Randomized Trial of Oxygen Saturation Targets during and after Resuscitation and Reversal of Ductal Flow in an Ovine Model of Meconium Aspiration and Pulmonary Hypertension
by
and
Amy L. Lesneski
1, 
Payam Vali
2,
Morgan E. Hardie
2,
Satyan Lakshminrusimha
2,* and
Deepika Sankaran
2 1
Department of Stem Cell Research, University of California, Davis, Sacramento, CA 95817, USA
2
Department of Pediatrics, University of California, Davis, Sacramento, CA 95817, USA
*
Author to whom correspondence should be addressed.
Children 2021, 8(7), 594; https://doi.org/10.3390/children8070594
Submission received: 9 June 2021
/
Revised: 8 July 2021
/
Accepted: 12 July 2021
/
Published: 14 July 2021
(This article belongs to the Special Issue Stabilization and Resuscitation of Newborns)
Abstract
:Neonatal resuscitation (NRP) guidelines suggest targeting 85–95% preductal SpO2 by 10 min after birth. Optimal oxygen saturation (SpO2) targets during resuscitation and in the post-resuscitation management of neonatal meconium aspiration syndrome (MAS) with persistent pulmonary hypertension (PPHN) remains uncertain. Our objective was to compare the time to reversal of ductal flow from fetal pattern (right-to-left), to left-to-right, and to evaluate pulmonary (QPA), carotid (QCA)and ductal (QDA) blood flows between standard (85–94%) and high (95–99%) SpO2 targets during and after resuscitation. Twelve lambs asphyxiated by endotracheal meconium instillation and cord occlusion to induce MAS and PPHN were resuscitated per NRP guidelines and were randomized to either standard (85–94%) or high (95–99%) SpO2 targets. Out of twelve lambs with MAS and PPHN, six each were randomized to standard and high SpO2 targets. Median [interquartile range] time to change in direction of blood flow across the ductus arteriosus from right-to-left, to left-to-right was significantly shorter with high SpO2 target (7.4 (4.4–10.8) min) compared to standard SpO2 target (31.5 (21–66.2) min, p = 0.03). QPA was significantly higher during the first 10 min after birth with higher SpO2 target. At 60 min after birth, the QPA, QCA and QDA were not different between the groups. To conclude, targeting SpO2 of 95–99% during and after resuscitation may hasten reversal of ductal flow in lambs with MAS and PPHN and transiently increase QPA but no differences were observed at 60 min. Clinical studies comparing low and high SpO2 targets assessing hemodynamics and neurodevelopmental outcomes are warranted.
1. Introduction
Successful transition of the fetus to extrauterine life involves a rapid increase in pulmonary blood flow (QPA) during the first few breaths after birth, allowing the lungs to establish as the site of gas exchange. A failure of this transition can lead to persistent pulmonary hypertension of the newborn (PPHN), characterized by sustained elevation of pulmonary vascular resistance (PVR), right-to-left shunting of blood across the foramen ovale and ductus arteriosus, and reduced QPA [1]. These newborns experience severe respiratory distress and labile hypoxemia soon after birth.
Oxygen (O2) mediates decrease in PVR after birth and has been used to correct the hypoxemia in PPHN, along with strategies to improve lung inflation with respiratory support [2,3]. Current neonatal resuscitation guidelines recommend initiating ventilation with 21% O2 with subsequent O2 titration to target goal preductal pulse oximetry O2 saturation (SpO2) ranges corresponding to the minute of life, to achieve 85–95% SpO2 by 10 min after birth. This strategy has been associated with optimal hemodynamics and gas exchange during resuscitation [4]. Rawat et al. reported that targeting 95–99% SpO2 in the post-resuscitation period lowered PVR and improved cerebral O2 delivery, while targeting 85–89% SpO2 increased PVR, and decreased QPA and cerebral O2 delivery in a term ovine model of meconium aspiration syndrome (MAS) with PPHN [5]. However, flow across the ductus arteriosus (QDA) was not evaluated in this study and ductal flow is a major contributor to QPA [6]. The optimal preductal SpO2 target range during resuscitation and post-resuscitation period that hastens reversal of shunting across the patent ductus arteriosus (PDA) from the fetal pattern to the postnatal pattern of left-to-right remains unknown.
We hypothesized that the time to reversal of shunting across the PDA is shorter with high SpO2 target of 95–99% compared to standard SpO2 target of 85–94%. Our objective was to compare the time to reversal of shunt across the PDA from the fetal (right-to-left) to the postnatal (left-to-right) pattern between standard (85–94%) and high (95–99%) SpO2 target ranges during resuscitation and the post-resuscitation period in a term ovine asphyxiated model of MAS and PPHN. We also evaluated the changes in QPA, QDA and carotid blood flow (QCA), and gas exchange at 10 min and 60 min after birth between low and high SpO2 targets as secondary outcomes.
