A Narrative Review of Drug Therapy in Adult and Pediatric Cardiac Arrest.

Drugs are used during cardiopulmonary resuscitation (CPR) in association with chest compressions and ventilation. The main purpose of drugs during resuscitation is either to improve coronary perfusion pressure and myocardial perfusion in order to achieve return of spontaneous circulation (ROSC). The aim of this up-to-date review is to provide an overview of the main drugs used during cardiac arrest (CA), highlighting their historical context, pharmacology, and the data to support them. Epinephrine remains the only recommended vasopressor. Regardless of the controversy about optimal dosage and interval between doses in recent papers, epinephrine should be administered as early as possible to be the most effective in non-shockable rhythms. Despite inconsistent survival outcomes, amiodarone and lidocaine are the only two recommended antiarrhythmics to treat shockable rhythms after defibrillation. Beta-blockers have also been recently evaluated as antiarrhythmic drugs and show promising results but further evaluation is needed. Calcium, sodium bicarbonate, and magnesium are still widely used during resuscitation but have shown no benefit. Available data may even suggest a harmful effect and they are no longer recommended during routine CPR. In experimental studies, sodium nitroprusside showed an increase in survival and favorable neurological outcome when combined with enhanced CPR, but as of today, no clinical data is available. Finally, we review drug administration in pediatric CA. Epinephrine is recommended in pediatric CA and, although they have not shown any improvement in survival or neurological outcome, antiarrhythmic drugs have a 2b recommendation in the current guidelines for shockable rhythms.

Epinephrine Dosing Use During Extracorporeal Cardiopulmonary Resuscitation: Single-Center Retrospective Cohort.

OBJECTIVES: During pediatric cardiac arrest, contemporary guidelines recommend dosing epinephrine at regular intervals, including in patients requiring extracorporeal membrane oxygenation (ECMO). The impact of epinephrine-induced vasoconstriction on systemic afterload and venoarterial ECMO support is not well-defined. DESIGN: Nested retrospective observational study within a single center. The primary exposure was time from last dose of epinephrine to initiation of ECMO flow; secondary exposures included cumulative epinephrine dose and arrest time. Systemic afterload was assessed by mean arterial pressure and use of systemic vasodilator therapy; ECMO pump flow and Vasoactive-Inotrope Score (VIS) were used as measures of ECMO support. Clearance of lactate was followed post-cannulation as a marker of systemic perfusion. SETTING: PICU and cardiac ICU in a quaternary-care center. PATIENTS: Patients 0-18 years old who required ECMO cannulation during resuscitation over the 6 years, 2014-2020. Patients were excluded if ECMO was initiated before cardiac arrest or if the resuscitation record was incomplete. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 92 events in 87 patients, with 69 events having complete data for analysis. The median (interquartile range) of total epinephrine dosing was 65 mcg/kg (37-101 mcg/kg), with the last dose given 6 minutes (2-16 min) before the initiation of ECMO flows. Shorter interval between last epinephrine dose and ECMO initiation was associated with increased use of vasodilators within 6 hours of ECMO ( p = 0.05), but not with mean arterial pressure after 1 hour of support (estimate, -0.34; p = 0.06). No other associations were identified between epinephrine delivery and mean arterial blood pressure, vasodilator use, pump speed, VIS, or lactate clearance. CONCLUSIONS: There is limited evidence to support the idea that regular dosing of epinephrine during cardiac arrest is associated with increased in afterload after ECMO cannulation. Additional studies are needed to validate findings against ECMO flows and clinically relevant outcomes.

Tau associated peripheral and central neurodegeneration: Identification of an early imaging marker for tauopathy.

Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD.

Epinephrine's effects on cerebrovascular and systemic hemodynamics during cardiopulmonary resuscitation.

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 < 0.001). The effects of epinephrine on CBF and cerebral tissue oxygenation decreased with subsequent doses. By the fifth dose of epinephrine, there were no demonstrable increases in CBF of cerebral tissue oxygenation. Invasive and noninvasive CBF measurements were highly correlated during asphyxia (slope effect 1.3, p < 0.001) and CPR (slope effect 0.20, p < 0.001). 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.

