Pediatric Swine Research Articles

Cardiopulmonary bypass with deep hypothermic circulatory arrest results in organ-specific transcriptomic responses in pediatric swine.

The organ-level molecular response to cardiac surgery with cardiopulmonary bypass (CPB) remains inadequately understood and may be heterogeneous. Here, we measured organ-specific gene expression in a piglet model of CPB with deep hypothermic circulatory arrest (DHCA). Infant piglets underwent peripheral CPB with 75min of DHCA and 6h of critical care after separation from CPB. Mechanically ventilated animals served as controls. Tissue was obtained from the lung, kidney, liver, heart, and ileum. RNA sequencing was performed using NovaSeq 6000 and evaluated via differentially expressed gene (DEG) and pathway/network analyses. CPB/DHCA induced significant transcriptomic alterations, with greater changes seen in liver (2,192 DEGs), heart (777 DEGs), and kidney (1,774 DEGs) compared to lung (410 DEGs) and ileum (11 DEGs), and little overlap across organs (<20% differentially expressed in >1 organ). Key upregulated systems included ribosomal proliferation and mitochondrial assembly in the liver, oxidative stress response and proximal tubular repair in the kidney, myofilament structural genes and pro-hypertrophy pathways in the heart, and solute channels and arginine metabolism in the lung. Downregulation of adaptive immunity genes occurred in multiple organs. Transcriptomics could inform the investigation of targeted therapies and adverse event screening after cardiac surgery.

Abstract Su202: Physiological response to vasopressor administration during hemodynamic-directed CPR

Background: The hemodynamic response to successive vasopressor doses during CPR and its association with survival is poorly defined. Understanding these relationships can facilitate identification of alternative vasopressor strategies. Hypothesis: Non-survival is associated with lower responsivity to successive vasopressors. Methods: We performed retrospective analysis of hemodynamic data acquired in pediatric swine models (sus scrofa, 9-12kg) of asphyxia-associated ventricular fibrillation cardiac arrest with use of hemodynamic-directed CPR (n=175). Starting 2m into CPR, if hemodynamic targets were not met, vasopressors were given in cycles comprising two doses of 0.02mg/kg epinephrine (Epi) followed by vasopressin (Vaso, 0.4U/kg), separated by a minimum of 1m. After a minimum of 2m, the cycle was repeated. Hemodynamic response was evaluated using the peak diastolic blood pressure (DBP) within 1m for Epi, 2m for Vaso administration and the difference between the initial and peak DBP (delta DBP). Subjects were classified as “responder” if either a delta DBP &gt; 5 mmHg or a peak DBP &gt; 25 mmHg was achieved, and a “non-responder” otherwise. Animals were deemed “survivors” if ROSC was achieved following initial defibrillation. The change in delta DBP for successive vasopressors was compared in survivors versus non-survivors using two-sided Wilcoxon rank-sum tests. Continuous variables are summarized using the median with interquartile ranges. The burden of “non-response” was used to a construct confusion matrix and calculate performance. Results: Non-survivors (n=30) had lower delta DBP than survivors (n=145) following successive vasopressor administration at the first cycle (first Epi dose: 7.8 [2.4, 14] vs 16 [7.5, 24], p&lt; 0.01; second Epi: 2.0 [0, 4.7] vs 7.1 [2.0, 12], p&lt; 0.01; Vaso : 1.1 [0, 2.3] vs 7.1 [2.0, 12], p&lt; 0.01). Classification as a “non-responder” at the first cycle (Epi-Epi-Vaso) was significantly predictive of non-survival (Sensitivity 32%, Specificity 92%). Animals that failed to respond to all vasopressors at the first cycle had a significantly increased rate of mortality (86%; 6 non-survivors, 1 survivors) compared to animals that responded to all 3 vasopressors (13%; 16 non-survivors, 111 survivors). Conclusion: Mortality was significantly associated with lower DBP response to successive vasopressors during hemodynamic-directed CPR in pediatric swine models of cardiac arrest, which may suggest a critical timepoint to activate ECPR.

Association of diastolic blood pressure with coronary perfusion pressure during resuscitation in pediatric swine.