2. Materials and Methods
The protocol was approved by the Institutional Animal Care and Use Committee (IACUC, protocol #20267) at the University of California Davis, CA, USA. This protocol involves a perinatal model of MAS and PPHN in term newborn lambs that has been extensively described previously [5,7]. All experiments were performed in accordance with animal ethical guidelines (ARRIVE) [8]. Time-dated near-term (139–141 days) gestation pregnant ewes from Van Laningham Farm (Arbuckle, CA, USA) underwent cesarean section following overnight fasting, after endotracheal intubation under general anesthesia with IV diazepam and ketamine, and inhaled 2% isoflurane, as previously described [9].
2.1. Fetal Instrumentation
The fetal lamb was partially exteriorized and intubated with a 4.5-mm cuffed endotracheal tube (ETT), the lung fluid was passively drained by gravity, and the ETT was occluded to prevent entry of air. The lamb was instrumented under maternal anesthesia after subcutaneous bupivacaine infiltration. Catheters were inserted into the right carotid artery and right jugular vein for preductal arterial blood draws, invasive blood pressure and heart rate monitoring, and IV access respectively. A flow probe (Transonics, Ithaca, NY, USA) was placed around the left carotid artery to measure blood flow. A left thoracotomy was performed, and flow probes were placed around the left pulmonary artery and ductus arteriosus to measure blood flows. Subsequently, the thoracotomy and neck incisions were closed in layers. The baseline hemodynamics were recorded and arterial blood gases were obtained.
2.2. Meconium Instillation, Asphyxia and Resuscitation
Fetal lambs were asphyxiated following instrumentation by umbilical cord occlusion (by manual compression) for 5 min or until heart rate decreased below 40 beats per minute. Meconium (5 mL/kg of 20% meconium suspended in ewe amniotic fluid) was simultaneously instilled into their endotracheal tube as previously described [7,10]. During asphyxiation, the lambs gasped and spontaneously aspirated the meconium into their lungs. The cord compression was released for 2 min to allow hemodynamic recovery, followed by another 5-min cord occlusion.
Lambs were randomized to standard SpO2 target (85–94%) or high SpO2 target (95–99%) using opaque envelopes prior to the beginning of the study (incision for cesarean section). The lambs were then delivered and ventilated with peak inflation pressures (PIP) of 30–35 cm H2O, PEEP of 5 cm H2O, rate of 40 breaths per minute and inspired O2 of 21% that was then titrated based on preductal SpO2 per Neonatal Resuscitation Program (NRP) guidelines during resuscitation to achieve a goal of 85–94% (standard target arm) [11] or titrated to achieve a goal of 95–99% SpO2 after delivery (high target arm). The titration of oxygen was proportional to the difference between observed SpO2 and target SpO2 and was performed every minute. The endotracheal tube was connected to a ventilator and PaCO2 was targeted in the 40–60 mm Hg range to allow permissive hypercapnia. The resuscitators were not blinded to the intervention. Hemodynamics were continuously monitored, and arterial blood gases were obtained at baseline, 10-min and subsequently at 15–min intervals. Lambs were monitored for up to 60 min and were finally euthanized using IV pentobarbital (Fatal-Plus, Vortech Pharmaceuticals, Dearborn, MI, USA).
2.3. Primary and Secondary Outcomes
Primary outcome measures were time to reversal of ductal shunt (from right-to-left to left-to-right) from the time of delivery.
Secondary outcome measures were changes in QPA, QDA and QCA, and gas exchange at 10 min and 60 min after birth between standard and high SpO2 targets. Cerebral oxygen delivery (mL/kg/min) was calculated by multiplying carotid artery oxygen content (CaO2 = (1.34 × Hemoglobin in g/dL × SaO2%/100%) + (partial pressure of O2 in mm Hg × 0.0031)) and left carotid artery blood flow (mL/kg/min).
2.4. Data Collection and Analysis
Hemodynamic variables were continuously monitored and recorded using BIOPAC systems data acquisition software (Goleta, CA, USA). Blood gases were analyzed using a blood gas analyzer (Radiometer ABL90 FLEX, Denmark). By convention, the right-to-left direction of QDA was labeled as negative and left-to-right direction of QDA was labeled as positive. Categorical data were analyzed using chi-squared test with Fisher’s exact test as appropriate, parametric continuous data were analyzed using unpaired t-test, and changes in QDA and QPA over time were compared using repeated measures ANOVA. The median time to reversal of shunting (non-parametric) was compared between standard and high SpO2 targets using Wilcoxon rank sum test. Statistical significance was defined as p < 0.05.
3. Results
Out of twelve near-term lambs that were asphyxiated, six were randomized to standard SpO2 target and the remaining six were randomized to high SpO2 target. Hemodynamic and arterial blood gas characteristics at fetal baseline prior to asphyxia were similar between the study groups (Table 1).
