Ryan W. Morgan

Persistently Altered Brain Mitochondrial Bioenergetics After Apparently Successful Resuscitation From Cardiac Arrest.

Background Although advances in cardiopulmonary resuscitation have improved survival from cardiac arrest (CA), neurologic injury persists and impaired mitochondrial bioenergetics may be critical for targeted neuroresuscitation. The authors sought to determine if excellent cardiopulmonary resuscitation and postresuscitation care and good traditional survival rates result in persistently disordered cerebral mitochondrial bioenergetics in a porcine pediatric model of asphyxia-associated ventricular fibrillation CA. Methods and Results After 7 minutes of asphyxia, followed by ventricular fibrillation, 5 female 1-month-old swine (4 sham) received blood pressure–targeted care: titration of compression depth to systolic blood pressure of 90 mm Hg and vasopressor administration to a coronary perfusion pressure >20 mm Hg. All animals received protocol-based vasopressor support after return of spontaneous circulation for 4 hours before they were killed. The primary outcome was integrated mitochondrial electron transport system (ETS) function. CA animals displayed significantly decreased maximal, coupled oxidative phosphorylating respiration (OXPHOSCI+CII) in cortex (P<0.02) and hippocampus (P<0.02), as well as decreased phosphorylation and coupling efficiency (cortex, P<0.05; hippocampus, P<0.05). Complex I– and complex II–driven respiration were both significantly decreased after CA (cortex: OXPHOSCI P<0.01, ETSCII P<0.05; hippocampus: OXPHOSCI P<0.03, ETSCII P<0.01). In the hippocampus, there was a significant decrease in maximal uncoupled, nonphosphorylating respiration (ETSCI+CII), as well as a 30% reduction in citrate synthase activity (P<0.04). Conclusions Mitochondria in both the cortex and hippocampus displayed significant alterations in respiratory function after CA despite excellent cardiopulmonary resuscitation and postresuscitation care in asphyxia-associated ventricular fibrillation CA. Analysis of integrated ETS function identifies mitochondrial bioenergetic failure as a target for goal-directed neuroresuscitation after CA. IACUC Protocol: IAC 13-001023.

A quantitative comparison of physiologic indicators of cardiopulmonary resuscitation quality: Diastolic blood pressure versus end-tidal carbon dioxide

AIM The American Heart Association (AHA) recommends monitoring invasive arterial diastolic blood pressure (DBP) and end-tidal carbon dioxide (ETCO2) during cardiopulmonary resuscitation (CPR) when available. In intensive care unit patients, both may be available to the rescuer. The objective of this study was to compare DBP vs. ETCO2 during CPR as predictors of cardiac arrest survival. METHODS In two models of cardiac arrest (primary ventricular fibrillation [VF] and asphyxia-associated VF), 3-month old swine received either standard AHA guideline-based CPR or patient-centric, BP-guided CPR. Mean values of DBP and ETCO2 in the final 2min before the first defibrillation attempt were compared using receiver operating characteristic curves (area under curve [AUC] analysis). The optimal DBP cut point to predict survival was derived and subsequently validated in two independent, randomly generated cohorts. RESULTS Of 60 animals, 37 (61.7%) survived to 45min. DBP was higher in survivors than in non-survivors (40.6±1.8mmHg vs. 25.9±2.4mmHg; p<0.001), while ETCO2 was not different (30.0±1.5mmHg vs. 32.5±1.8mmHg; p=0.30). By AUC analysis, DBP was superior to ETCO2 (0.82 vs. 0.60; p=0.025) in discriminating survivors from non-survivors. The optimal DBP cut point in the derivation cohort was 34.1mmHg. In the validation cohort, this cut point demonstrated a sensitivity of 0.78, specificity of 0.81, positive predictive value of 0.64, and negative predictive value of 0.89 for survival. CONCLUSIONS In both primary and asphyxia-associated VF porcine models of cardiac arrest, DBP discriminates survivors from non-survivors better than ETCO2. Failure to attain a DBP >34mmHg during CPR is highly predictive of non-survival.

Variability in the Implementation of Rapid Response Teams at Academic American Pediatric Hospitals

Pediatric rapid response teams have become standard over the past decade, but are organized heterogeneously at US academic hospitals, with rare financial support. To compare rapid response team efficacy, pediatric hospitals should agree on standard outcome measures, whether it be a standard definition of floor arrest or of clinical deterioration.

A hemodynamic-directed approach to pediatric cardiopulmonary resuscitation (HD-CPR) improves survival

AIM Most pediatric in-hospital cardiac arrests (IHCAs) occur in ICUs where invasive hemodynamic monitoring is frequently available. Titrating cardiopulmonary resuscitation (CPR) to the hemodynamic response of the individual improves survival in preclinical models of adult cardiac arrest. The objective of this study was to determine if titrating CPR to systolic blood pressure (SBP) and coronary perfusion pressure (CoPP) in a pediatric porcine model of asphyxia-associated ventricular fibrillation (VF) IHCA would improve survival as compared to traditional CPR. METHODS After 7min of asphyxia followed by VF, 4-week-old piglets received either hemodynamic-directed CPR (HD-CPR; compression depth titrated to SBP of 90mmHg and vasopressor administration to maintain CoPP ≥20mmHg); or Standard Care (compression depth 1/3 of the anterior-posterior chest diameter and epinephrine every 4min). All animals received CPR for 10min prior to the first defibrillation attempt. CPR was continued for a maximum of 20min. Protocolized intensive care was provided to all surviving animals for 4h. The primary outcome was 4-h survival. RESULTS Survival rate was greater with HD-CPR (12/12) than Standard Care (6/10; p=0.03). CoPP during HD-CPR was higher compared to Standard Care (point estimate +8.1mmHg, CI95: 0.5-15.8mmHg; p=0.04). Chest compression depth was lower with HD-CPR than Standard Care (point estimate -14.0mm, CI95: -9.6 to -18.4mm; p<0.01). Prior to the first defibrillation attempt, more vasopressor doses were administered with HD-CPR vs. Standard Care (median 5 vs. 2; p<0.01). CONCLUSIONS Hemodynamic-directed CPR improves short-term survival compared to standard depth-targeted CPR in a porcine model of pediatric asphyxia-associated VF IHCA.

