Placental transfusion during neonatal resuscitation in an asphyxiated preterm model.

BACKGROUND: Neonatal Resuscitation Program does not recommend placental transfusion in depressed preterm neonates. METHODS: Our objectives were to study the effect of delayed cord clamping (DCC) with ventilation for 5 min (DCCV, n-5), umbilical cord milking (UCM) without ventilation (n-6), UCM with ventilation (UCMV, n-6), early cord clamping followed by ventilation (ECCV, n-6) on red cell volume (RCV), and hemodynamic changes in asphyxiated preterm lambs. Twenty-three preterm lambs at 127-128 days gestation were randomized to DCCV, UCM, UCMV, and ECCV. We defined asphyxia as heart rate <100/min. RESULTS: The UCMV had the highest neonatal RCV as a percentage of fetoplacental volume compared to the other groups (UCMV 85.5 ± 10%, UCM 72 ± 10%, ECCV 65 ± 14%, DCCV 61 ± 10%, p < 0.01). The DCCV led to better ventilation (66 ± 1 mmHg) and higher pulmonary blood flow (75 ± 24 ml/kg/min). The carotid flow was significantly higher in UCM without ventilation. The fluctuations in carotid flow with milking were 25 ± 6% higher from baseline during UCM, compared to 6 ± 3% in UCMV (p < 0.01). CONCLUSIONS: Cord milking with ventilation led to higher RCV than other interventions. Ventilation during cord milking reduced fluctuation in carotid flow compared to UCM alone. DCCV led to better ventilation and pulmonary blood flow but did not increase RCV. IMPACT: The best practice of placental transfusion in a depressed preterm neonate remains unknown. Ventilation with an intact cord improves gas exchange and hemodynamics in an asphyxiated preterm model. Cord milking without ventilation led to lower red cell volume but higher carotid blood flow fluctuations compared to milking with ventilation. Our data can be translated to bedside and could impact preterm resuscitation.

Optimal Oxygen Targets in Term Lambs with Meconium Aspiration Syndrome and Pulmonary Hypertension.

Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (FiO2) = 1.0 irrespective of SpO2, and three groups had FiO2 titrated to keep preductal SpO2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% SpO2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO2 but were exposed to higher FiO2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO2 through the first 6 hours are higher with target SpO2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower FiO2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% SpO2 target range in term infants with PPHN are warranted.

Effect of various inspired oxygen concentrations on pulmonary and systemic hemodynamics and oxygenation during resuscitation in a transitioning preterm model.

BACKGROUND: The Neonatal Resuscitation Program recommends initial resuscitation of preterm infants with low oxygen (O2) followed by titration to target preductal saturations (SpO2). We studied the effect of resuscitation with titrated O2 on gas exchange, pulmonary, and systemic hemodynamics. METHODOLOGY: Twenty-nine preterm lambs (127 d gestation) were randomized to resuscitation with 21% O2 (n = 7), 100% O2 (n = 6), or initiation at 21% and titrated to target SpO2 (n = 16). Seven healthy term control lambs were ventilated with 21% O2. RESULTS: Preductal SpO2 achieved by titrating O2 was within the desired range similar to term lambs in 21% O2. Resuscitation of preterm lambs with 21% and 100% O2 resulted in SpO2 below and above the target, respectively. Ventilation of preterm lambs with 100% O2 and term lambs with 21% O2 effectively decreased pulmonary vascular resistance (PVR). In contrast, preterm lambs with 21% O2 and titrated O2 demonstrated significantly higher PVR than term lambs on 21% O2. CONCLUSION(S): Initial resuscitation with 21% O2 followed by titration of O2 led to suboptimal pulmonary vascular transition at birth in preterm lambs. Ventilation with 100% O2 in preterm lambs caused hyperoxia but reduced PVR similar to term lambs on 21% O2. Studies evaluating the initiation of resuscitation at a higher O2 concentration followed by titration based on SpO2 in preterm neonates are needed.

