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Cardiac arrest often results in severe neurologic injury. Improving care for these patients is difficult as few noninvasive biomarkers exist that allow physicians to monitor neurologic health. The amount of low-frequency power (LFP, 0.01-0.1 Hz) in cerebral haemodynamics has been used in functional magnetic resonance imaging as a marker of neuronal activity. Our hypothesis was that increased LFP in cerebral blood flow (CBF) would be correlated with improvements in invasive measures of neurologic health.We adapted the use of LFP for to monitoring of CBF with diffuse correlation spectroscopy. We asked whether LFP (or other optical biomarkers) correlated with invasive microdialysis biomarkers (lactate-pyruvate ratio - LPR - and glycerol concentration) of neuronal injury in the 4 h after return of spontaneous circulation in a swine model of paediatric cardiac arrest (Sus scrofa domestica, 8-11 kg, 51% female). Associations were tested using a mixed linear effects model.We found that higher LFP was associated with higher LPR and higher glycerol concentration. No other biomarkers were associated with LPR; cerebral haemoglobin concentration, oxygen extraction fraction, and one EEG metric were associated with glycerol concentration.Contrary to expectations, higher LFP in CBF was correlated with worse invasive biomarkers. Higher LFP may represent higher neurologic activity, or disruptions in neurovascular coupling. Either effect may be harmful in the acute period after cardiac arrest. Thus, these results suggest our methodology holds promise for development of new, clinically relevant biomarkers than can guide resuscitation and post-resuscitation care. Institutional protocol number: 19-001327.

Rationale: Animal studies of cardiac arrest suggest that shorter epinephrine dosing intervals than currently recommended (every 3–5 min) may be beneficial in select circumstances. Objectives: To ev...

Aim Inhaled nitric oxide (iNO) during cardiopulmonary resuscitation (CPR) improved systemic hemodynamics and outcomes in a preclinical model of adult in-hospital cardiac arrest (IHCA) and may also have a neuroprotective role following cardiac arrest. The primary objectives of this study were to determine if iNO during CPR would improve cerebral hemodynamics and mitochondrial function in a pediatric model of lipopolysaccharide-induced shock-associated IHCA. Methods After lipopolysaccharide infusion and ventricular fibrillation induction, 20 1-month-old piglets received hemodynamic-directed CPR and were randomized to blinded treatment with or without iNO (80 ppm) during and after CPR. Defibrillation attempts began at 10 min with a 20-min maximum CPR duration. Cerebral tissue from animals surviving 1-h post-arrest underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and immunohistochemical analyses to assess neuropathology. Results During CPR, the iNO group had higher mean aortic pressure (41.6 ± 2.0 vs. 36.0 ± 1.4 mmHg; p = 0.005); diastolic BP (32.4 ± 2.4 vs. 27.1 ± 1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ± 2.6 vs. 19.1 ± 1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ± 54.1 vs. 115.5 ± 37.2%; p = 0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O2/s mg; p = 0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O2/s mg; p = 0.02). There were no other differences in mitochondrial respiration or brain injury between groups. Conclusions Treatment with iNO during CPR resulted in superior systemic hemodynamics, rCBF, and cerebral mitochondrial Complex I respiration in this pediatric cardiac arrest model.

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 (w, 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 2] 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.

OBJECTIVES Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics. METHODS Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured. RESULTS There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P CONCLUSIONS Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.