Diastolic blood pressure (DBP) is suggested as a surrogate for coronary perfusion pressure (CPP) during cardiopulmonary resuscitation. We examined the correlation between DBP and CPP and hypothesized that both would be associated with survival in a pediatric swine model of asphyxial cardiac arrest. We performed a retrospective, secondary analysis of 102 pediatric swine resuscitations. DBP and CPP were recorded every 30 s during resuscitation. Values were compared between survivors and non-survivors. DBP mirrored CPP in survivors and non-survivors throughout resuscitation and both were associated with survival. Improvements in DBP and CPP after the first epinephrine administration were greater in survivors (DBP: 25.1 ± 3.0 vs. 5.4 ± 0.8 mmHg, p < 0.01; CPP: 24.9 ± 3.2 vs. 4.8 ± 0.9 mmHg, p < 0.01). DBP and CPP after epinephrine administration were highly predictive of survival, with an area under the curve of 0.95 (0.89-1.00) for DBP and 0.90 (0.81-0.99) for CPP. The optimal threshold for DBP was 22.5 mmHg, whereas that for CPP was 14.5 mmHg. DBP and CPP were associated with survival throughout resuscitation, and the response of both to the first epinephrine administration was highly predictive of survivalin this model. Clinically, the availability of DBP makes it useful as a target for physiologic feedback during resuscitation. Diastolic blood pressure (DBP) mirrored coronary perfusion pressure (CPP) throughout prolonged resuscitation in a pediatric model of asphyxial cardiac arrest. Mean DBP and CPP were significantly greater in survivors than in non-survivors both before and after administration of epinephrine. The response of both DBP and CPP to the first dose of epinephrine was highly predictive of return of spontaneous circulation. Given the clinical availability of DBP, these findings support its use as a surrogate for CPP to guide high-quality cardiopulmonary resuscitation in this pediatric swine model.

Chassis-based fiber-coupled opticalprobe design for reproducible quantitative diffuse optical spectroscopy measurements.

Advanced optical neuromonitoring of cerebral hemodynamics with hybrid diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) methods holds promise for non-invasive characterization of brain health in critically ill patients. However, the methods' fiber-coupled patient interfaces (probes) are challenging to apply in emergent clinical scenarios that require rapid and reproducible attachment to the head. To address this challenge, we developed a novel chassis-based optical probe design for DOS/DCS measurements and validated its measurement accuracy and reproducibility against conventional, manually held measurements of cerebral hemodynamics in pediatric swine (n = 20). The chassis-based probe design comprises a detachable fiber housing which snaps into a 3D-printed, circumferential chassis piece that is secured to the skin. To validate its reproducibility, eight measurement repetitions of cerebral tissue blood flow index (BFI), oxygen saturation (StO2), and oxy-, deoxy- and total hemoglobin concentration were acquired at the same demarcated measurement location for each pig. The probe was detached after each measurement. Of the eight measurements, four were acquired by placing the probe into a secured chassis, and four were visually aligned and manually held. We compared the absolute value and intra-subject coefficient of variation (CV) of chassis versus manual measurements. No significant differences were observed in either absolute value or CV between chassis and manual measurements (p > 0.05). However, the CV for BFI (mean ± SD: manual, 19.5% ± 9.6; chassis, 19.0% ± 10.8) was significantly higher than StO2 (manual, 5.8% ± 6.7; chassis, 6.6% ± 7.1) regardless of measurement methodology (p<0.001). The chassis-based DOS/DCS probe design facilitated rapid probe attachment/re-attachment and demonstrated comparable accuracy and reproducibility to conventional, manual alignment. In the future, this design may be adapted for clinical applications to allow for non-invasive monitoring of cerebral health during pediatric critical care.

Prediction of Return of Spontaneous Circulation in a Pediatric Swine Model of Cardiac Arrest Using Low-Resolution Multimodal Physiological Waveforms.