Continuous capnography monitoring during resuscitation in a transitional large mammalian model of asphyxial cardiac arrest.

BACKGROUND: In neonates requiring chest compression (CC) during resuscitation, neonatal resuscitation program (NRP) recommends against relying on a single feedback device such as end-tidal carbon dioxide (ETCO2) or saturations (SpO2) to determine return of spontaneous circulation (ROSC) until more evidence becomes available. METHODS: We evaluated the role of monitoring ETCO2 during resuscitation in a lamb model of cardiac arrest induced by umbilical cord occlusion (n = 21). Lambs were resuscitated as per NRP guidelines. Systolic blood pressure (SBP), carotid and pulmonary blood flows along with ETCO2 and blood gases were continuously monitored. Resuscitation was continued for 20 min or until ROSC (whichever was earlier). Adequate CC was arbitrarily defined as generation of 30 mmHg SBP during resuscitation. ETCO2 thresholds to predict adequacy of CC and detect ROSC were determined. RESULTS: Significant relationship between ETCO2 and adequate CC was noted during resuscitation (AUC-0.735, P < 0.01). At ROSC (n = 12), ETCO2 rapidly increased to 57 ± 20 mmHg with a threshold of ≥32 mmHg being 100% sensitive and 97% specific to predict ROSC. CONCLUSION: In a large mammalian model of perinatal asphyxia, continuous ETCO2 monitoring predicted adequacy of CC and detected ROSC. These findings suggest ETCO2 in conjunction with other devices may be beneficial during CC and predict ROSC.

Continuous Chest Compressions During Sustained Inflations in a Perinatal Asphyxial Cardiac Arrest Lamb Model.

OBJECTIVE: Continuous chest compressions are more effective during resuscitation in adults. Sustained inflation rapidly establishes functional residual capacity in fluid-filled lungs at birth. We sought to compare the hemodynamics and success in achieving return of spontaneous circulation in an asphyxial cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs between subjects receiving continuous chest compressions during sustained inflation and those receiving conventional 3:1 compression-to-ventilation resuscitation. DESIGN: Prospective, randomized, animal model study. SETTING: An experimental laboratory. SUBJECTS: Fourteen newborn term gestation lambs. INTERVENTIONS: Lambs were randomized into two groups: 3:1 compression-to-ventilation (control) and continuous chest compressions during sustained inflation. The umbilical cord was occluded to induce asphyxia and asystole. The control group was resuscitated per NRP guidelines. In the sustained inflation + continuous chest compressions group, sustained inflation at 35 cm H2O was provided for 30 seconds with 1-second interruptions before another sustained inflation was provided. One hundred twenty chest compressions/min started after the initial sustained inflation. The first dose of IV epinephrine was given at 6 minutes if return of spontaneous circulation was not achieved and then every 3 minutes until return of spontaneous circulation or for a total of four doses. MEASUREMENT AND RESULTS: All lambs achieved return of spontaneous circulation in a comparable median time (interquartile range) of 390 seconds (225-405 s) and 345 seconds (204-465 s) in the sustained inflation + continuous chest compressions and control groups, respectively. Four of seven (sustained inflation + continuous chest compressions) and three of six (control) lambs required epinephrine to achieve return of spontaneous circulation. Diastolic blood pressures were lower in the sustained inflation + continuous chest compressions (4 ± 2 mm Hg) compared to the control group (7 ± 2 mm Hg), p < 0.05. PaCO2, PaO2, and lactate were similar between the groups during the study period. CONCLUSION: In this perinatal cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs, sustained inflation + continuous chest compressions is as effective as 3:1 compression-to-ventilation resuscitation in achieving return of spontaneous circulation. Half the lambs achieved return of spontaneous circulation without epinephrine. continuous chest compressions during sustained inflation reduced diastolic pressures but did not alter gas exchange or carotid blood flow compared to 3:1 compression-to-ventilation resuscitation.

Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration.