3.1. Time to Reversal of Shunt across the PDA
Median (interquartile range) time to transition from right-to-left to exclusive left-to-right shunting across the ductus arteriosus was significantly shorter with high SpO2 target (7.4 (4.4–10.8) min) compared to standard SpO2 target (31.5 (12–66.2) min, p = 0.03, Figure 1). The mean QDA (left-to-right) flow was increased with the high SpO2 targets from 0.5 to 10 min by ANOVA repeated measures. The QDA significantly increased from fetal baseline to 5-min after birth in both standard and high SpO2 targets (p < 0.05) and decreased significantly by 60 min in high SpO2 target (p < 0.05).
3.2. Comparison of Hemodynamics and Arterial Blood Gas Parameters at 5 and 10 min after Birth
During the first 10 min after delivery, the QDA (left-to-right, Figure 1, p = 0.002) and QPA (Figure 2, p = 0.048) were significantly higher with high SpO2 target compared to standard SpO2 target by ANOVA repeated measures. The QPA significantly decreased from 5-min to 60-min after birth with high SpO2 target. The hemodynamic parameters at 5 min and at 10 min time points after delivery are depicted in Table 2 and Table 3 respectively and were not different. The arterial blood gas parameters were not different at 10-min after delivery (Table 3). Although the PaO2 and SpO2 were higher in the high SpO2 target group, these differences did not reach statistical significance.
3.3. Comparison of Hemodynamics and Arterial Blood Gas Parameters at 60 min after Birth
There was no significant difference in mean QCA, QDA, or QPA blood flows at 60 min after birth (Table 4). One lamb randomized in the standard SpO2 group maintained a bidirectional QDA shunt throughout the study period. There were no significant differences in inspired O2 concentration, arterial O2 content, cerebral O2 delivery or PaO2 between the standard and high SpO2 target groups at 60 min after birth. However, the pH was higher (p = 0.046) and PaCO2 was lower (p = 0.042) with high SpO2 target at the 60 min timepoint.
An illustration summarizing the hemodynamics and gas exchange at 60 min after birth is presented as Figure 3A,B.
4. Discussion
Neonatal PPHN is commonly associated with parenchymal lung disease such as MAS [1]. Mortality rates of 4–33% have been reported for neonatal PPHN [12]. Right-to-left shunting via the PDA and PFO resulting in labile hypoxemia is characteristic of PPHN. Supplemental O2 can decrease PVR thus improving QPA, hastening reversal of extrapulmonary shunting to left-to-right. We demonstrate quicker reversal of ductal shunting to left-to-right with higher (95–99%) compared to the lower (85–94%) SpO2 target during resuscitation and in the post-resuscitation period.
The American Academy of Pediatrics (AAP) NRP Textbook of Neonatal Resuscitation recommends initiating resuscitation with 21% O2, titrating inspired O2 to achieve the target SpO2 range for every minute, and finally 85–95% by 10 min after birth. Maintaining SpO2 within the range recommended by NRP by actively titrating the inspired O2 led to effective oxygenation and QPA in an ovine model of MAS [4]. However, there is wide variation among neonatologists in their preference of SpO2 targets immediately after the initial resuscitation period [13,14]. In a recent animal study by Rawat et al., higher SpO2 target of 95–99% resulted in lower PVR, higher QPA, higher cerebral O2 delivery with lower lactate levels, but was associated with higher inspired O2 and higher lung 3-nitrotyrosine, a marker of oxidative stress compared to lower ranges of target SpO2 [5]. However, the authors did not evaluate direction of ductal flow and QDA in that study.
During neonatal resuscitation, O2 needs to be titrated judiciously to avoid hypo or hyperoxia. Kapadia et al. reported that post-resuscitation hyperoxia with perinatal acidemia is associated with higher incidence of moderate to severe hypoxic ischemic encephalopathy [15]. Thus, it is prudent to decrease supplemental O2 in a timely manner to avoid hyperoxemia. We show that the benefits of targeting higher SpO2 are transient and QPA is identical between the two study groups by 60 min after birth. We also observed lower PaCO2 in the high SpO2 target group at 60 min after birth. We speculate that the higher SpO2 target may have caused a transient surge in QPA (Figure 2) that might have contributed to better gas exchange and lower PaCO2 (Figure 3A,B). Additionally, the initial increase in left-to-right QDA and increase in QPA were not persistent at 60 min after birth (Figure 1 and Figure 2). We speculate that reduction in QPA could be secondary to transient effect of increased inspired O2 on PVR or ductal constriction limiting QDA leading to lower QPA. As the ductal flow remained steady between 5 min and 60 min after birth (Figure 1), we suspect that the PDA remained patent at 60 min in these lambs. We speculate that higher SpO2 target is associated with earlier ductal narrowing and less cardiac dysfunction with quicker cardiovascular recovery from the asphyxial insult resulting in better mean arterial pressures (MAPs). Whereas in the standard SpO2 target group, there may be slower ductal constriction and cardiovascular recovery from the asphyxial insult resulting in lower MAPs. Higher volume of shunt from the aorta-to-pulmonary artery is likely to expose ductal tissue to higher PaO2 and hasten narrowing of the ductus. Furthermore, the diastolic BP were higher with high SpO2 target at 60 min after delivery when compared to standard SpO2 target (65 ± 13 vs. 45 ± 6, p = 0.02), possibly due to ductal constriction, thus contributing to higher MAPs.