Monitoring physiological waveforms, specifically hemodynamic variables (e.g., blood pressure waveforms) and end-tidal CO2 (EtCO2), during pediatric cardiopulmonary resuscitation (CPR) has been demonstrated to improve survival rates and outcomes when compared to standard depth-guided CPR. However, waveform guidance has largely been based on thresholds for single parameters and therefore does not leverage all the information contained in multimodal data. We hypothesize that the combination of multimodal physiological features improves the prediction of the return of spontaneous circulation (ROSC), the clinical indicator of short-term CPR success. We used machine learning algorithms to evaluate features extracted from eight low-resolution (4 samples per minute) physiological waveforms to predict ROSC. The waveforms were acquired from the 2nd to 10th minute of CPR in pediatric swine models of cardiac arrest (N = 89, 8-12 kg). The waveforms were divided into segments with increasing length (both forward and backward) for feature extraction, and machine learning algorithms were trained for ROSC prediction. For the full CPR period (2nd to 10th minute), the area under the receiver operating characteristics curve (AUC) was 0.93 (95% CI: 0.87-0.99) for the multivariate model, 0.70 (0.55-0.85) for EtCO2 and 0.80 (0.67-0.93) for coronary perfusion pressure. The best prediction performances were achieved when the period from the 6th to the 10th minute was included. Poor predictions were observed for some individual waveforms, e.g., right atrial pressure. In conclusion, multimodal waveform features carry relevant information for ROSC prediction. Using multimodal waveform features in CPR guidance has the potential to improve resuscitation success and reduce mortality.

PB0790 Pediatric Swine Model of Escherichia coli Sepsis - Induced Disseminated Intravascular Coagulation (DIC) and Multiple Organ Dysfunction Syndrome (MODS)

PB0790 Pediatric Swine Model of Escherichia coli Sepsis - Induced Disseminated Intravascular Coagulation (DIC) and Multiple Organ Dysfunction Syndrome (MODS)

Abstract 14959: Mitochondrial Transplantation in Pediatric and Neonatal Porcine Hearts in a Model of DCD Heart Transplantation

Introduction: Heart transplantation in pediatric and neonatal patients is limited by the donor pool. Donation after circulatory death (DCD) could potentially expand the donor pool by offering an additional source of cardiac allografts. In this study, we investigated the efficacy of mitochondrial transplantation to enhance myocardial function in pediatric and neonatal DCD hearts. Hypothesis: Autologous mitochondrial transplantation enhances the viability and function of pediatric and neonatal DCD donor hearts. Methods: Circulatory death was induced by extubation in neonatal (25 - 50g heart weight, representing 4-16 month human) and pediatric (68 - 98g heart weight, representing 4-6 year human) swine model. Hearts were subjected to 20 min of warm ischemia and 10 min of cold cardioplegic arrest and then harvested. The aorta and pulmonary artery were cannulated, inferior and superior venae cavae ligated and a balloon was inserted in the left ventricle. The hearts were then mounted on the ex situ perfusion device. After 15 minutes of reperfusion, hearts received either vehicle alone ([VEH], 10 mL n = 6) or vehicle containing autologous mitochondria ([MT] 5x10 9 in 10 mL; n = 6). A Sham non-ischemic group (n = 4) did not undergo warm ischemia, mimicking donor after brain death (DBD). Hearts were machine perfused for 2 hours unloaded and 2 hours of loaded conditions. Results: Following 4 hours of reperfusion, neonatal and pediatric DCD hearts receiving VEH showed significantly decreased myocardial function and viability as compared to Sham non-ischemic control hearts. In contrast, in both neonatal and pediatric DCD hearts receiving MT, LVDP, dP/dt max, and fractional shortening were significantly increased (p &lt; 0.001 for each) and were equal or better than that observed in Sham non-ischemic hearts. Infarct size was significantly decreased in both neonatal and pediatric DCD hearts receiving MT as compared to VEH (p &lt; 0.001). Conclusions: Mitochondrial transplantation provides for significantly enhanced preservation of myocardial function and viability in neonatal and pediatric DCD hearts that is equivalent to or better than that observed in DBD hearts. Mitochondrial transplantation provides a possible option to expand the pediatric and neonatal heart donor pool.