BACKGROUND: The Neonatal Resuscitation Program (NRP) recommends upper and lower limits of preductal saturations (SpO2) extrapolated from studies in infants resuscitated in room air. These limits have not been validated in asphyxia and lung disease. METHODS: Seven control term lambs delivered by cesarean section were ventilated with 21% O2. Thirty lambs with asphyxia with meconium aspiration were randomly assigned to resuscitation with 21% O2 (n = 6), 100% O2 (n = 6), or initiation with 21% O2 followed by variable FIO2 to maintain NRP target SpO2 ranges (n = 18). Hemodynamic and ventilation parameters were recorded for 15 min. RESULTS: Control lambs maintained preductal SpO2 near the lower limit of NRP target range. Asphyxiated lambs had low SpO2 (38 ± 2%), low arterial pH (6.99 ± 0.01), and high PaCO2 (96 ± 7 mm Hg) at birth. Resuscitation with 21% O2 resulted in SpO2 values below the target range with low pulmonary blood flow (Qp) compared to variable FIO2 group. The increase in PaO2 and Qp with variable FIO2 resuscitation was similar to control lambs. CONCLUSION: Maintaining SpO2 as recommended by NRP by actively adjusting inspired O2 leads to effective oxygenation and higher Qp in asphyxiated lambs with lung disease. Our findings support the current NRP SpO2 guidelines for O2 supplementation during resuscitation of an asphyxiated neonate.

Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration.

BACKGROUND: Current neonatal resuscitation guidelines recommend tracheal suctioning of nonvigorous neonates born through meconium-stained amniotic fluid. METHODS: We evaluated the effect of tracheal suctioning at birth in 29 lambs with asphyxia induced by cord occlusion and meconium aspiration during gasping. RESULTS: Tracheal suctioning at birth (n = 15) decreased amount of meconium in distal airways (53 ± 29 particles/mm(2) lung area) compared to no suction (499 ± 109 particles/mm(2); n = 14; P < 0.001). Three lambs in the suction group had cardiac arrest during suctioning, requiring chest compressions and epinephrine. Onset of ventilation was delayed in the suction group (146 ± 11 vs. 47 ± 3 s in no-suction group; P = 0.005). There was no difference in pulmonary blood flow, carotid blood flow, and pulmonary or systemic blood pressure between the two groups. Left atrial pressure was significantly higher in the suction group. Tracheal suctioning resulted in higher Pao2/FiO2 levels (122 ± 21 vs. 78 ± 10 mm Hg) and ventilator efficiency index (0.3 ± 0.05 vs.0.16 ± 0.03). Two lambs in the no-suction group required inhaled nitric oxide. Lung 3-nitrotyrosine levels were higher in the suction group (0.65 ± 0.03 ng/µg protein) compared with the no-suction group (0.47 ± 0.06). CONCLUSION: Tracheal suctioning improves oxygenation and ventilation. Suctioning does not improve pulmonary/systemic hemodynamics or oxidative stress in an ovine model of acute meconium aspiration with asphyxia.

A novel swine model of selective middle meningeal artery catheterization and embolization.

BACKGROUND: Middle meningeal artery (MMA) embolization is a promising intervention as a stand-alone or adjunct treatment to surgery in patients with chronic subdural hematomas. There are currently no large animal models for selective access and embolization of the MMA for preclinical evaluation of this endovascular modality. Our objective was to introduce a novel in vivo model of selective MMA embolization in swine. METHODS: Diagnostic cerebral angiography with selective microcatheter catheterization into the MMA was performed under general anesthesia in five swine. Anatomical variants in arterial meningeal supply were examined. In two animals, subsequent embolization of the MMA with a liquid embolic agent (Onyx-18) was performed, followed by brain tissue harvest and histological analysis. RESULTS: The MMA was consistently localized as a branch of the internal maxillary artery just distal to the origin of the ascending pharyngeal artery. Additional meningeal supply was observed from the external ophthalmic artery, although not present consistently. MMA embolization with Onyx was technically successful and feasible. Histological analysis showed Onyx material within the MMA lumen. CONCLUSIONS: Microcatheter access into the MMA in swine with liquid embolic agent delivery represents a reproducible model of MMA embolization. Anatomical variations in the distribution of arterial supply to the meninges exist. This model has a potential application for comparing therapeutic effects of various embolic agents in a preclinical setting that closely resembles the MMA embolization procedure in humans.