Our study has several limitations. The severity of asphyxia was mild to moderate. Despite this, we did demonstrate significant degree of hypoxemia, low QPA and right-to-left shunting across the PDA following delivery in all the lambs (Table 1 and Table 2 and Figure 1). We did not measure the pulmonary artery and left atrial pressures, and hence could not evaluate the PVR. In addition, we did not evaluate the shunting across the PFO. We had a small sample size and larger number of lambs might have led to different results. The markers of oxidative stress have not been evaluated. We did not recover the lambs and assess for long term outcomes. Although we targeted to achieve preductal SpO2 within a narrow set range, the achieved SpO2 was 88 ± 7% and 95 ± 3% in the standard and high SpO2 target groups, respectively. This difficulty in achieving a set SpO2 target range has previously been demonstrated in randomized trials in preterm infants [16,17].
To our knowledge, this is the first comparison of time to reversal of ductal shunting in PPHN between standard and high SpO2 targets during resuscitation and in the post-resuscitation period. The novel aspect of this study is the measurement of QDA along with the direction of flow in a large mammalian model of MAS and PPHN closely mimicking human cardiopulmonary physiology. The lambs underwent meconium aspiration by spontaneous aspiration with negative pressure in the perinatal period during transition rather forceful instillation of meconium in the postnatal (1–3 days, often the case in piglet models) period [18]. Although an ovine model of PPHN can be induced by prenatal ductal ligation, we are unable to assess QDA in that model. Finally, the randomized study design is a major strength of this study.
5. Conclusions
In this term lamb model of MAS and PPHN, targeting SpO2 at a higher range (95–99%) during resuscitation and in the immediate post-resuscitation period, led to a quicker transition to left-to-right shunting across the PDA but did not result in sustained increase in pulmonary blood flow. These findings support the current NRP recommendations to target preductal SpO2 between 85–95% by 10 min. Clinical trials evaluating hemodynamics and long-term neurocognitive outcomes in term neonates comparing current recommended range to higher SpO2 targets are warranted in patients at risk of PPHN such as MAS with asphyxia and congenital diaphragmatic hernia.
Author Contributions
A.L.L.: data extraction and analysis, conducting experiments, and writing the manuscript. P.V.: conducting experiments, critiquing, and revising the manuscript. M.E.H.: conducting experiments, data extraction, critiquing and revising the manuscript. S.L.: concept, procuring funds, conducting experiments, writing, critiquing, and revising the manuscript. D.S.: conducting studies, analysis of data, writing, critiquing and revising the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by NICHD 5R01 HD072929 (S.L.), Children’s Miracle Network at University of California, Davis, First Tech Federal Credit Union and UC Davis Pediatrics, and Canadian Pediatric Society NRP research grant (D.S.).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of California Davis, Davis, CA, USA (protocol #20267).
Informed Consent Statement
Not applicable.
Data Availability Statement
The data presented in this study are available in this article.