TriService Nursing Research Program: A critical component to support military nursing science

TriService Nursing Research Program: A critical component to support military nursing science

Abstract 13358: Pediatric Defibrillation; Safety and Efficacy of Shocks in Both Ventricular Fibrillation and Sinus Rhythm in a Porcine Model

Introduction: Pediatric sudden cardiac arrest may require the delivery of a defibrillating shock to promote return of spontaneous circulation (ROSC). Fear of harm is a barrier for the use of automated external defibrillators by lay personnel, particularly when the patient is a child. The aim of this study was to observe the effects of delivering pediatric defibrillation shocks to pediatric weight swine who are in a perfusing rhythm or ventricular fibrillation (VF). Methods: Eight swine (10.3-26.8 kg) were studied under anesthesia. Up to 30 shocks were applied using modified samaritan AEDs (HeartSine, UK) to animals either in sinus rhythm or after 30 seconds of VF. Shocks delivered in sinus rhythm were unsynchronized. Four different shock types were applied, utilizing two different waveforms (Waveform-A at 50 J, Waveform-A at 75 J, Waveform-A at 90J and Waveform-B at 50 J). Left ventricular (LV) pressures were recorded invasively (Millar, USA). If the shock was successful, the animal entered a rest period of approximately 5 minutes, after which the next shock was applied. Results: Data presented in Table 1. Out of a total of 77 shocks delivered in sinus rhythm, 2 (2.6%) resulted in conversion to a cardiac arrest rhythm. Analysis of LV pressures demonstrated no significant differences in the change of LV dP/dt from baseline at 1, 10 and 60 seconds post-shock. There was no significant difference in shock success or ROSC between the shock types for defibrillation of VF. Analysis of LV pressures demonstrated no significant differences in the change of LV dP/dt from baseline at at 1, 10 and 60 seconds post-shock between the groups. Conclusions: The results of this study indicate defibrillation shocks applied to swine in sinus rhythm rarely result in conversion to an arrhythmia. Additionally, the variety of shock types demonstrated similar levels of safety and efficacy in this porcine model.

Non-invasive diffuse optical neuromonitoring during cardiopulmonary resuscitation predicts return of spontaneous circulation

Neurologic injury is a leading cause of morbidity and mortality following pediatric cardiac arrest. In this study, we assess the feasibility of quantitative, non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) neuromonitoring during cardiopulmonary resuscitation (CPR), and its predictive utility for return of spontaneous circulation (ROSC) in an established pediatric swine model of cardiac arrest. Cerebral tissue optical properties, oxy- and deoxy-hemoglobin concentration ([HbO2], [Hb]), oxygen saturation (StO2) and total hemoglobin concentration (THC) were measured by a FD-DOS probe placed on the forehead in 1-month-old swine (8–11 kg; n = 52) during seven minutes of asphyxiation followed by twenty minutes of CPR. ROSC prediction and time-dependent performance of prediction throughout early CPR (< 10 min), were assessed by the weighted Youden index (Jw, w = 0.1) with tenfold cross-validation. FD-DOS CPR data was successfully acquired in 48/52 animals; 37/48 achieved ROSC. Changes in scattering coefficient (785 nm), [HbO2], StO2 and THC from baseline were significantly different in ROSC versus No-ROSC subjects (p < 0.01) after 10 min of CPR. Change in [HbO2] of + 1.3 µmol/L from 1-min of CPR achieved the highest weighted Youden index (0.96) for ROSC prediction. We demonstrate feasibility of quantitative, non-invasive FD-DOS neuromonitoring, and stable, specific, early ROSC prediction from the third minute of CPR.

Brain Contrast-Enhanced Ultrasound Evaluation of a Pediatric Swine Model.