Masked Randomized Trial of Epinephrine versus Vasopressin in an Ovine Model of Perinatal Cardiac Arrest.

BACKGROUND: Current neonatal resuscitation guidelines recommend the use of epinephrine for bradycardia/arrest not responding to ventilation and chest compressions. Vasopressin is a systemic vasoconstrictor and is more effective than epinephrine in postnatal piglets with cardiac arrest. There are no studies comparing vasopressin with epinephrine in newly born animal models with cardiac arrest induced by umbilical cord occlusion. Objective: To compare the effect of epinephrine and vasopressin on the incidence and time to return of spontaneous circulation (ROSC), hemodynamics, plasma drug levels, and vasoreactivity in perinatal cardiac arrest. Design/Methods: Twenty-seven term fetal lambs in cardiac arrest induced by cord occlusion were instrumented and resuscitated following randomization to epinephrine or vasopressin through a low umbilical venous catheter. Results: Eight lambs achieved ROSC prior to medication. Epinephrine achieved ROSC in 7/10 lambs by 8 ± 2 min. Vasopressin achieved ROSC in 3/9 lambs by 13 ± 6 min. Plasma vasopressin levels in nonresponders were much lower than responders after the first dose. Vasopressin caused in vivo increased pulmonary blood flow and in vitro coronary vasoconstriction. Conclusions: Vasopressin resulted in lower incidence and longer time to ROSC compared to epinephrine in a perinatal model of cardiac arrest supporting the current recommendations for exclusive use of epinephrine in neonatal resuscitation.

Femoral Occlusion during Neonatal Cardiopulmonary Resuscitation Improves Outcomes in an Ovine Model of Perinatal Cardiac Arrest.

BACKGROUND: The goal of chest compressions during neonatal resuscitation is to increase cerebral and coronary blood flow leading to the return of spontaneous circulation (ROSC). During chest compressions, bilateral femoral occlusion may increase afterload and promote carotid and coronary flow, an effect similar to epinephrine. Our objectives were to determine the impact of bilateral femoral occlusion during chest compressions on the incidence and timing of ROSC and hemodynamics. METHODOLOGY: In this randomized study, 19 term fetal lambs in cardiac arrest were resuscitated based on the Neonatal Resuscitation Program guidelines and randomized into two groups: femoral occlusion or controls. Bilateral femoral arteries were occluded by applying pressure using two fingers during chest compressions. RESULTS: Seventy percent (7/10) of the lambs in the femoral occlusion group achieved ROSC in 5 ± 2 min and three lambs (30%) did not receive epinephrine. ROSC was achieved in 44% (4/9) of the controls in 13 ± 6 min and all lambs received epinephrine. The femoral occlusion group had higher diastolic blood pressures, carotid and coronary blood flow. CONCLUSION: Femoral occlusion resulted in faster and higher incidence of ROSC, most likely due to attaining increased diastolic pressures, coronary and carotid flow. This is a low-tech intervention that can be easily adapted in resource limited settings, with the potential to improve survival and neurodevelopmental outcomes.

The first endovascular rat glioma model for pre-clinical evaluation of intra-arterial therapeutics.