AIM: The mathematical method used to calculate chest compression (CC) rate during cardiopulmonary resuscitation varies in the literature and across device manufacturers. The objective of this study was to determine the variability in calculated CC rates by applying four published methods to the same dataset. METHODS: This study was a secondary investigation of the first 200 pediatric cardiac arrest events with invasive arterial line waveform data in the ICU-RESUScitation Project (NCT02837497). Instantaneous CC rates were calculated during periods of uninterrupted CCs. The defined minimum interruption length affects rate calculation (e.g., if an interruption is defined as a break in CCs ≥ 2 seconds, the lowest possible calculated rate is 30 CCs/min). Average rates were calculated by four methods: 1) rate with an interruption defined as ≥ 1 second; 2) interruption ≥ 2 seconds; 3) interruption ≥ 3 seconds; 4) method #3 excluding top and bottom quartiles of calculated rates. American Heart Association Guideline-compliant rate was defined as 100–120 CCs/min. A clinically important change was defined as ± 5 CCs/min. The percentage of events and epochs (30 second periods) that changed Guideline-compliant status was calculated. RESULTS: Across calculation methods, mean CC rates (118.7 – 119.5/min) were similar. Comparing all methods, 14 events (7%) and 114 epochs (6%) changed Guideline-compliant status. CONCLUSION: Using four published methods for calculating CC rate, average rates were similar, but 7% of events changed Guideline-compliant status. These data suggest that a uniform calculation method (interruption ≥ 1 second) should be adopted to decrease variability in resuscitation science.

Aim In-hospital cardiac arrest occurs in >5000 children each year in the US and almost half will not survive to discharge. Animal data demonstrate that an immediate post-resuscitation burst of hypertension is associated with improved survival. We aimed to determine if systolic and diastolic invasive arterial blood pressures immediately (0–20 min) after return of spontaneous circulation (ROSC) are associated with survival and neurologic outcomes at hospital discharge. Methods This is a secondary analysis of the Pediatric Intensive Care Quality of CPR (PICqCPR) study of invasively measured blood pressures during intensive care unit CPR. Patients were eligible if they achieved ROSC and had at least one invasively measured blood pressure within the first 20 min following ROSC. Post-ROSC blood pressures were normalized for age, sex and height. “Immediate hypertension” was defined as at least one systolic or diastolic blood pressure >90th percentile. The primary outcome was survival to hospital discharge. Results Of 102 children, 70 (68.6%) had at least one episode of immediate post-CPR diastolic hypertension. After controlling for pre-existing hypotension, duration of CPR, calcium administration, and first documented rhythm, patients with immediate post-CPR diastolic hypertension were more likely to survive to hospital discharge (79.3% vs. 54.5%; adjusted OR = 2.93; 95%CI, 1.16–7.69). Conclusions In this post hoc secondary analysis of the PICqCPR study, 68.6% of subjects had diastolic hypertension within 20 min of ROSC. Immediate post-ROSC hypertension was associated with increased odds of survival to discharge, even after adjusting for covariates of interest.

Animal studies have established deleterious hemodynamic effects of interrupting chest compressions. The objective of this study was to evaluate the effect of interruptions on invasively measured blood pressures (BPs) during pediatric in-hospital cardiac arrest (IHCA).This was a single-center, observational study of pediatric (18 years) intensive care unit IHCAs in patients with invasive arterial catheters in place. Interruptions were defined as ≥1 s between chest compressions. Diastolic BP (DBP) and systolic BP (SBP) were determined for individual compressions. For the primary analysis, the average DBP and SBP of the 20 compressions preceding each interruption were compared to the average DBP and SBP of the first 20 compressions following each interruption utilizing non-parametric paired analyses. Linear regression evaluated the change in DBP during interruptions and following interruptions.Thirty-two IHCA events met inclusion criteria, yielding 161 evaluable interruptions. The median age was 2.1 years. Return of circulation was achieved in 24 (75%). The median interruption duration was 2.4 [1.4, 7.0] seconds. Most patients were intubated pre-arrest and received epinephrine during CPR. BPs were not different pre- vs. post-interruption (DBP: 28.7 [21.6, 38.2] vs. 28.3 [21.0, 37.4] mmHg, p = 0.81; SBP: 82.0 [51.7, 116.7] vs. 85.4 [55.7, 122.2] mmHg, p = 0.07). DBP decreased 8.41 ± 0.73 mmHg (p 0.001) during the first second of interruptions and 0.19 ± 0.02 mmHg/s (p 0.001) in subsequent seconds.BPs following chest compression interruptions did not differ from pre-interruption BPs. These findings suggest that in the setting of high-quality in-hospital CPR, brief chest compression interruptions do not have persistent detrimental hemodynamic impact.

