasia, and 1 succumbed to herpes simplex virus encephalitis. Eight of the 14 patients (57%) were on ECLS prior to compassionate decannulation. The 6 patients who did not receive ECLS had known pre-existing injuries or anomalies thought to be irreversible, including severe HIE and pulmonary hypoplasia.

On linear regression analysis of infants surviving until discharge, HRF/PH score category did not correlate with duration of iNO, IMV, or ECLS, maximum VIS score, or total or ICU LOS. Outcomes shown in Table 2. Scatter figures demonstrating distribution of iNO, IMV and ECLS duration, and ICU and total LOS across the total HRF/PH scores are provided in the supplement to note both some outliers as well as trends.

To our knowledge, our study is the first to combine comprehensive blood gas/pulse oximetry data and echocardiogram findings to create a combined score to assess hypoxemia and severity of pulmonary hypertension. In addition, we preliminarily validated this score in relation to short-term outcomes in a small sample of patients with HRF/PPHN.

Classic RCTs evaluating therapy for HRF/PPHN such as iNO have used OI as entry criteria and often also as secondary outcome [4, 5, 17] with primary outcome being death or ECLS. Authors assessing whether echocardiographic findings serve as prognostic factors have also used these primary outcomes [18–22]. Except CDH, the rates of ECLS and death have decreased for PPHN. Recruitment to trials evaluating PPHN and HRF have been difficult with many trials stopping early due to poor enrollment [23–26]. An effective strategy to enhance enrollment would be to broaden inclusion criteria to accept patients without an indwelling arterial line (to calculate OI) and use a combination of pulse oximetry and echocardiographic criteria. Our score correlates well with not only mortality and ECLS cannulation, but also need for most intensive supportive care measures. This may be of particular interest in periods of critical shortage, when it is important to gauge not only likelihood of mortality, but need for limited resources.

A major limitation to our study is the small sample size used to validate this score. Although we had a small number of patients, they were representative of HRF/PPHN patients from other studies. Similar to other studies, our patient population with moderate to severe HRF/PH showed a male predominance [27] had associated fetal distress and required intubation for PPV during resuscitation after birth. Meconium aspiration and sepsis/pneumonia were common causes for PPHN, similar to epidemiological studies from California [28].

We attempted to utilize commonly used echocardiographic parameters to create the PH component of the HRF/PH score. While it is difficult to use any single aspect of echocardiography to diagnose PPHN or determine its severity, a variety of echocardiogram findings have been used in conjunction with clinical findings as inclusion criteria in studying patients with PPHN [29–31]. The IVS normally bows into the right ventricle (with a O-shaped left ventricle and a crescent or D shaped right ventricle). A flat septum indicates moderate PPHN and a septum bowing into the left ventricle suggests suprasystemic pulmonary hypertension. Tricuspid regurgitation (TR) jet serves as a proxy for systolic pulmonary artery pressure (SPAP) using the modified Bernoulli equation. TR jet is an attractive measure for use in our score as it is the most direct non-invasive measure of SPAP, it is quantitative, it has been shown to correlate with poor outcomes specifically in infants with PPHN [27], and it has previously been shown to correlate to cardiac catheterization data exceptionally well in adult patients with pulmonary hypertension [32–35]. However, it cannot always be observed – it is present in approximately 60–85% of patients with PPHN and may not be visible on echocardiography in the setting of poor right ventricular contractility [5]. Additionally, its correlation with cardiac catheterization data in children under 2 appears to be poor, though such studies are extremely limited and only in specific populations such as those with chronic lung disease, and its performance is improved when used in combination with other echocardiogram findings [36]. In the current study, we used estimated RVsP in relation to systemic blood pressure to assess severity of PPHN. TAPSE was included as the second measure of severity of PPHN. It is a simple but highly reproducible and robust measure of right ventricular deformation that is minimally influenced by imaging artifact, and reference values in neonates are published [37]. Additionally, Malowitz et al. found that infants with PPHN who died or needed ECLS had comparatively higher OI and lower TAPSE than those who survived without ECLS. Right ventricular dysfunction worsens the outcome in PPHN [22]. Hence the presence of right ventricular dysfunction was added as factor.