BACKGROUND: Several translational animal models have been described assessing intra-arterial (IA) treatments for malignant gliomas. We describe the first endovascular animal model that allows testing of IA drug delivery as a first-line treatment, which is difficult to do in actual patients. We report a unique protocol for vascular access and IA delivery in the rat model that, unlike prior reports, does not require direct puncture and opening of proximal cerebrovasculature which carries risk of ischemia in the animal brain post-delivery. METHODS: Wistar rats underwent left femoral artery catherization with a Balt Magic 1.2F catheter or Marathon Flow directed 1.5F Microcatheter with an Asahi Chikai 0.008 micro-guidewire which was navigated to the left internal carotid artery under x-ray. 25% mannitol was administered to test blood brain barrier breakdown (BBBB). Additional rats were implanted with C6 glioma cells in the left frontal lobe. C6 Glioma-Implanted Rats (C6GRs) were monitored for overall survival and tumor growth. Tumor volumes from MRI images were calculated utilizing 3D slicer. Additional rats underwent femoral artery catheterization with Bevacizumab, carboplatin, or irinotecan injected into the left internal carotid artery to test feasibility and safety. RESULTS: A successful endovascular access and BBBB protocol was established. BBBB was confirmed with positive Evans blue staining. 10 rats were successfully implanted with C6 gliomas with confirmed growths on MRI. Overall survival was 19.75 ± 2.21 days. 5 rats were utilized for the development of our femoral catheterization protocol and BBBB testing. With regards to IA chemotherapy dosage testing, control rats tolerated targeted 10 mg/kg of bevascizumab, 2.4 mg/kg of carboplatin, and 15 mg/kg of irinotecan IA ICA injections without any complications. CONCLUSIONS: We present the first endovascular IA rat glioma model that allows selective catheterization of the intracranial vasculature and assessment of IA therapies for gliomas without need for access and sacrifice of proximal cerebrovasculature.

Tectonic infarct analysis: A computational tool for automated whole-brain infarct analysis from TTC-stained tissue.

Background: Infarct volume measured from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices is critical to in vivo stroke models. In this study, we developed an interactive, tunable, software that automatically computes whole-brain infarct metrics from serial TTC-stained brain sections. Methods: Three rat ischemic stroke cohorts were used in this study (Total n = 91 rats; Cohort 1 n = 21, Cohort 2 n = 40, Cohort 3 n = 30). For each, brains were serially-sliced, stained with TTC and scanned on both anterior and posterior sides. Ground truth annotation and infarct morphometric analysis (e.g., brain-Vbrain, infarct-Vinfarct, and non-infarct-Vnon-infarct volumes) were completed by domain experts. We used Cohort 1 for brain and infarct segmentation model development (n = 3 training cases with 36 slices [18 anterior and posterior faces], n = 18 testing cases with 218 slices [109 anterior and posterior faces]), as well as infarct morphometrics automation. The infarct quantification pipeline and pre-trained model were packaged as a standalone software and applied to Cohort 2, an internal validation dataset. Finally, software and model trainability were tested as a use-case with Cohort 3, a dataset from a separate institute. Results: Both high segmentation and statistically significant quantification performance (correlation between manual and software) were observed across all datasets. Segmentation performance: Cohort 1 brain accuracy = 0.95/f1-score = 0.90, infarct accuracy = 0.96/f1-score = 0.89; Cohort 2 brain accuracy = 0.97/f1-score = 0.90, infarct accuracy = 0.97/f1-score = 0.80; Cohort 3 brain accuracy = 0.96/f1-score = 0.92, infarct accuracy = 0.95/f1-score = 0.82. Infarct quantification (cohort average): Vbrain (ρ = 0.87, p < 0.001), Vinfarct (0.92, p < 0.001), Vnon-infarct (0.80, p < 0.001), %infarct (0.87, p = 0.001), and infarct:non-infact ratio (ρ = 0.92, p < 0.001). Conclusion: Tectonic Infarct Analysis software offers a robust and adaptable approach for rapid TTC-based stroke assessment.

Inadequate Bioavailability of Intramuscular Epinephrine in a Neonatal Asphyxia Model.