Conflicts of Interest
The authors declare no conflict of interest. S.L. is a member of the AAP NRP steering committee. The views expressed in this article are his own and does not represent the official position of AAP or NRP. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
References
- Lakshminrusimha, S.; Keszler, M. Persistent Pulmonary Hypertension of the Newborn. Neoreviews 2015, 16, e680–e692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morin, F.C., 3rd; Egan, E.A.; Ferguson, W.; Lundgren, C.E. Development of pulmonary vascular response to oxygen. Am. J. Physiol. Heart Circ. Physiol. 1988, 254, H542–H546. [Google Scholar] [CrossRef] [PubMed]
- Teitel, D.F.; Iwamoto, H.S.; Rudolph, A.M. Changes in the Pulmonary Circulation during Birth-Related Events. Pediatr. Res. 1990, 27, 372–378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rawat, M.; Chandrasekharan, P.K.; Swartz, D.D.; Mathew, B.; Nair, J.; Gugino, S.F.; Koenigsknecht, C.; Vali, P.; Lakshminrusimha, S. Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration. Pediatr. Res. 2016, 79, 583–588. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rawat, M.; Chandrasekharan, P.; Gugino, S.F.; Koenigsknecht, C.; Nielsen, L.; Wedgwood, S.; Mathew, B.; Nair, J.; Steinhorn, R.; Lakshminrusimha, S. Optimal Oxygen Targets in Term Lambs with Meconium Aspiration Syndrome and Pulmonary Hypertension. Am. J. Respir. Cell Mol. Biol. 2020, 63, 510–518. [Google Scholar] [CrossRef] [PubMed]
- Smolich, J.J.; Kenna, K.R.; Mynard, J.P. Antenatal betamethasone augments early rise in pulmonary perfusion at birth in preterm lambs: Role of ductal shunting and right ventricular outflow distribution. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 316, R716–R724. [Google Scholar] [CrossRef] [PubMed]
- Lakshminrusimha, S.; Mathew, B.; Nair, J.; Gugino, S.F.; Koenigsknecht, C.; Rawat, M.; Nielsen, L.; Swartz, D.D. Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration. Pediatr. Res. 2015, 77, 347–355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kilkenny, C.; Browne, W.J.; Cuthill, I.C.; Emerson, M.; Altman, D.G. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol. 2010, 8, e1000412. [Google Scholar] [CrossRef] [PubMed]
- Sankaran, D.; Chandrasekharan, P.K.; Gugino, S.F.; Koenigsknecht, C.; Helman, J.; Nair, J.; Mathew, B.; Rawat, M.; Vali, P.; Nielsen, L.; et al. Randomised trial of epinephrine dose and flush volume in term newborn lambs. Arch. Dis. Child. Fetal Neonatal Ed. 2021. [Google Scholar] [CrossRef] [PubMed]
- Sankaran, D.; Vali, P.; Chen, P.; Lesneski, A.L.; Hardie, M.E.; Alhassen, Z.; Wedgwood, S.; Wyckoff, M.H.; Lakshminrusimha, S. Randomized trial of oxygen weaning strategies following chest compressions during neonatal resuscitation. Pediatr. Res. 2021, 1–9. [Google Scholar] [CrossRef]
- American Academy of Pediatrics; Weiner, G.M.; American Heart Association; Zaichkin, J. Textbook of Neonatal Resuscitation, 7th ed.; American Academy of Pediatrics: Itasca, IL, USA, 2016. [Google Scholar]
- Walsh-Sukys, M.C.; Tyson, J.E.; Wright, L.L.; Bauer, C.R.; Korones, S.B.; Stevenson, D.K.; Verter, J.; Stoll, B.J.; Lemons, J.A.; Papile, L.A.; et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes. Pediatrics 2000, 105, 14–20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nakwan, N.; Chaiwiriyawong, P. An international survey on persistent pulmonary hypertension of the newborn: A need for an evidence-based management. J. Neonatal-Perinat. Med. 2016, 9, 243–250. [Google Scholar] [CrossRef] [PubMed]
- Alapati, D.; Jassar, R.; Shaffer, T.H. Management of Supplemental Oxygen for Infants with Persistent Pulmonary Hypertension of Newborn: A Survey. Am. J. Perinatol. 2017, 34, 276–282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kapadia, V.S.; Chalak, L.F.; DuPont, T.L.; Rollins, N.K.; Brion, L.P.; Wyckoff, M.H. Perinatal asphyxia with hyperoxemia within the first hour of life is associated with moderate to severe hypoxic-ischemic encephalopathy. J. Pediatr. 2013, 163, 949–954. [Google Scholar] [CrossRef] [PubMed]
- Askie, L.M.; Darlow, B.A.; Finer, N.; Schmidt, B.; Stenson, B.; Tarnow-Mordi, W.; Davis, P.G.; Carlo, W.A.; Brocklehurst, P.; Davies, L.C.; et al. Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration. JAMA 2018, 319, 2190–2201. [Google Scholar] [CrossRef] [PubMed]
- Lakshminrusimha, S.; Manja, V.; Mathew, B.; Suresh, G.K. Oxygen targeting in preterm infants: A physiological interpretation. J. Perinatol. 2015, 35, 8–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wiswell, T.E.; Peabody, S.S.; Davis, J.M.; Slayter, M.V.; Bent, R.C.; Merritt, T.A. Surfactant therapy and high-frequency jet ventilation in the management of a piglet model of the meconium aspiration syndrome. Pediatr. Res. 1994, 36, 494–500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1.
Mean ductus arteriosus blood flow (QDA) and direction of flow over timepoints from asphyxia, 0.5 min and up to 60 min after delivery between the two oxygen target groups. Delivery of lamb is indicated by the dashed, vertical line. Positive flow indicates left-to-right shunting from aorta to the pulmonary artery. Negative flow indicates right-to-left shunting from pulmonary artery to the aorta. Median (interquartile range) time for exclusive left-to-right ductal shunting post-delivery was significantly shorter in the high SpO2 target group (median 7.4 vs. 31.5 min, by Wilcoxon rank sum test). * p < 0.05, left-to-right ductal flow was significantly higher with high SpO2 target compared to standard SpO2 target (p = 0.002, ANOVA repeated measures). However, by 60 min after delivery, the QDA was not different between the two SpO2 targets. The QDA significantly increased in both high and standard SpO2 targets from fetal baseline to 5-min after birth, and significantly decreased by 60 min after birth in the high SpO2 target.