Mild hypothermic cardiopulmonary bypass (CPB) is used during neonatal cardiac surgery. To elucidate potential risk factors for brain injury, diffuse optical spectroscopy, diffuse correlation spectroscopy, and cerebral microdialysis techniques were employed to monitor cerebral hemodynamics during mild hypothermic CPB in a swine model. Optical metrics were further compared with microdialysis metrics. Stable microdialysis metabolite levels, a significant decrease in CMRO2, and trending (but not significant) decreases in CBF and increases in OEF were observed. This suggests that the optical metrics may be more sensitive to neurologic injury during CPB than microdialysis.

Extracorporeal membrane oxygenation (ECMO) is an important therapy for critically ill children but survivors have neurodevelopmental impairments. Cerebral inflammatory response resulting in brain edema is observed on ECMO. This pathologic response may adversely impact the quantitative accuracy of diffuse optical spectroscopy (DOS) neuromonitoring (including commercial NIRS) which commonly assumes a 75% water fraction. Using fresh brain tissue desiccation, we directly quantified the severity of cerebral edema in pediatric swine following cardiac arrest, CPR and 22-24 hours of ECMO therapy. The fractional error in DOS quantification of cerebral hemodynamics from assuming 75% water fraction was determined to be

We examine the correlation of non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) measurements of cerebral tissue oxygen extraction fraction (OEF) and relative cerebral blood flow (rCBF) with invasive cerebral microdialysis measurement of the cerebral lactate-pyruvate ratio (LPR), a biomarker of metabolic stress, during extracorporeal membrane oxygenation (ECMO) in a pediatric swine model of ECMO assisted cardiopulmonary resuscitation (n=15). During 22-24 hours of ECMO, non-invasive FD-DOS/DCS neuromonitoring of OEF and rCBF demonstrated significant correlations with cerebral LPR. Non-invasive detection of critical neurometabolic stress at the bedside may facilitate brain-targeted ECMO management after cardiac arrest.

Aim Pseudo-pulseless electrical activity (pseudo-PEA) is a global hypotensive ischemic state with retained coordinated myocardial contractile activity and an organized ECG with no clinically detectable pulses. The role of standard external chest compressions (CPR) and its associated intrinsic hemodynamics remains unclear in the setting of pseudo-PEA. We undertook an experimental trial to compare epinephrine alone versus epinephrine with CPR in the treatment of pseudo-PEA. Methods Using a porcine model of hypoxic pseudo-PEA, we randomized 12 Yorkshire male swine to resuscitation with epinephrine only (control) (0.0015 mg/kg) versus epinephrine plus standard CPR (intervention). Animals who achieved return of spontaneous circulation (ROSC) were stabilized, fully recovered to hemodynamic and respiratory baseline, and rearrested up to 6 times. Primary outcome was ROSC defined as a sustained systolic blood pressure (SBP) of 60 mmHg for 2 min. Secondary outcomes included time to ROSC, coronary perfusion pressure (CoPP), and end-tidal carbon dioxide (ETCO2). Results Among 47 events of pseudo-PEA in 12 animals, we observed significantly higher proportion of ROSC when treatment included CPR (14/21 – 67%) compared to epinephrine alone (4/26 – 15%) (p = 0.0007). CoPP, aortic pressures and ETCO2 were significantly higher, and right atrial pressures were lower in the intervention group. Conclusions In a swine model of hypoxia-induced pseudo-PEA, epinephrine plus CPR was associated with improved intra-arrest hemodynamics and higher probability of ROSC. Thus, epinephrine plus CPR may be superior to epinephrine alone in the treatment of patients with pseudo-PEA.

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 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.