Frequently used in other studies is bidirectional or right-to-left shunting through a PDA, which theoretically indicates pulmonary pressures near or above systemic pressures. However, shunt directionality is also influenced by intrathoracic pressure and may change minute-to-minute in response to ventilator adjustments, physical pressure, and pain or agitation. Authors that have assessed whether directionality of shunt correlates to PPHN outcomes have found mixed results [18–20, 22], and have suggested that bidirectional shunting should not rule out severe disease. Interestingly, a more recent prospective study [38] employed serial echocardiography, showing that right-to-left ductus arteriosus shunting on second echocardiography after initial stabilization is associated with death before day 28. It is possible that persistence of right-to-left shunting may represent more severe disease; however, we opted not to use this measure as a single visualization is unlikely to be useful for stratification into severity categories.

Newer modalities of assessing pulmonary hypertension such as pulmonary arterial acceleration time (PAAT) and PAAT/Right ventricular ejection time (RVET) ratio are being increasingly used in diagnosis and management of neonatal pulmonary hypertension. Indices of left ventricular dysfunction, which can cause pulmonary venous hypertension and worsen outcomes, have also been used. However, they have correlated largely to the infrequent outcomes of ECLS cannulation and mortality [18, 20, 22]. As our priority was determining a range in severity of pulmonary hypertension and maintaining relative simplicity in our score, we excluded these measures. The precise components of the HRF/PH score may require modifications to include newer modalities of assessing hypoxemia and pulmonary hypertension and optimize its utilization in clinical practice and trials.

Our HRF/PH score and score categories correlate well to several outcomes that may make them useful at the bedside, as well as in research. Score category predicts requirement for iNO, IMV, HFOV, vasoactive infusions, and ECLS. This could be utilized in clinical settings to facilitate timely transport to appropriate centers, particularly as ECLS remains a limited resource, and HFOV and IMV management in neonates is dependent on skilled, pediatric-specific clinicians. HRF/PH score did not correlate with ICU or total LOS; we suspect this is for multiple reasons. Several infants required surgical intervention unrelated to PPHN during hospitalization, including duodenal atresia repair (n = 2), urethral valve ablation (n = 1), and gastrostomy tube placement (n = 8). One patient with an omphalocele, though only scored as mild PPHN with minimal oxygen requirement, was unable to wean from PPV after a long period in the ICU and ultimately had a tracheostomy placed – this patient had the longest ICU and total LOS by more than 70 days. This patient appeared to have primarily hypercapnic respiratory failure, presumably in part due to inadequate ventilation from abdominal competition. Other patients required medical management of pathologies unrelated to PPHN which prolonged their course, including refractory hypoglycemia, unexplained hypercalcemia, and infections. Future studies with larger sample sizes should attempt to control for these factors in analyzing correlation between HRF/PH score and LOS. Our score categories also did not correlate with duration of iNO, IMV, or ECLS. However, this may be due to relatively smaller proportion of patients in the severe category. When assessing duration of iNO and IMV against the total HRF/PH score as a continuous variable opposed to the score category, it was significant, but with few patients with an HRF/PH at the most severe end of the range. The scatter plots of score total and duration of iNO, IMV, and LOS are shown in Supplement Figure.

There are additional limitations to our study. The retrospective design limited us only to data that were available from the care the patients received. For example, infants were scored at different days after birth depending on when an echocardiography was obtained. As pulmonary hypertension changes with time, it is possible that infants would score higher or lower if echocardiography was performed sooner or later. However, a majority of patients were scored on the first day after birth and no infants were scored later than three days from birth, meaning echocardiograms included were likely to capture PPHN at a similar acute phase without chronic structural remodeling. We also did not assess longer term outcomes such as neurological development, which should be considered in future studies.

In conclusion, we attempted to combine the hypoxemia and echocardiographic evidence of pulmonary hypertension into a combined score for assessment of neonates with HRF/PH. Our findings suggest that the HRF/PH score developed for the purpose of assessing PPHN offers a promising representation of combined disease severity of hypoxemia and pulmonary hypertension, particularly when it comes to need for of intensive supportive care measures, and possibly the duration. Validation and further refining of this score might be beneficial using large, multicenter datasets.

Funding:

This research was funded by National Center for Advancing Translational Science (NCATS), National Institutes of Health (NIH), through grant number UL1 TR001860 and linked award KL2 TR001859, and by Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), NIH through grant number R01 HD072929. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author contributions:

Authors jointly conceived of the study design. SS, SL, and HS developed the scoring method. ST and AB collected data. SS reviewed imaging when necessary. ST, DT, and HS performed statistical analysis. ST wrote the initial draft of the manuscript, with contributions and edits from all other authors. All authors approve the final manuscript.

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There is NO conflict of interest to disclose.

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published 25 Aug, 2023

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Novel scoring tool of hypoxemic respiratory failure and pulmonary hypertension for defining severity of persistent pulmonary hypertension of newborn

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