Physiology-directed cardiopulmonary resuscitation: advances in precision monitoring during cardiac arrest.

PURPOSE OF REVIEW: We review the recent advances in physiologic monitoring during cardiac arrest and offer an evidence-based framework for prioritizing physiologic targets during cardiopulmonary resuscitation (CPR). RECENT FINDINGS: Current CPR guidelines recommend a uniform approach for all patients in cardiac arrest, but newer data support a precision strategy that uses the individual patient's physiology to guide resuscitation. Coronary perfusion pressure and arterial DBP are associated with survival outcomes in recent animal and human studies. End-tidal carbon dioxide is a reasonable noninvasive alternative, but may be inferior to invasive hemodynamic endpoints. Cerebral oximetry and cardiac ultrasound are emerging physiologic indicators of CPR effectiveness. SUMMARY: Physiologic monitoring can and should be used to deliver precision CPR whenever possible and may improve outcomes after cardiac arrest.

Prediction of Catheter-Associated Thrombosis in Critically Ill Children.

OBJECTIVE: We determined whether in critically ill children with an untunneled central venous catheter, the risk of catheter-associated deep venous thrombosis can be predicted within 24 hours after insertion of the catheter. DESIGN: Secondary analysis of two multicenter prospective cohort studies. SETTING: PICUs in Northeastern United States. PATIENTS: A total of 175 children admitted to the PICU within 24 hours after insertion of an untunneled central venous catheter who did not receive anticoagulation were included. Of these, 53 (30.3%) developed catheter-associated thrombosis detected with active surveillance with ultrasonography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used logistic regression (models 1 and 2) and recursive partitioning (models 3 and 4) methods to develop risk prediction models with predictors present at any time while catheterized (models 1 and 3), or within 24 hours after insertion of the catheter (models 2 and 4). Age, recent surgery, catheter in the subclavian vein, and blood product transfusion were included in models 1 and 2. Areas under the receiver operating characteristic curves were similar for these models (model 1: 0.80 vs model 2: 0.80; p = 0.44). Except for recent surgery, predictors in model 1 were identified as partitioning variables for model 3. In addition to the predictors in model 2, severity of illness was used in partitioning for model 4. The area under the curve of model 3 appeared smaller than that of model 4 (0.75 vs 0.80; p = 0.08). Groups of children at low, intermediate, and high risks of catheter-associated thrombosis were identified using model 4. CONCLUSIONS: Critically ill children at high risk of catheter-associated thrombosis can be identified within 24 hours after insertion of an untunneled central venous catheter.

The cerebral and cardiac effects of Norepinephrine in an experimental cardiac arrest model.

Introduction: Epinephrine has been the main drug recommended for decades during cardiopulmonary resuscitation (CPR). But epinephrine's ß-adrenergic effects might increase myocardial oxygen consumption and may cause arrythmias after ROSC. Norepinephrine has a weaker ß-adrenergic effect and could be useful during CPR. Studies on norepinephrine's effect on hemodynamic parameters and cerebral perfusion are scarce. This study aimed to assess norepinephrine's hemodynamic impact in an experimental model of cardiac arrest. Methods: After an initial dose study to determine the optimal dose, we conducted a prospective randomized study with 19 pigs. After 3 minutes of untreated ventricular fibrillation, animals received boluses of 0.5 mg Epinephrine (EPI) or 1 mg Norepinephrine (NE) every 5 minutes during CPR. Coronary perfusion pressure (CPP), carotid blood flow (CBF) and cerebral perfusion pressure (CePP) were evaluated. Results: At baseline, hemodynamic parameters did not differ between the two groups. During CPR, CPP and CBF were similar: 17.3 (12.8; 31.8) in the EPI group vs 16.0 (11.1; 37.7) in the NE group, p = 0.9 and 28.4 (22.0; 54.8) vs 30.8 (12.2; 56.3) respectively, p = 0.9. CePP was not significantly lower during resuscitation in the NE group compared to the EPI group: 12.2 (-8.2; 42.2) vs 7.8 (-2.0; 32.0) p = 0.4. Survival rate was low with only one animal in the EPI group and 2 in the NE group. Conclusion: Cerebral perfusion pressure, coronary perfusion pressure and carotid blood flow during CPR did not significantly differ between the norepinephrine group and the epinephrine group. Further investigations should evaluate different options such as a continuous NE infusion.