Figure 1.
Mean ductus arteriosus blood flow (QDA) and direction of flow over timepoints from asphyxia, 0.5 min and up to 60 min after delivery between the two oxygen target groups. Delivery of lamb is indicated by the dashed, vertical line. Positive flow indicates left-to-right shunting from aorta to the pulmonary artery. Negative flow indicates right-to-left shunting from pulmonary artery to the aorta. Median (interquartile range) time for exclusive left-to-right ductal shunting post-delivery was significantly shorter in the high SpO2 target group (median 7.4 vs. 31.5 min, by Wilcoxon rank sum test). * p < 0.05, left-to-right ductal flow was significantly higher with high SpO2 target compared to standard SpO2 target (p = 0.002, ANOVA repeated measures). However, by 60 min after delivery, the QDA was not different between the two SpO2 targets. The QDA significantly increased in both high and standard SpO2 targets from fetal baseline to 5-min after birth, and significantly decreased by 60 min after birth in the high SpO2 target.
Figure 2.
Mean pulmonary blood flow (QPA) during the immediate post-natal period in a lamb model of meconium aspiration syndrome (MAS) and persistent pulmonary hypertension (PPHN). Delivery of lamb is indicated by the dashed, vertical line. The QPA was significantly higher from 0.5 min to 10 min after delivery with high SpO2 target compared to standard SpO2 target (p = 0.048). However, by 60 min after delivery, the QPA was not different between the two SpO2 targets. * p < 0.05.
Figure 2.
Mean pulmonary blood flow (QPA) during the immediate post-natal period in a lamb model of meconium aspiration syndrome (MAS) and persistent pulmonary hypertension (PPHN). Delivery of lamb is indicated by the dashed, vertical line. The QPA was significantly higher from 0.5 min to 10 min after delivery with high SpO2 target compared to standard SpO2 target (p = 0.048). However, by 60 min after delivery, the QPA was not different between the two SpO2 targets. * p < 0.05.
Figure 3.
(A) Graphical summary of the results demonstrating the hemodynamics and gas exchange at 60 min after birth with high (95–99%) oxygen saturation (SpO2) targets in an ovine model of meconium aspiration and pulmonary hypertension. Median time to reversal of shunting was 7.4 (4.4–10.8) min after birth. The inspired oxygen concentration, preductal SpO2 and arterial oxygen saturation (SaO2), left-to-right ductal shunting (QDA), left pulmonary artery blood flow (QPA), left carotid artery blood flow (QCA), cerebral O2 delivery (C-DO2) and arterial partial pressure of carbon dioxide (PaCO2) are shown. Shorter time to reversal of QDA shunt to left-to-right, transiently increased QDA and QPA from 0.5–10 min after birth, and lower PaCO2 at 60 min were observed with high SpO2 target. * p < 0.05 compared to standard SpO2 target group in (B). (B) Graphical summary of the results demonstrating the hemodynamics and gas exchange at 60 min after birth with standard (85–94%) oxygen saturation (SpO2) targets in an ovine model of meconium aspiration and pulmonary hypertension. Median time to reversal of shunting was 31.5 (12–66.2) min after birth. The inspired oxygen concentration, preductal SpO2 and arterial oxygen saturation (SaO2), left-to-right ductal shunting (QDA), left pulmonary artery blood flow (QPA), left carotid artery blood flow (QCA), cerebral O2 delivery (C-DO2) and arterial partial pressure of carbon dioxide (PaCO2) are shown. Longer time to reversal of QDA shunt to left-to-right and higher PaCO2 at 60 min were observed with standard SpO2 target. * p < 0.05 compared to high SpO2 target group shown in (A).
Figure 3.
(A) Graphical summary of the results demonstrating the hemodynamics and gas exchange at 60 min after birth with high (95–99%) oxygen saturation (SpO2) targets in an ovine model of meconium aspiration and pulmonary hypertension. Median time to reversal of shunting was 7.4 (4.4–10.8) min after birth. The inspired oxygen concentration, preductal SpO2 and arterial oxygen saturation (SaO2), left-to-right ductal shunting (QDA), left pulmonary artery blood flow (QPA), left carotid artery blood flow (QCA), cerebral O2 delivery (C-DO2) and arterial partial pressure of carbon dioxide (PaCO2) are shown. Shorter time to reversal of QDA shunt to left-to-right, transiently increased QDA and QPA from 0.5–10 min after birth, and lower PaCO2 at 60 min were observed with high SpO2 target. * p < 0.05 compared to standard SpO2 target group in (B). (B) Graphical summary of the results demonstrating the hemodynamics and gas exchange at 60 min after birth with standard (85–94%) oxygen saturation (SpO2) targets in an ovine model of meconium aspiration and pulmonary hypertension. Median time to reversal of shunting was 31.5 (12–66.2) min after birth. The inspired oxygen concentration, preductal SpO2 and arterial oxygen saturation (SaO2), left-to-right ductal shunting (QDA), left pulmonary artery blood flow (QPA), left carotid artery blood flow (QCA), cerebral O2 delivery (C-DO2) and arterial partial pressure of carbon dioxide (PaCO2) are shown. Longer time to reversal of QDA shunt to left-to-right and higher PaCO2 at 60 min were observed with standard SpO2 target. * p < 0.05 compared to high SpO2 target group shown in (A).