Background: Over half a million newborn deaths are attributed to intrapartum related events annually, the majority of which occur in low resource settings. While progress has been made in reducing the burden of asphyxia, novel approaches may need to be considered to further decrease rates of newborn mortality. Administration of intravenous, intraosseous or endotracheal epinephrine is recommended by the Newborn Resuscitation Program (NRP) with sustained bradycardia at birth. However, delivery by these routes requires both advanced skills and specialized equipment. Intramuscular (IM) epinephrine may represent a simple, low cost and highly accessible alternative for consideration in the care of infants compromised at birth. At present, the bioavailability of IM epinephrine in asphyxia remains unclear. Methods: Four term fetal lambs were delivered by cesarean section and asphyxiated by umbilical cord occlusion with resuscitation after 5 min of asystole. IM epinephrine (0.1 mg/kg) was administered intradeltoid after 1 min of positive pressure ventilation with 30 s of chest compressions. Serial blood samples were obtained for determination of plasma epinephrine concentrations by ELISA. Results: Epinephrine concentrations failed to increase following administration via IM injection. Delayed absorption was observed after return of spontaneous circulation (ROSC) in half of the studies. Conclusions: Inadequate absorption of epinephrine occurs with IM administration during asphyxial cardiac arrest, implying this route would be ineffective in infants who are severely compromised at birth. Late absorption following ROSC raises concerns for risks of side effects. However, the bioavailability and efficacy of intramuscular epinephrine in less profound asphyxia may warrant further evaluation.

Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs.

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147-150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

Sustained Inflation Reduces Pulmonary Blood Flow during Resuscitation with an Intact Cord.

The optimal timing of cord clamping in asphyxia is not known. Our aims were to determine the effect of ventilation (sustained inflation-SI vs. positive pressure ventilation-V) with early (ECC) or delayed cord clamping (DCC) in asphyxiated near-term lambs. We hypothesized that SI with DCC improves gas exchange and hemodynamics in near-term lambs with asphyxial bradycardia. A total of 28 lambs were asphyxiated to a mean blood pressure of 22 mmHg. Lambs were randomized based on the timing of cord clamping (ECC-immediate, DCC-60 s) and mode of initial ventilation into five groups: ECC + V, ECC + SI, DCC, DCC + V and DCC + SI. The magnitude of placental transfusion was assessed using biotinylated RBC. Though an asphyxial bradycardia model, 2-3 lambs in each group were arrested. There was no difference in primary outcomes, the time to reach baseline carotid blood flow (CBF), HR ≥ 100 bpm or MBP ≥ 40 mmHg. SI reduced pulmonary (PBF) and umbilical venous (UV) blood flow without affecting CBF or umbilical arterial blood flow. A significant reduction in PBF with SI persisted for a few minutes after birth. In our model of perinatal asphyxia, an initial SI breath increased airway pressure, and reduced PBF and UV return with an intact cord. Further clinical studies evaluating the timing of cord clamping and ventilation strategy in asphyxiated infants are warranted.

Resuscitation with an Intact Cord Enhances Pulmonary Vasodilation and Ventilation with Reduction in Systemic Oxygen Exposure and Oxygen Load in an Asphyxiated Preterm Ovine Model.

(1) Background: Optimal initial oxygen (O2) concentration in preterm neonates is controversial. Our objectives were to compare the effect of delayed cord clamping with ventilation (DCCV) to early cord clamping followed by ventilation (ECCV) on O2 exposure, gas exchange, and hemodynamics in an asphyxiated preterm ovine model. (2) Methods: Asphyxiated preterm lambs (127-128 d) with heart rate <90 bpm were randomly assigned to DCCV or ECCV. In DCCV, positive pressure ventilation (PPV) was initiated with 30-60% O2 and titrated based on preductal saturations (SpO2) with an intact cord for 5 min, followed by clamping. In ECCV, the cord was clamped, and PPV was initiated. (3) Results: Fifteen asphyxiated preterm lambs were randomized to DCCV (N = 7) or ECCV (N = 8). The inspired O2 (40 ± 20% vs. 60 ± 20%, p < 0.05) and oxygen load (520 (IQR 414-530) vs. 775 (IQR 623-868), p-0.03) in the DCCV group were significantly lower than ECCV. Arterial oxygenation and carbon dioxide (PaCO2) levels were significantly lower and peak pulmonary blood flow was higher with DCCV. (4) Conclusion: In asphyxiated preterm lambs, resuscitation with an intact cord decreased O2 exposure load improved ventilation with an increase in peak pulmonary blood flow in the first 5 min.