Bleeding and Thrombosis in Patients With Out-of-Hospital Ventricular Tachycardia/Ventricular Fibrillation Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation improves outcomes after out-of-hospital cardiac arrest. However, bleeding and thrombosis are common complications. We aimed to describe the incidence and predictors of bleeding and thrombosis and their association with in-hospital mortality. METHODS AND RESULTS: Consecutive patients presenting with refractory ventricular tachycardia/ventricular fibrillation out-of-hospital cardiac arrest between December 2015 and March 2022 who met the criteria for extracorporeal cardiopulmonary resuscitation initiation at our center were included. Major bleeding was defined by the Extracorporeal Life Support Organization's criteria. Adjusted analyses were done to seek out risk factors for bleeding and thrombosis and evaluate their association with mortality. Major bleeding occurred in 135 of 200 patients (67.5%), with traumatic bleeding from cardiopulmonary resuscitation in 73 (36.5%). Baseline demographics and arrest characteristics were similar between groups. In multivariable analysis, decreasing levels of fibrinogen were independently associated with bleeding (adjusted hazard ratio [aHR], 0.98 per every 10 mg/dL rise [95% CI, 0.96-0.99]). Patients who died had a higher rate of bleeds per day (0.21 versus 0.03, P<0.001) though bleeding was not significantly associated with in-hospital death (aHR, 0.81 [95% CI. 0.55-1.19]). A thrombotic event occurred in 23.5% (47/200) of patients. Venous thromboembolism occurred in 11% (22/200) and arterial thrombi in 15.5% (31/200). Clinical characteristics were comparable between groups. In adjusted analyses, no risk factors for thrombosis were identified. Thrombosis was not associated with in-hospital death (aHR, 0.65 [95% CI, 0.42-1.03]). CONCLUSIONS: Bleeding is a frequent complication of extracorporeal cardiopulmonary resuscitation that is associated with decreased fibrinogen levels on admission whereas thrombosis is less common. Neither bleeding nor thrombosis was significantly associated with in-hospital mortality.

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Acute lung injury and recovery in patients with refractory VT/VF cardiac arrest treated with prolonged CPR and veno-arterial extracorporeal membrane oxygenation.

AIM: Describe the lung injury patterns among patients presenting with refractory ventricular tachycardia/ventricular fibrillation out-of-hospital cardiac arrest (VT/VF OHCA) supported with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) facilitated resuscitation. METHODS: In this retrospective single-center cohort study including VT/VF OHCA patients supported with VA ECMO, we compared OHCA characteristics, post-arrest computed tomography (CT) scans, ventilator parameters, and other lung-related pathology between survivors, patients who developed brain death, and those with other causes of death. RESULTS: Among 138 patients, 48/138 (34.8%) survived, 31/138 (22.4%) developed brain death, and 59/138 (42.7%) died of other causes. Successful extubation was achieved in 39/138 (28%) with a median time to extubation of 8.0 days (6.0, 11.0) in those who survived. Tracheostomy was required in 15/48 (31.3%) survivors. Chest CT obtained on all patients showed lung injury in at least one lung area in 124/135 (91.8%) patients, predominantly in the dependent posterior areas. There was no association between the number of affected areas and survival. Lung compliance was low on admission [26 (19,33) ml/cmH20], improved throughout hospitalization (p = 0.03), and recovered faster in survivors compared to those who died (p < 0.001). VA-ECMO allowed the use of lung-protective ventilation while maintaining normalized PaO2 and PaCO2. Patients treated with V-A ECMO and either IABP or Impella had lower pulmonary compliance and more affected areas on their CT compared to those treated with V-A ECMO alone. CONCLUSIONS: Lung injury is common among patients with refractory VT/VF OHCA requiring V-A ECMO, but imaging severity is not associated with survival. Reductions in lung compliance accompany post-arrest lung injury while compliance recovery is associated with survival.