Introduction: Inhaled nitric oxide (iNO) may result in higher systemic BP during CPR and may have a neuroprotective role post-arrest, but its effects on cerebral perfusion pressure (CePP), cerebral blood flow (CBF), and mitochondrial function when administered during CPR are unknown. Hypotheses: We hypothesized that administration of iNO during CPR would lead to higher CePP, higher CBF, and less brain injury as measured by cerebral mitochondrial function, neuronal apoptosis, and microglial activation. Methods: In 1-month-old swine (n=20), lipopolysaccharide was intravenously infused to induce a shock state, followed by induction of VF and treatment with hemodynamic-directed CPR (HD-CPR). Animals were randomized to blinded treatment with either: 1) HD-CPR with iNO (beginning 1 minute into CPR), or 2) HD-CPR without iNO. Defibrillation attempts began at 10 minutes with a maximum CPR duration of 20 minutes. Among animals surviving 1-hour post-arrest, cerebral tissue underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and quantification of neuronal apoptosis and microglial activation. Chi-square test, Fisher’s exact test, Student’s t-test, Wilcoxon rank-sum test, and a generalized estimating equation regression model compared the two groups. Results: During CPR, the iNO group had higher mean aortic pressure (41.6±2.0 vs. 36.0±1.4 mmHg; p=0.005); diastolic BP (32.4±2.4 vs. 27.1±1.7 mmHg; p=0.03); CePP (25.0±2.6 vs. 19.1±1.8 mmHg; p=0.02); and CBF relative to pre-CPR baseline (243.2±54.1 vs. 115.5±37.2%; p=0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O 2 /s*mg; p=0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O 2 /s*mg; p=0.02). There were no other differences in mitochondrial respiration or brain injury between groups. Conclusions: Blinded treatment with iNO during CPR in a model of pediatric shock-associated cardiac arrest resulted in superior CePP, CBF, and cerebral mitochondrial Complex I respiration. These data suggest that iNO treatment during CPR may lead to improved neurologic outcomes from pediatric cardiac arrest.

Aim: Compare vasopressin to a second dose of epinephrine as rescue therapy after ineffective initial doses of epinephrine in diverse models of pediatric in-hospital cardiac arrest. Methods: 67 one- to three-month old female swine (10−30 kg) in six experimental cohorts from one laboratory received hemodynamic-directed CPR, a resuscitation method where high quality chest compressions are provided and vasopressor administration is titrated to coronary perfusion pressure (CoPP) ≥20 mmHg. Vasopressors are given when CoPP is

OBJECTIVES: The objective of this study was to compare survival outcomes and intra-arrest arterial blood pressures between children receiving cardiopulmonary resuscitation for bradycardia and poor perfusion and those with pulseless cardiac arrests. DESIGN: Prospective, multicenter observational study. SETTING: PICUs and cardiac ICUs of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Children (< 19 yr old) who received greater than or equal to 1 minute of cardiopulmonary resuscitation with invasive arterial blood pressure monitoring in place. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 164 patients, 96 (59%) had bradycardia and poor perfusion as the initial cardiopulmonary resuscitation rhythm. Compared to those with initial pulseless rhythms, these children were younger (0.4 vs 1.4 yr; p = 0.005) and more likely to have a respiratory etiology of arrest (p < 0.001). Children with bradycardia and poor perfusion were more likely to survive to hospital discharge (adjusted odds ratio, 2.31; 95% CI, 1.10–4.83; p = 0.025) and survive with favorable neurologic outcome (adjusted odds ratio, 2.21; 95% CI, 1.04–4.67; p = 0.036). There were no differences in diastolic or systolic blood pressures or event survival (return of spontaneous circulation or return of circulation via extracorporeal cardiopulmonary resuscitation). Among patients with bradycardia and poor perfusion, 49 of 96 (51%) had subsequent pulselessness during the cardiopulmonary resuscitation event. During cardiopulmonary resuscitation, these patients had lower diastolic blood pressure (point estimate, −6.68 mm Hg [−10.92 to −2.44 mm Hg]; p = 0.003) and systolic blood pressure (point estimate, −12.36 mm Hg [−23.52 to −1.21 mm Hg]; p = 0.032) and lower rates of return of spontaneous circulation (26/49 vs 42/47; p < 0.001) than those who were never pulseless. CONCLUSIONS: Most children receiving cardiopulmonary resuscitation in ICUs had an initial rhythm of bradycardia and poor perfusion. They were more likely to survive to hospital discharge and survive with favorable neurologic outcomes than patients with pulseless arrests, although there were no differences in immediate event outcomes or intra-arrest hemodynamics. Patients who progressed to pulselessness after cardiopulmonary resuscitation initiation had lower intra-arrest hemodynamics and worse event outcomes than those who were never pulseless.