Randomised trial of epinephrine dose and flush volume in term newborn lambs.

OBJECTIVES: Neonatal resuscitation guidelines recommend 0.5-1 mL saline flush following 0.01-0.03 mg/kg of epinephrine via low umbilical venous catheter for persistent bradycardia despite effective positive pressure ventilation (PPV) and chest compressions (CC). We evaluated the effects of 1 mL vs 3 mL/kg flush volumes and 0.01 vs 0.03 mg/kg doses on return of spontaneous circulation (ROSC) and epinephrine pharmacokinetics in lambs with cardiac arrest. DESIGN: Forty term lambs in cardiac arrest were randomised to receive 0.01 or 0.03 mg/kg epinephrine followed by 1 mL or 3 mL/kg flush after effective PPV and CC. Epinephrine (with 1 mL flush) was repeated every 3 min until ROSC or until 20 min. Haemodynamics, blood gases and plasma epinephrine concentrations were monitored. RESULTS: Ten lambs had ROSC before epinephrine administration and 2 died during instrumentation. Among 28 lambs that received epinephrine, 2/6 in 0.01 mg/kg-1 mL flush, 3/6 in 0.01 mg/kg-3 mL/kg flush, 5/7 in 0.03 mg/kg-1 mL flush and 9/9 in 0.03 mg/kg-3 mL/kg flush achieved ROSC (p=0.02). ROSC was five times faster with 0.03 mg/kg epinephrine compared with 0.01 mg/kg (adjusted HR (95% CI) 5.08 (1.7 to 15.25)) and three times faster with 3 mL/kg flush compared with 1 mL flush (3.5 (1.27 to 9.71)). Plasma epinephrine concentrations were higher with 0.01 mg/kg-3 mL/kg flush (adjusted geometric mean ratio 6.0 (1.4 to 25.7)), 0.03 mg/kg-1 mL flush (11.3 (2.1 to 60.3)) and 0.03 mg/kg-3 mL/kg flush (11.0 (2.2 to 55.3)) compared with 0.01 mg/kg-1 mL flush. CONCLUSIONS: 0.03 mg/kg epinephrine dose with 3 mL/kg flush volume is associated with the highest ROSC rate, increases peak plasma epinephrine concentrations and hastens time to ROSC. Clinical trials evaluating optimal epinephrine dose and flush volume are warranted.

Effect of a Larger Flush Volume on Bioavailability and Efficacy of Umbilical Venous Epinephrine during Neonatal Resuscitation in Ovine Asphyxial Arrest.

The 7th edition of the Textbook of Neonatal Resuscitation recommends administration of epinephrine via an umbilical venous catheter (UVC) inserted 2-4 cm below the skin, followed by a 0.5-mL to 1-mL flush for severe bradycardia despite effective ventilation and chest compressions (CC). This volume of flush may not be adequate to push epinephrine to the right atrium in the absence of intrinsic cardiac activity during CC. The objective of our study was to evaluate the effect of 1-mL and 2.5-mL flush volumes after UVC epinephrine administration on the incidence and time to achieve return of spontaneous circulation (ROSC) in a near-term ovine model of perinatal asphyxia induced cardiac arrest. After 5 min of asystole, lambs were resuscitated per Neonatal Resuscitation Program (NRP) guidelines. During resuscitation, lambs received epinephrine through a UVC followed by 1-mL or 2.5-mL normal saline flush. Hemodynamics and plasma epinephrine concentrations were monitored. Three out of seven (43%) and 12/15 (80%) lambs achieved ROSC after the first dose of epinephrine with 1-mL and 2.5-mL flush respectively (p = 0.08). Median time to ROSC and cumulative epinephrine dose required were not different. Plasma epinephrine concentrations at 1 min after epinephrine administration were not different. From our pilot study, higher flush volume after first dose of epinephrine may be of benefit during neonatal resuscitation. More translational and clinical trials are needed.