Table 1.
Comparison of fetal baseline hemodynamic and arterial blood gas parameters and end-asphyxia hemodynamic parameters in a near-term ovine model of meconium aspiration syndrome (MAS) and persistent pulmonary hypertension (PPHN) randomized to standard (85–94%) and high (95–99%) preductal SpO2 target groups.
Table 1.
Comparison of fetal baseline hemodynamic and arterial blood gas parameters and end-asphyxia hemodynamic parameters in a near-term ovine model of meconium aspiration syndrome (MAS) and persistent pulmonary hypertension (PPHN) randomized to standard (85–94%) and high (95–99%) preductal SpO2 target groups.
| Parameter | Standard SpO2 Target (85–94%, n = 6) | High SpO2 Target (95–99%, n = 6) |
|---|---|---|
| Weight (kg) | 3.4 ± 0.8 | 3.3 ± 0.4 |
| Gestational Age (days) | 139.7 ± 0.7 | 139.3 ± 0.8 |
| Parameters at Fetal Baseline | ||
| Hemoglobin, g/dL | 13.88 ± 2.47 | 11.93 ± 1.52 |
| pH | 7.18 ± 0.08 | 7.19 ± 0.06 |
| PaCO2 (mm Hg) | 74.73 ± 12.58 | 64.95 ± 5.17 |
| PaO2 (mm Hg) | 22.08 ± 6.22 | 28.38 ± 4.51 |
| Cerebral Oxygen Delivery (mL/kg/min) | 4.26 ± 2.17 | 2.40 ± 0.64 |
| Lactate (mmol/L) | 2.20 ± 0.53 | 2.37 ± 0.96 |
| Heart Rate (bpm) | 155.17 ± 21.95 | 164.23 ± 21.50 |
| Mean Arterial Blood Pressure (mm Hg) | 55.52 ± 4.42 | 61.11 ± 3.8 |
| Mean Ductal Blood Flow (mL/kg/min) | −125.89 ± 64.77 | −84.33 ± 36.09 |
| Mean Pulmonary Artery Blood Flow (mL/kg/min) | 25.21 ± 8.25 | 49.39 ± 23.59 |
| Duration of Asphyxia (min) | 13.43 ± 0.63 | 15.32 ± 1.82 |
| Parameters at End of Asphyxia | ||
| Mean Carotid Artery Blood Flow (mL/kg/min) | 24.0 (5.5) | 21.2 (4.4) |
| Mean Ductal Blood Flow (mL/kg/min) | −18.3 (6.9) | −15 (7.7) |
| Mean Pulmonary Artery Blood Flow (mL/kg/min) | 18.3 (2.7) | 29.4 (13.2) |
Data presented as mean ± standard deviation. Data were not different by unpaired t test. PaCO2 = arterial carbon dioxide pressure; PaO2 = arterial oxygen pressure; SpO2 = oxygen saturation.
Table 2.
Comparison of hemodynamics at 5 min after birth in a perinatal lamb model of MAS and PPHN.
| Parameter | Standard SpO2 Target (85–94%, n = 6) | High SpO2 Target (95–99%, n = 6) |
|---|---|---|
| Heart Rate (bpm) | 182.12 ± 12.14 | 170.78 ± 13.08 |
| Mean Arterial Blood Pressure (mm Hg) | 52.91 ± 18.79 | 65.38 ± 8.81 |
| Mean Carotid Flow (QCA, mL/kg/min) | 34.10 ± 14.84 | 20.22 ± 8.47 |
Data presented as mean and standard deviation. Positive flow indicates left-to-right ductus arteriosus blood flow. There was no significant difference between the two SpO2 targets at 5-min timepoint by unpaired t-test.
Table 3.
Comparison of hemodynamics and oxygenation at 10 min after birth in a perinatal lamb model of MAS and PPHN.
Table 3.