Background Hyperoxia during cardiopulmonary resuscitation (CPR) may lead to oxidative injury from mitochondrial‐derived reactive oxygen species, despite guidelines recommending 1.0 inspired oxygen during CPR . We hypothesized exposure to 1.0 inspired oxygen during CPR would result in cerebral hyperoxia, higher mitochondrial‐derived reactive oxygen species, increased oxidative injury, and similar survival compared with those exposed to 21% oxygen. Methods and Results Four‐week‐old piglets (n=25) underwent asphyxial cardiac arrest followed by randomization and blinding to CPR with 0.21 (n=10) or 1.0 inspired oxygen (n=10) through 10 minutes post return of spontaneous circulation. Sham was n=5. Survivors received 4 hours of protocolized postarrest care, whereupon brain was obtained for mitochondrial analysis and neuropathology. Groups were compared using Kruskal‐Wallis test, Wilcoxon rank‐sum test, and generalized estimating equations regression models. Both 1.0 and 0.21 groups were similar in systemic hemodynamics and cerebral blood flow, as well as survival (8/10). The 1.0 animals had relative cerebral hyperoxia during CPR and immediately following return of spontaneous circulation (brain tissue oxygen tension, 85% [interquartile range, 72%–120%] baseline in 0.21 animals versus 697% [interquartile range, 515%–721%] baseline in 1.0 animals; P =0.001 at 10 minutes postarrest). Cerebral mitochondrial reactive oxygen species production was higher in animals treated with 1.0 compared with 0.21 ( P P P Conclusions Exposure to 1.0 inspired oxygen during CPR caused cerebral hyperoxia during resuscitation, and resultant increased mitochondrial‐derived reactive oxygen species and oxidative injury following cardiac arrest.

Background Despite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first. Methods One-month-old piglets (n = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10–20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO2]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first. Results With the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures (p p p Conclusions This model suggests that epinephrine increases CBF and cerebral tissue oxygenation, but that effects wane following the third dose. Noninvasive measurements of neurological health parameters hold promise for developing and directing resuscitation strategies.

Near-infrared spectroscopy and diffuse correlation spectroscopy were applied to measure oxygen saturation and blood flow changes in the brain at four timepoints in swine models during cardiopulmonary bypass.

AIM: The primary aim of this study was to evaluate the association between chest compression rates and 1) arterial blood pressure and 2) survival outcomes during pediatric in-hospital cardiopulmonary resuscitation (CPR). METHODS: Prospective observational study of children ≥37 weeks gestation and 120–140, >140) and outcomes. RESULTS: Compression rate data were available for 164 patients. More than half (98/164; 60%) were < 1 year old. Return of circulation was achieved in 148/164 (90%); survival to hospital discharge in 77/164 (47%). Percentage of events with average rate within Guidelines was 32.9%. Compared to Guidelines, higher rate categories were associated with lower systolic blood pressures (>120–140, p=0.010; >140, p=0.077), but not survival. A rate between 80