Protection from systemic pyruvate at resuscitation in newborn lambs with asphyxial cardiac arrest.

BACKGROUND: Infants with hypoxic-ischemic injury often require cardiopulmonary resuscitation. Mitochondrial failure to generate adenosine triphosphate (ATP) during hypoxic-ischemic reperfusion injury contributes to cellular damage. Current postnatal strategies to improve outcome in hypoxic-ischemic injury need sophisticated equipment to perform servo-controlled cooling. Administration of intravenous pyruvate, an antioxidant with favorable effects on mitochondrial bioenergetics, is a simple intervention that can have a global impact. We hypothesize that the administration of pyruvate following the return of spontaneous circulation (ROSC) would improve cardiac function, systemic hemodynamics, and oxygen utilization in the brain in newborn lambs with cardiac arrest (CA). METHODS: Term lambs were instrumented, delivered by C-section and asphyxia induced by umbilical cord occlusion along with clamping of the endotracheal tube until asystole; Lambs resuscitated following 5 min of CA; upon ROSC, lambs were randomized to receive pyruvate or saline infusion over 90 min and ventilated for 150 min postinfusion. Pulmonary and systemic hemodynamics and arterial gases monitored. We measured plasma pyruvate, tissue lactate, and ATP levels (heart and brain) in both groups. RESULTS: Time to ROSC was not different between the two groups. Systolic and diastolic blood pressures, stroke volume, arterial oxygen content, and cerebral oxygen delivery were similar between the two groups. The cerebral metabolic rate of oxygen was higher following pyruvate infusion; higher oxygen consumption in the brain was associated with lower plasma levels but higher brain ATP levels compared to the saline group. CONCLUSIONS: Pyruvate promotes energy generation accompanied by efficient oxygen utilization in the brain and may facilitate additional neuroprotection in the presence of hypoxic-ischemic injury.

Oxygenation and Hemodynamics during Chest Compressions in a Lamb Model of Perinatal Asphyxia Induced Cardiac Arrest.

The current guidelines recommend the use of 100% O2 during resuscitation of a neonate requiring chest compressions (CC). Studies comparing 21% and 100% O2 during CC were conducted in postnatal models and have not shown a difference in incidence or timing of return of spontaneous circulation (ROSC). The objective of this study is to evaluate systemic oxygenation and oxygen delivery to the brain during CC in an ovine model of perinatal asphyxial arrest induced by umbilical cord occlusion. Pulseless cardiac arrest was induced by umbilical cord occlusion in 22 lambs. After 5 min of asystole, lambs were resuscitated with 21% O2 as per Neonatal Resuscitation Program (NRP) guidelines. At the onset of CC, inspired O2 was either increased to 100% O2 (n = 25) or continued at 21% (n = 9). Lambs were ventilated for 30 min post ROSC and FiO2 was gradually titrated to achieve preductal SpO2 of 85-95%. All lambs achieved ROSC. During CC, PaO2 was 21.6 ± 1.6 mm Hg with 21% and 23.9 ± 6.8 mm Hg with 100% O2 (p = 0.16). Carotid flow was significantly lower during CC (1.2 ± 1.6 mL/kg/min in 21% and 3.2 ± 3.4 mL/kg/min in 100% oxygen) compared to baseline fetal levels (27 ± 9 mL/kg/min). Oxygen delivery to the brain was 0.05 ± 0.06 mL/kg/min in the 21% group and 0.11 ± 0.09 mL/kg/min in the 100% group and was significantly lower than fetal levels (2.1 ± 0.3 mL/kg/min). Immediately after ROSC, lambs ventilated with 100% O2 had higher PaO2 and pulmonary flow. It was concluded that carotid blood flow, systemic PaO2, and oxygen delivery to the brain are very low during chest compressions for cardiac arrest irrespective of 21% or 100% inspired oxygen use during resuscitation.