Brain injury remains a leading cause of morbidity and mortality in children. We evaluated the feasibility of using a pediatric swine model to develop contrast-enhanced ultrasound (CEUS)-based measures of brain perfusion for clinical application in various types of brain injury monitoring. Six-week-old, 10-kg swine (N = 10) were anesthetized, and an acoustic window was created in the right frontal cranium to provide visualization of an oblique coronal plane and bilateral thalami. Ultrasound contrast agent was administered via a femoral venous catheter as a weight-based (0.03 mL/kg) bolus. After localization of the imaging plane, CEUS cine clips were acquired for 90 seconds. Bolus injection of contrast agent provided global visualization of cerebral perfusion and highlighted microvasculature in the brain. Preliminary evaluation of bolus kinetics in piglets showed a central gray nuclei-to-cortex ratio similar to human infants with a steep wash-in that crossed and remained above the 1.0 threshold for most of the enhancement period. We demonstrated the similarity in brain perfusion between piglets and human infants, specifically central gray nuclei-to-cortex ratio, showing preliminary feasibility of its use as a pediatric model of brain perfusion. Contrast-enhanced ultrasound can be performed at the bedside as a minimally invasive procedure, and quantitative CEUS may provide critical information regarding changes in brain perfusion as a result of injury or as a response to therapy.

The association between early impairment in cerebral autoregulation and outcome in a pediatric swine model of cardiac arrest

AimsEvaluate cerebral autoregulation (CAR) by intracranial pressure reactivity index (PRx) and cerebral blood flow reactivity index (CBFx) during the first four hours following return of spontaneous circulation (ROSC) in a porcine model of pediatric cardiac arrest. Determine whether impaired CAR is associated with neurologic outcome. MethodsFour-week-old swine underwent seven minutes of asphyxia followed by ventricular fibrillation induction and hemodynamic-directed CPR. Those achieving ROSC had arterial blood pressure, intracranial pressure (ICP), and microvascular cerebral blood flow (CBF) monitored for 4h. Animals were assigned an 8-h post-ROSC swine cerebral performance category score (1=normal; 2–4=abnormal neurologic function). In this secondary analytic study, we calculated PRx and CBFx using a continuous, moving correlation coefficient between mean arterial pressure (MAP) and ICP, and between MAP and CBF, respectively. Burden of impaired CAR was the area under the PRx or CBFx curve using a threshold of 0.3 and normalized as percentage of monitoring duration. ResultsAmong 23 animals, median PRx was 0.14 [0.06,0.25] and CBFx was 0.36 [0.05,0.44]. Median burden of impaired CAR was 21% [18,27] with PRx and 30% [17,40] with CBFx. Neurologically abnormal animals (n=10) did not differ from normal animals (n=13) in post-ROSC MAP (63 vs. 61mmHg, p=0.74), ICP (15 vs. 14mmHg, p=0.78) or CBF (274 vs. 397 Perfusion Units, p=0.12). CBFx burden was greater among abnormal than normal animals (45% vs. 24%, p=0.001), but PRx burden was not (25% vs. 20%, p=0.38). ConclusionCAR is impaired early after ROSC. A greater burden of CAR impairment measured by CBFx was associated with abnormal neurologic outcome.CHOP Institutional Animal Care and Use Committee protocol 19-001327.

Abstract 153: Non-invasive Measurement of Cerebral Tissue Oxygen Extraction Fraction is Correlated with Microdialysis Brain Injury Biomarkers During Extracorporeal Cardiopulmonary Resuscitation

Introduction: Extracorporeal membrane oxygenation (ECMO) assisted CPR (ECPR) can improve outcomes after prolonged or unsuccessful resuscitative efforts, but neurological injury remains common in survivors. The lack of routine neuromonitoring during ECPR and ECMO prohibits brain-targeted management to help improve neurological outcomes. In this study, we examine the association of non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) measurements of cerebral tissue oxygen extraction fraction (OEF), an indicator of metabolic stress, with invasively collected brain injury biomarkers to explore the utility of this monitoring modality during ECPR. Hypothesis: FD-DOS measurement of cerebral OEF is positively correlated with biomarkers of brain injury (lactate-pyruvate ratio, LPR; glycerol). Methods: Cerebral OEF was continuously monitored by FD-DOS in nine pediatric swine (8-11 kg) who underwent 30-60 minutes of manual CPR, were cannulated for ECMO, and remained on ECMO for 22-24 hours. Cerebral pyruvate, lactate, glycerol and glucose content were measured from cerebral microdialysate samples collected hourly. The correlation between OEF and microdialysis parameters were assessed using a linear mixed-effects model incorporating subject-specific random slope and intercept effects. Significance was determined at p&lt;0.05. Results: Microdialysis parameters from 192 samples were compared against non-invasive OEF values. OEF was significantly correlated with LPR (p=0.001), and relative change in glycerol (p=0.005) and glucose (p=0.020) concentrations from baseline. Conclusions: Non-invasive FD-DOS neuromonitoring of OEF demonstrated significant correlations with invasive brain injury biomarkers; increasing OEF was associated with elevated LPR and glycerol, and diminished glucose. FD-DOS detection of critical neurometabolic stress at the bedside may facilitate brain-targeted ECMO management after cardiac arrest.