Many in-hospital cardiac arrests are precipitated by hypotension, often associated with systemic inflammation. These patients are less likely to be successfully resuscitated, and novel approaches to their treatment are needed.To determine if the addition of inhaled nitric oxide (iNO) to hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) would improve short-term survival from cardiac arrest associated with shock and systemic inflammation.In 3-month-old swine (n = 21), LPS was intravenously infused, inducing systemic hypotension. Ventricular fibrillation was induced, and animals were randomized to blinded treatment with either: 1) HD-CPR with iNO, or 2) HD-CPR without iNO. During HD-CPR, chest compression depth was titrated to peak aortic compression pressure of 100 mm Hg, and vasopressor administration was titrated to coronary perfusion pressure greater than or equal to 20 mm Hg. Defibrillation attempts began after 10 minutes of resuscitation. The primary outcome was 45-minute survival.The iNO group had higher rates of 45-minute survival (10 of 10 vs. 3 of 11; P = 0.001). During cardiopulmonary resuscitation, the iNO group had lower pulmonary artery relaxation pressure (mean ± SEM, 10.9 ± 2.4 vs. 18.4 ± 2.4 mm Hg; P = 0.03), higher coronary perfusion pressure (21.1 ± 1.5 vs. 16.9 ± 1.0 mm Hg; P = 0.005), and higher aortic relaxation pressure (36.6 ± 1.6 vs. 30.4 ± 1.1 mm Hg; P 0.001) despite shallower chest compressions (5.88 ± 0.25 vs. 6.46 ± 0.40 cm; P = 0.02) and fewer vasopressor doses in the first 10 minutes (median, 4 [interquartile range, 3-4] vs. 5 [interquartile range, 5-6], P = 0.03).The addition of iNO to HD-CPR in LPS-induced shock-associated cardiac arrest improved short-term survival and intraarrest hemodynamics.

Background: Lifeless shock (LS) (previously called EMD and pseudo-PEA) is a global hypotensive ischemic state with retained coordinated myocardial contractile activity and an organized ECG. We have previously described our hypoxic LS model. The role of standard external chest compressions remains unclear in the setting of LS and its associated intrinsic hemodynamics. Although it is known the patients with LS have better prognosis compared to PEA, it is unclear what is the best treatment strategy. Prior work has shown that chest compressions (CC) when synchronized with native systole results in significant hemodynamic improvement, most notably coronary perfusion pressure (CPP), and hence it is plausible that standard dyssynchronous CC may be detrimental to hemodynamics. Furthermore, retrospective clinical data has shown that LS patients treated with vasopressors and no CC, may have better outcomes. We compared epinephrine only versus epinephrine and chest compression, in a porcine model of LS. Methods: Our porcine model of hypoxic LS has previously been described. We randomized pigs to episodes of LS treated with epinephrine only (control) (0.0015 mg/kg) versus epinephrine plus standard external chest compressions (intervention). Animals were endotracheally intubated and mechanically ventilated, and the fraction of inspired oxygen (FiO 2 ) was gradually lowered from room air (20-30% O 2 ) to a target FiO 2 of 3-7% O 2 . This target FiO 2 was maintained until the systolic blood pressure (SBP) dropped to 30 mmHg for 30 seconds, or the animal became bradycardic (HR less than 40), which was defined as the start of LS. FiO 2 was then raised to 100%, and then animal would receive control or intervention. Return of spontaneous circulation (ROSC) was defined as SBP 60 mmHg, stable after 2 minutes. Results: Twenty-six episodes of LS in 11 animals received epinephrine only control and 21 episodes the epinephrine plus chest compression intervention. The rates of ROSC in two minutes or less were 5/26 (19%) in the control arm vs 14/21 (67%) in the intervention arm (P=0.001;95% CI 19.7 %-67.2%). Conclusions: In a swine model of hypoxia induced LS, epinephrine plus CPR may be superior to epinephrine alone.