Comparison of hemodynamics and oxygenation at 10 min after birth in a perinatal lamb model of MAS and PPHN.
| Parameter | Standard SpO2 Target (85–94%, n = 6) | High SpO2 Target (95–99%, n = 6) |
|---|---|---|
| Hemoglobin, g/dL | 13.18 ± 1.95 | 11.9 ± 1.40 |
| pH | 7.05 ± 0.24 | 7.11 ± 0.19 |
| PaCO2 (mm Hg) | 79.48 ± 48.89 | 64.5 ± 42.89 |
| PaO2 (mm Hg) | 53.42 ± 22.97 | 60.13 ± 2.55 |
| SaO2 (%) | 89.7 ± 4.32 | 93.9 ± 3.96 |
| SpO2 (%) | 77.75 ± 30.61 | 91.33 ± 6.51 |
| CaO2 (mL O2/dL) | 15.98 ± 2.14 | 15.14 ± 1.62 |
| Cerebral Oxygen Delivery (mL/kg/min) | 4.78 ± 2.23 | 3.69 ± 0.47 |
| Lactate (mmol/L) | 6.02 ± 1.97 | 5.90 ± 1.75 |
| Heart Rate (bpm) | 176.0 ± 13.22 | 162.55 ± 31.18 |
| Mean Arterial Blood Pressure (mmHg) | 59.34 ± 9.497 | 65.67 ± 8.98 |
| Mean Carotid Flow (QCA, mL/kg/min) | 29.17 ± 12.31 | 20.44 ± 7.32 |
| Inspired O2 (%) at 10 min | 40.75 ± 39.5 | 30.67 ± 16.74 |
Data presented as mean and standard deviation. No significant differences in parameters between the standard and high SpO2 target groups at 10-min time point by unpaired t-test.
Table 4.
Comparison of hemodynamics and oxygenation comparisons at 60 min after birth in a perinatal lamb model of MAS and PPHN.
Table 4.
Comparison of hemodynamics and oxygenation comparisons at 60 min after birth in a perinatal lamb model of MAS and PPHN.
| Parameter | Standard SpO2 Target (85–94%, n = 6) | High SpO2 Target (95–99%, n = 6) |
|---|---|---|
| Hemoglobin, g/dL | 12.32 ± 3.17 | 11.85 ± 1.08 |
| pH | 7.12 ± 0.11 | 7.25 ± 0.09 ǂ |
| PaCO2 (mmHg) | 61.23 ± 15.42 | 44.08 ± 7.07 ǂ |
| PaO2 (mmHg) | 48.14 ± 21.76 | 65.08 ± 18.77 |
| SaO2 (%) | 86.66 ± 12.29 | 94.68 ± 3.55 |
| SpO2 (%) | 88.4 ± 7.3 | 95.33 ± 2.50 |
| CaO2 (mlO2/dL) | 14.96 ± 4.22 | 15.23 ± 1.44 |
| Cerebral Oxygen Delivery (ml/kg/min) | 2.54 ± 0.68 | 2.12 ± 0.9 |
| Lactate (mmol/L) | 4.25 ± 1.94 | 4.07 ± 1.75 |
| Heart Rate (bpm) | 167.76 ± 32.46 | 154.56 ± 9.94 |
| Mean Arterial Blood Pressure (mmHg) | 53.41 ± 14.30 | 71.51 ± 8.14 ǂ |
| Mean Carotid Flow (QCA-mL/kg/min) | 16.01 ± 4.96 | 14.28 ± 7.21 |
| Inspired O2 (%) at 60 min | 41.5 ± 13.25 | 64.66 ± 31.51 |
PaCO2 = arterial carbon dioxide pressure; PaO2 = arterial oxygen pressure; SaO2 = arterial oxygen saturation from blood gas; SpO2 = preductal pulse oximeter oxygen saturation; CaO2 = arterial oxygen content. ǂ Significantly different from the 85–94% target group; p < 0.05, unpaired student t-test, unequal variances.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Lesneski, A.L.; Vali, P.; Hardie, M.E.; Lakshminrusimha, S.; Sankaran, D. Randomized Trial of Oxygen Saturation Targets during and after Resuscitation and Reversal of Ductal Flow in an Ovine Model of Meconium Aspiration and Pulmonary Hypertension. Children 2021, 8, 594. https://doi.org/10.3390/children8070594
AMA Style
Lesneski AL, Vali P, Hardie ME, Lakshminrusimha S, Sankaran D. Randomized Trial of Oxygen Saturation Targets during and after Resuscitation and Reversal of Ductal Flow in an Ovine Model of Meconium Aspiration and Pulmonary Hypertension. Children. 2021; 8(7):594. https://doi.org/10.3390/children8070594
Chicago/Turabian StyleLesneski, Amy L., Payam Vali, Morgan E. Hardie, Satyan Lakshminrusimha, and Deepika Sankaran. 2021. "Randomized Trial of Oxygen Saturation Targets during and after Resuscitation and Reversal of Ductal Flow in an Ovine Model of Meconium Aspiration and Pulmonary Hypertension" Children 8, no. 7: 594. https://doi.org/10.3390/children8070594
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