Abstract 249: Association of Diastolic Blood Pressure and Myocardial Perfusion Pressure with Survival During Pediatric Cardiopulmonary Resuscitation

Introduction: Myocardial perfusion pressure (MPP), defined as the aortic diastolic pressure minus the central venous diastolic pressure, is an important determinant of return of spontaneous circulation (ROSC) in cardiac arrest. However, measuring MPP requires both arterial and venous catheters and is often not possible. When only invasive arterial monitoring is available, diastolic blood pressure (DBP) is suggested as a surrogate for MPP during resuscitation and is also associated with survival after cardiac arrest. Hypothesis: We hypothesized that DBP measured during chest compression delivery would mirror MPP during resuscitation and both would be associated with survival. Methods: We performed a retrospective, secondary analysis of 102 swine resuscitations. Pediatric swine underwent asphyxial cardiac arrest and were resuscitated with predefined periods of basic and advanced life support (BLS and ALS). MPP and DBP were recorded every 30 s during chest compression delivery. Results: For both survivors and non-survivors, DBP mirrored MPP throughout resuscitation ( Figure 1A, B ). During BLS, both MPP and DBP were significantly greater in survivors (MPP: 8.5 0.6 vs. 1.1 0.5 mmHg; p &lt; 0.0001; DBP 17.3 0.6 vs. 8.7 0.5 mmHg; p &lt; 0.0001). During ALS, MPP and DBP were greater in survivors than non-survivors (MPP: 20.5 1.0 vs. 0.7 0.3 mmHg; p &lt; 0.0001; DBP 32.3 0.9 vs. 8.8 0.2 mmHg; p &lt; 0.0001). During ALS, the magnitude of change in both MPP and DBP after the first epinephrine administration in survivors was greater than in non-survivors (MPP: 24.4 3.3 vs. 4.8 0.9 mmHg; p &lt; 0.0001; DBP: 24.5 3.1 vs. 5.4 0.8 mmHg; p &lt; 0.0001). Conclusion: These observations confirm that both DBP and MPP are associated with survival in cardiac arrest and validate the use of DBP as a surrogate for MPP. Figure 1: Myocardial perfusion pressure (MPP) and diastolic blood pressure (DBP) during BLS and ALS in survivors (A) and non-survivors (B). Arrows indicate administration of epinephrine during ALS.

Neurologic effects of short-term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric swine

BackgroundCardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3–4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors.ResultsPiglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits.ConclusionTreatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

Coagulopathy Characterized by Rotational Thromboelastometry in a Porcine Pediatric ECMO Model