ObjectivesThe objective of this study was to associate ventilation rates during in-hospital cardiopulmonary resuscitation with 1) arterial blood pressure during cardiopulmonary resuscitation and 2) survival outcomes.DesignProspective, multicenter observational study.SettingPediatric and pediatric cardiac ICUs of the Collaborative Pediatric Critical Care Research Network.PatientsIntubated children (≥ 37 wk gestation and < 19 yr old) who received at least 1 minute of cardiopulmonary resuscitation.InterventionsNone.Measurements and main resultsArterial blood pressure and ventilation rate (breaths/min) were manually extracted from arterial line and capnogram waveforms. Guideline rate was defined as 10 ± 2 breaths/min; high ventilation rate as greater than or equal to 30 breaths/min in children less than 1 year old, and greater than or equal to 25 breaths/min in older children. The primary outcome was survival to hospital discharge. Regression models using Firth penalized likelihood assessed the association between ventilation rates and outcomes. Ventilation rates were available for 52 events (47 patients). More than half of patients (30/47; 64%) were less than 1 year old. Eighteen patients (38%) survived to discharge. Median event-level average ventilation rate was 29.8 breaths/min (interquartile range, 23.8-35.7). No event-level average ventilation rate was within guidelines; 30 events (58%) had high ventilation rates. The only significant association between ventilation rate and arterial blood pressure occurred in children 1 year old or older and was present for systolic blood pressure only (-17.8 mm Hg/10 breaths/min; 95% CI, -27.6 to -8.1; p < 0.01). High ventilation rates were associated with a higher odds of survival to discharge (odds ratio, 4.73; p = 0.029). This association was stable after individually controlling for location (adjusted odds ratio, 5.97; p = 0.022), initial rhythm (adjusted odds ratio, 3.87; p = 0.066), and time of day (adjusted odds ratio, 4.12; p = 0.049).ConclusionsIn this multicenter cohort, ventilation rates exceeding guidelines were common. Among the range of rates delivered, higher rates were associated with improved survival to hospital discharge.

BACKGROUND In infants and young children, anesthetic dosing is based on population pharmacokinetics and patient hemodynamics not on patient-specific brain activity. Electroencephalography (EEG) provides insight into brain activity during anesthesia. The primary goal of this prospective observational pilot study was to assess the prevalence of isoelectric EEG events-a sign of deep anesthesia-in infants and young children undergoing general anesthesia using sevoflurane or propofol infusion for maintenance. METHODS Children 0-37 months of age requiring general anesthesia for surgery excluding cardiac, intracranial, and emergency cases were enrolled by age: 0-3, 4-6, 7-12, 13-18, and 19-37 months. Anesthesia was maintained with sevoflurane or propofol infusion. EEG was recorded from induction to extubation. Isoelectric EEG events (amplitude

Aims Evaluate 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. Methods Four-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 4 h. 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. Results Among 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. 61 mmHg, p = 0.74), ICP (15 vs. 14 mmHg, 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). Conclusion CAR 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.

Introduction: Despite controversies, epinephrine remains a mainstay of CPR. Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. Hypothesis: Epinephrine will increase CBF and cerebral oxygenation during CPR. Methods: One-month old piglets (n=20, 8-10kg) underwent asphyxia for 7 minutes, VF, and CPR according to AHA guidelines for 10-20 minutes. Epinephrine boluses (20 mcg/kg) were administered at minutes 2, 6, 10, and 14 of CPR. Invasive (laser Doppler) and noninvasive (diffuse optical) continuous measurements of CBF and oxygenation were recorded. Wilcoxon Rank-Sum test was used to compare measurements 15 seconds prior to epinephrine doses to sequential measurements at 1-minute intervals following epinephrine; data are described as median [IQR]. Results: Compared to pre-epinephrine values, CBF was most significantly increased one minute after the first dose of epinephrine (noninvasive: +37.7% [6.1, 79]; invasive: +24% [-0.3, 118], p Conclusions: In a swine model of pediatric in-hospital cardiac arrest, bolus-dosed epinephrine increases CBF and cerebral tissue oxygen saturation. These effects are only significant following the first two doses. Our findings are underscore the importance of further research to elucidate the transient pharmacodynamics of epinephrine to optimize both survival and neurological outcomes.