The Minnesota first-responder AED project: Aiming to increase survival in out-of-hospital cardiac arrest.

There are 350,000 out-of-hospital cardiac arrest (OHCA) cases annually in the United States of America. Using automated external defibrillators (AEDs) has increased survival in cardiac arrests (CA) with an initial shockable rhythm. Thus, guidelines recommend complete geographical coverage with AEDs. To fill in the gaps in Minnesota, the Center for Resuscitation Medicine at the University of Minnesota raised an $18.8 million grant from the Helmsley Charitable Trust to supply law enforcement first responders with AEDs and, thus, increase survival rates after OHCA by reducing the time to first shock. This report elaborates on the decision-making, fundraising, and logistic strategy required to reach statewide AED coverage. Methods: The baseline need for AEDs was analyzed using a questionnaire sent out to state law enforcement agencies, state patrols, city and county agencies, and tribal agencies in 2021. Furthermore, OHCA cases of 2021 were reviewed. The combination of this information led to an action plan to equip and train all agencies throughout the state's eight regions with AEDs. Results: The electronic survey was initially sent out to 358 agencies. The initial response rate was 77% (n = 276). This resulted in a total need of 8300 AEDs to be deployed over three years (2022-2025). As of 2023, over 4769 AEDs have been distributed, covering 237 sites. Conclusion: By equipping first responders with AED systems, the Center for Resuscitation Medicine aims to shorten the gap in statewide AED coverage, thus increasing the chances of survival after OHCA.

Hemodynamic Patterns Before Inhospital Cardiac Arrest in Critically Ill Children: An Exploratory Study.

To characterize prearrest hemodynamic trajectories of children suffering inhospital cardiac arrest. DESIGN: Exploratory retrospective analysis of arterial blood pressure and electrocardiogram waveforms. SETTING: PICU and cardiac critical care unit in a tertiary-care children's hospital. PATIENTS: Twenty-seven children with invasive blood pressure monitoring who suffered a total of 31 inhospital cardiac arrest events between June 2017 and June 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed changes in cardiac output, systemic vascular resistance, stroke volume, and heart rate derived from arterial blood pressure waveforms using three previously described estimation methods. We observed substantial prearrest drops in cardiac output (population median declines of 65-84% depending on estimation method) in all patients in the 10 minutes preceding inhospital cardiac arrest. Most patients' mean arterial blood pressure also decreased, but this was not universal. We identified three hemodynamic patterns preceding inhospital cardiac arrest: subacute pulseless arrest (n = 18), acute pulseless arrest (n = 7), and bradycardic arrest (n = 6). Acute pulseless arrest events decompensated within seconds, whereas bradycardic and subacute pulseless arrest events deteriorated over several minutes. In the subacute and acute pulseless arrest groups, decreases in cardiac output were primarily due to declines in stroke volume, whereas in the bradycardic group, the decreases were primarily due to declines in heart rate. CONCLUSIONS: Critically ill children exhibit distinct physiologic behaviors prior to inhospital cardiac arrest. All events showed substantial declines in cardiac output shortly before inhospital cardiac arrest. We describe three distinct prearrest patterns with varying rates of decline and varying contributions of heart rate and stroke volume changes to the fall in cardiac output. Our findings suggest that monitoring changes in arterial blood pressure waveform-derived heart rate, pulse pressure, cardiac output, and systemic vascular resistance estimates could improve early detection of inhospital cardiac arrest by up to several minutes. Further study is necessary to verify the patterns witnessed in our cohort as a step toward patient rather than provider-centered definitions of inhospital cardiac arrest.

A Gas-Powered, Patient-Responsive Automatic Resuscitator for Use in Acute Respiratory Failure: A Bench and Experimental Study.