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is used to support patients with reversible cardiopulmonary insufficiency. Although it is a lifesaving technology, bleeding, inflammation, and thrombosis are well-described complications of ECMO. Adult porcine models of ECMO have been used to recapitulate the physiology and hemostatic consequences of ECMO cannulation in adults. However, these models lack the unique physiology and persistence of fetal forms of coagulation factors and fibrinogen as in human infants. We aimed to describe physiologic and coagulation parameters of piglets cannulated and supported with VA-ECMO. Four healthy piglets (5.7–6.4 kg) were cannulated via jugular vein and carotid artery by cutdown and supported for a maximum of 20 hours. Heparin was used with a goal activated clotting time of 180–220 seconds. Arterial blood gas (ABG) was performed hourly, and blood was transfused from an adult donor to maintain hematocrit (Hct) &gt; 24%. Rotational thromboelastometry (ROTEM) was performed at seven time points. All animals achieved adequate flow with a patent circuit throughout the run (pre- and post-oxygenator pressure gradient &lt;10 mmHg). There was slow but significant hemorrhage at cannulation, arterial line, and bladder catheter sites. All animals required the maximum blood transfusion volume available. All animals became anemic after exhaustion of blood for transfusion. ABG showed progressively declining Hct and adequate oxygenation. ROTEM demonstrated decreasing fibrin-only ROTEM (FIBTEM) clot firmness. Histology was overall unremarkable. Pediatric swine are an important model for the study of pediatric ECMO. We have demonstrated the feasibility of such a model while providing descriptions of physiologic, hematologic, and coagulation parameters throughout. Weak whole-blood clot firmness by ROTEM suggested defects in fibrinogen, and there was a clinical bleeding tendency in all animals studied. This model serves as an important means to study the complex derangements in hemostasis during ECMO.

Coagulopathy Characterized by Rotational Thromboelastometry in a Porcine Pediatric ECMO Model.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is used to support patients with reversible cardiopulmonary insufficiency. Although it is a lifesaving technology, bleeding, inflammation, and thrombosis are well-described complications of ECMO. Adult porcine models of ECMO have been used to recapitulate the physiology and hemostatic consequences of ECMO cannulation in adults. However, these models lack the unique physiology and persistence of fetal forms of coagulation factors and fibrinogen as in human infants. We aimed to describe physiologic and coagulation parameters of piglets cannulated and supported with VA-ECMO. Four healthy piglets (5.7-6.4 kg) were cannulated via jugular vein and carotid artery by cutdown and supported for a maximum of 20 hours. Heparin was used with a goal activated clotting time of 180-220 seconds. Arterial blood gas (ABG) was performed hourly, and blood was transfused from an adult donor to maintain hematocrit (Hct) > 24%. Rotational thromboelastometry (ROTEM) was performed at seven time points. All animals achieved adequate flow with a patent circuit throughout the run (pre- and post-oxygenator pressure gradient <10 mmHg). There was slow but significant hemorrhage at cannulation, arterial line, and bladder catheter sites. All animals required the maximum blood transfusion volume available. All animals became anemic after exhaustion of blood for transfusion. ABG showed progressively declining Hct and adequate oxygenation. ROTEM demonstrated decreasing fibrin-only ROTEM (FIBTEM) clot firmness. Histology was overall unremarkable. Pediatric swine are an important model for the study of pediatric ECMO. We have demonstrated the feasibility of such a model while providing descriptions of physiologic, hematologic, and coagulation parameters throughout. Weak whole-blood clot firmness by ROTEM suggested defects in fibrinogen, and there was a clinical bleeding tendency in all animals studied. This model serves as an important means to study the complex derangements in hemostasis during ECMO.

Does the pediatric hemodynamic cliff exist in response to hemorrhagic shock?

BackgroundThe paradigm that children maintain normal blood pressure during hemorrhagic shock until 30%–45% hemorrhage is widely accepted. There are minimal data supporting when decompensation occurs and how a child's vasculature compensates up to that point. We aimed to observe the arterial response to hemorrhage and when mean arterial pressure (MAP) decreased from baseline in pediatric swine. MethodsPiglets were hemorrhaged in 20% increments of their total blood volume to 60%. MAP and angiograms of the thoracic aorta (TA) and abdominal arteries were obtained. Percent change in area of the vessels from baseline was calculated. ResultsPiglets (n = 8) had a differential vasoconstriction starting at 20% hemorrhage (celiac artery 36.3% [31.4–44.6] vs TA 16.7% [10.7–19.1] p = 0.0012). At 40% hemorrhage, the differential vasoconstriction favored shunting blood away from the abdominal visceral branches to the TA (celiac artery 54.7% [36.9–60.6] vs TA 29.5% [23.9–36.2] p = 0.0056 superior mesenteric artery 46.7% [43.9–68.6] vs TA 29.5% [23.9–36.2] p = 0.0100). This was exacerbated at 60% hemorrhage. MAP decreased from baseline at 20% hemorrhage (66.4 ± 6.0 mmHg vs 41.4 ± 10.4 mmHg, p < 0.0001), and worsened at 40% and 60% hemorrhage. ConclusionIn piglets, a differential vasocontriction shunting blood proximally occurred in response to hemorrhage. This did not maintain normal MAP at 20%, 40% or 60% hemorrhage. Level of evidenceLevel II.