Introduction: We have shown that during CPR, novel non-invasive monitoring of cerebral tissue oxygenation (StO 2 , %) and total hemoglobin concentration (THC, μmol/L) by frequency-domain diffuse optical spectroscopy (FD-DOS) is associated with ROSC in a swine model of pediatric cardiac arrest. Our objective is to find the optimal non-invasive predictor for ROSC and assess feasibility of a stable critical threshold over time in early CPR. Hypothesis: Stable critical thresholds with high sensitivity or specificity for ROSC may be established in early CPR (2 and THC measurements initiated at CPR start. Methods: One-month-old swine (n=31) underwent 7 minutes of asphyxia, induction of ventricular fibrillation, and up to 20 minutes of CPR till ROSC or death (no ROSC). Absolute StO 2 and THC and absolute and relative change from 1 minute into CPR (time for chest molding and FD-DOS placement) were evaluated as ROSC predictors over time. For each variable, an ROC curve and two critical thresholds, maximizing specificity (=1) or sensitivity (=1), were determined at 1-min intervals from 2-10 minutes of CPR using univariate logistic regression. Optimal predictor was selected by highest mean AUC. A stable specificity or sensitivity threshold was feasible if the mean threshold had a specificity or sensitivity >0.9 over all intervals, respectively. Results: Absolute change in StO 2 (ΔStO 2 ) had the highest mean (SD) AUC of 0.90 (0.07). Consistently >0.8, the AUC exceeded 0.9 after 7 minutes of CPR ( see Fig. ). The mean specificity threshold (ΔStO 2 = +5.1%) and sensitivity threshold (ΔStO 2 = +1.4%) achieved an overall specificity of 0.93 and sensitivity of 0.98, respectively. Conclusions: Non-invasive monitoring of absolute change in StO 2 was most predictive of ROSC and stable critical thresholds with high specificity or sensitivity were established in early CPR. Future work will independently validate this promising tool for CPR optimization.

Introduction: Pulmonary hypertension may play a role in preventing ROSC during prolonged CPR. Targeted pulmonary vasodilation with inhaled nitric oxide (iNO) during CPR may improve pulmonary blood flow and improve outcomes. The purpose of this study was to study the effects of iNO in a randomized, blinded, placebo controlled, pediatric swine model of asphyxial cardiac arrest. Hypothesis: Animals treated with iNO will have lower pulmonary artery pressure, improved systemic hemodynamics, and increased cerebral blood flow during prolonged CPR compared to control. Methods: Four-week-old piglets (n=10) that underwent seven minutes of asphyxia, induction of VF, and 10 minutes of CPR were randomized to either iNO (20 ppm) or placebo in a blinded fashion starting one min into CPR and needed more than 1 defibrillation attempt. Defibrillation was attempted after 10 minutes of CPR. Animals that did not achieve ROSC by 20 minutes were euthanized. Invasive pulmonary and systemic hemodynamics, and both invasive and noninvasive cerebral hemodynamics were continuously measured. Data described as mean ± SD and compared using a generalized estimating equation regression model. Results: All 5 iNO-treated animals and 2/5 placebo-treated animals achieved ROSC. Those treated with iNO had lower mean pulmonary artery pressures (29.5 ± 9.1 vs. 48.3 ± 5.6 mmHg, p=0.04); higher mean aortic pressures (51.9 ± 6.4 vs. 35.5 ± 4.4 mmHg, p=0.01); higher cerebral blood flow (invasive: 230.4 ± 57.4 vs. 28.7 ± 42.1 % baseline, p Conclusions: Treatment with iNO during prolonged CPR results in lower pulmonary artery pressure, improved systemic hemodynamics, and increased cerebral blood flow and oxygenation. Pulmonary vasodilation may have an important role during prolonged CPR for asphyxial cardiac arrests.