BACKGROUND: During the COVID-19 pandemic, a need for innovative, inexpensive, and simple ventilator devices for mass use has emerged. The Oxylator (CPR Medical Devices, Markham, Ontario, Canada) is an FDA-approved, fist-size, portable ventilation device developed for out-of-hospital emergency ventilation. It has not been tested in conditions of severe lung injury or with added PEEP. We aimed to assess the performance and reliability of the device in simulated and experimental conditions of severe lung injury, and to derive monitoring methods to allow the delivery of safe, individualized ventilation during situations of surge. METHODS: We bench-tested the functioning of the device with an added PEEP valve extensively, mimicking adult patients with various respiratory mechanics during controlled ventilation, spontaneous breathing, and prolonged unstable conditions where mechanics or breathing effort was changed at every breath. The device was further tested on a porcine model (4 animals) after inducing lung injury, and these results were compared with conventional ventilation modes. RESULTS: The device was stable and predictable, delivering a constant flow (30 L/min) and cycling automatically at the inspiratory pressure set (minimum of 20 cm H2O) above auto-PEEP. Changes in respiratory mechanics manifested as changes in respiratory timing, allowing prediction of tidal volumes from breathing frequency. Simulating lung injury resulted in relatively low tidal volumes (330 mL with compliance of 20 mL/cm H2O). In the porcine model, arterial oxygenation, CO2, and pH were comparable to conventional modes of ventilation. CONCLUSIONS: The Oxylator is a simple device that delivered stable ventilation with tidal volumes within a clinically acceptable range in bench and porcine lung models with low compliance. External monitoring of respiratory timing is advisable, allowing tidal volume estimation and recognition of changes in respiratory mechanics. The device can be an efficient, low-cost, and practical rescue solution for providing short-term ventilatory support as a temporary bridge, but it requires a caregiver at the bedside.

A randomized and blinded trial of inhaled nitric oxide in a piglet model of pediatric cardiopulmonary resuscitation.

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 ±â€¯2.0 vs. 36.0 ±â€¯1.4 mmHg; p = 0.005); diastolic BP (32.4 ±â€¯2.4 vs. 27.1 ±â€¯1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ±â€¯2.6 vs. 19.1 ±â€¯1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ±â€¯54.1 vs. 115.5 ±â€¯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.

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.

Oxygen Exposure During Cardiopulmonary Resuscitation Is Associated With Cerebral Oxidative Injury in a Randomized, Blinded, Controlled, Preclinical Trial.

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<0.03). Exposure to 1.0 oxygen led to increased cerebral oxidative injury to proteins and lipids, as evidenced by significantly higher protein carbonyls and 4-hydroxynoneals compared with 0.21 (P<0.05) and sham (P<0.001). 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.

The physiologic response to rescue therapy with vasopressin versus epinephrine during experimental 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 <20 mmHg, in sequences of two doses of 0.02 mg/kg epinephrine separated by minimum one-minute, then a rescue dose of 0.4 U/kg vasopressin followed by minimum two-minutes. Invasive measurements were used to evaluate and compare the hemodynamic and neurologic effects of each vasopressor dose. RESULTS: Increases in CoPP and cerebral blood flow (CBF) were greater with vasopressin rescue than epinephrine rescue (CoPP: +8.16 [4.35, 12.06] mmHg vs. + 5.43 [1.56, 9.82] mmHg, p = 0.02; CBF: +14.58 [-0.05, 38.12] vs. + 0.00 [-0.77, 18.24] perfusion units (PFU), p = 0.005). Twenty animals (30%) failed to achieve CoPP ≥20 mmHg after two doses of epinephrine; 9/20 (45%) non-responders achieved CoPP ≥20 mmHg after vasopressin. Among all animals, the increase in CBF was greater with vasopressin (+14.58 [-0.58, 38.12] vs. 0.00 [-0.77, 18.24] PFU, p = 0.005). CONCLUSIONS: CoPP and CBF rose significantly more after rescue vasopressin than after rescue epinephrine. Importantly, CBF increased after vasopressin rescue, but not after epinephrine rescue. In the 30% that failed to meet CoPP of 20 mmHg after two doses of epinephrine, 45% achieved target CoPP with a single rescue vasopressin dose.

Hemodynamic effects of chest compression interruptions during pediatric in-hospital cardiopulmonary resuscitation.

AIM: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.