Endotracheal Administered Epinephrine Is Effective in Return of Spontaneous Circulation Within a Pediatric Swine Hypovolemic Cardiac Arrest Model.

Early administration of epinephrine increases the incidence of return of spontaneous circulation (ROSC) and improves outcomes among pediatric cardiac arrest victims. Rapid endotracheal (ET) intubation can facilitate early administration of epinephrine to pediatric victims. To date, no studies have evaluated the use of ET epinephrine in a pediatric hypovolemic cardiac arrest model to determine the incidence of ROSC. This prospective, experimental study evaluated the pharmacokinetics and/or incidence of ROSC following ET administered epinephrine and compared it to these experimental groups: intravenous (IV) administered epinephrine, cardiopulmonary resuscitation only (CPR), and CPR + defibrillation (CPR + Defib). Endotracheal administered epinephrine, at the Pediatric Advanced Life Support (PALS) recommended dose, was not significantly different than IV administered epinephrine in maximum plasma concentrations, time to maximum plasma concentration, area under the curve, or ROSC, or mean plasma concentrations at various time points (P > 0.05). The odds of ROSC in the ET group were 2.4 times greater than the IV group. The onset to ROSC in the ET group was significantly shorter than the IV group (P < 0.0001). These data support that ET epinephrine administration remains an alternative to IV administered epinephrine and faster at restoring ROSC among pediatric hypovolemic cardiac arrest victims in the acute setting when an endotracheal tube is present. Although further research is required to determine long-term outcomes of high-dose ET epinephrine administration, these data reinforce the therapeutic potential of ET administration of epinephrine to restore ROSC before IV access.

Volumetric Capnography Monitoring and Effects of Epinephrine on Volume of Carbon Dioxide Elimination during Resuscitation after Cardiac Arrest in a Swine Pediatric Ventricular Fibrillatory Arrest.

The aim of this study was to examine the use of volumetric capnography monitoring to assess cardiopulmonary resuscitation (CPR) effectiveness by correlating it with cardiac output (CO), and to evaluate the effect of epinephrine boluses on both end-tidal carbon dioxide (EtCO 2 ) and the volume of CO 2 elimination (VCO 2 ) in a swine ventricular fibrillation cardiac arrest model. Planned secondary analysis of data collected to investigate the use of noninvasive monitors in a pediatric swine ventricular fibrillation cardiac arrest model was performed. Twenty-eight ventricular fibrillatory arrests with open cardiac massage were conducted. During CPR, EtCO 2 and VCO 2 had strong correlation with CO, measured as a percentage of baseline pulmonary blood flow, with correlation coefficients of 0.83 ( p < 0.001) and 0.53 ( p = 0.018), respectively. However, both EtCO 2 and VCO 2 had weak and nonsignificant correlation with diastolic blood pressure during CPR 0.30 ( p = 0.484) (95% confidence interval [CI], -0.51-0.83) and 0.25 ( p = 0.566) (95% CI, -0.55-0.81), respectively. EtCO 2 and VCO 2 increased significantly after the first epinephrine bolus without significant change in CO. The correlations between EtCO 2 and VCO 2 and CO were weak 0.20 ( p = 0.646) (95% CI, -0.59-0.79), and 0.27 ( p = 0.543) (95% CI, -0.54-0.82) following epinephrine boluses. Continuous EtCO 2 and VCO 2 monitoring are potentially useful metrics to ensure effective CPR. However, transient epinephrine administration by boluses might confound the use of EtCO 2 and VCO 2 to guide chest compression.