Sepsis-associated in-hospital cardiac arrest: Epidemiology, pathophysiology, and potential therapies

Abstract Sepsis‐associated cardiac arrest is a relatively common occurrence with especially poor outcomes. Of the greater than 200,000 in‐hospital cardiac arrests that occur in the United States annually, between 30,000 and 60,000 occur in patients with underlying sepsis. These patients are less likely to survive than cardiac arrest victims without sepsis. In this review, we discuss the epidemiology of sepsis‐associated in‐hospital cardiac arrest in adults and children, the relevant physiology responsible for its pathogenesis and poor outcomes, and potential therapeutic interventions based on this pathophysiology. We postulate that persistence of sepsis pathophysiology during and after cardiac arrest is responsible for these poor outcomes. This includes derangements of vascular tone and intravascular volume status; myocardial dysfunction; hypoxemia, acidemia, and other metabolic derangements; and pulmonary hypertension. Potential interventions that specifically target this pathophysiology before, during, and after cardiac arrest may augment standard cardiopulmonary resuscitation and post‐resuscitation care for patients with sepsis and septic shock. HighlightsAmong patients who suffer an in‐hospital cardiac arrest, those with sepsis or septic shock have worse outcomes than those without sepsis.The complex pathophysiologic derangements that occur during septic shock can both precipitate cardiac arrest and impede resuscitation efforts.Therapies individualized to patients that specifically target this pathophysiology before, during, and after cardiac arrest have the potential to improve outcomes.

Cerebral mitochondrial dysfunction associated with deep hypothermic circulatory arrest in neonatal swine

Abstract OBJECTIVES Controversy remains regarding the use of deep hypothermic circulatory arrest (DHCA) in neonatal cardiac surgery. Alterations in cerebral mitochondrial bioenergetics are thought to contribute to ischaemia–reperfusion injury in DHCA. The purpose of this study was to compare cerebral mitochondrial bioenergetics for DHCA with deep hypothermic continuous perfusion using a neonatal swine model. METHODS Twenty-four piglets (mean weight 3.8 kg) were placed on cardiopulmonary bypass (CPB): 10 underwent 40-min DHCA, following cooling to 18°C, 10 underwent 40 min DHCA and 10 remained at deep hypothermia for 40 min; animals were subsequently rewarmed to normothermia. 4 remained on normothermic CPB throughout. Fresh brain tissue was harvested while on CPB and assessed for mitochondrial respiration and reactive oxygen species generation. Cerebral microdialysis samples were collected throughout the analysis. RESULTS DHCA animals had significantly decreased mitochondrial complex I respiration, maximal oxidative phosphorylation, respiratory control ratio and significantly increased mitochondrial reactive oxygen species (P < 0.05 for all). DHCA animals also had significantly increased cerebral microdialysis indicators of cerebral ischaemia (lactate/pyruvate ratio) and neuronal death (glycerol) during and after rewarming. CONCLUSIONS DHCA is associated with disruption of mitochondrial bioenergetics compared with deep hypothermic continuous perfusion. Preserving mitochondrial health may mitigate brain injury in cardiac surgical patients. Further studies are needed to better understand the mechanisms of neurological injury in neonatal cardiac surgery and correlate mitochondrial dysfunction with neurological outcomes.

Pulmonary Vasodilator Therapy in Shock-associated Cardiac Arrest

Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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). Conclusions: The addition of iNO to HD‐CPR in LPS‐induced shock‐associated cardiac arrest improved short‐term survival and intraarrest hemodynamics.

Can gentle chest compressions result in substantial ventilation

Cardiopulmonary resuscitation with chest compressions and ssisted ventilations (rescue breaths) is a complex psychomoor task. Hands-only CPR (i.e., chest compressions without ssisted ventilation) is easier to teach, learn, remember, and erform.1–4 Importantly, experimental animal data and clinical ata suggest that hands-only CPR can be as effective as conentional CPR with chest compressions and assisted ventilation n selected circumstances.5–9 Most notably, a meta-analysis of hree randomized controlled trials comparing hands-only telehone dispatcher-assisted bystander CPR with dispatcher-assisted onventional CPR revealed that hands-only CPR in adults was assoiated with improved chance of survival-to hospital discharge ompared with conventional CPR (14% [211/1500] versus 12% 178/1531]; risk ratio 1.22, 95% CI 1.01–1.46).10 Based on these tudies, hands-only CPR is the recommended approach for telehone dispatcher-assisted CPR for adult victims of out of hospital ardiac arrest.11 Because oxygenation and ventilation are clearly important for urvival from cardiac arrest, why is assisted ventilation (“rescue reathing”) often not necessary for VF cardiac arrest? Immeditely after ventricular fibrillation cardiac arrest, aortic oxygen and arbon dioxide concentrations do not vary from the pre-arrest tate because there is no blood flow and minimal aortic oxygen onsumption. Therefore, when chest compressions are initiated, lood flowing from the aorta to the coronary and cerebral cirulation provides adequate oxygenation at an acceptable pH. At hat time, myocardial and cerebral oxygen delivery are limited by lood flow rather than oxygen content. Importantly, the lung at he time of VF is a reservoir with substantial oxygen and limited arbon dioxide. During chest compressions, this oxygen reseroir provides adequate oxygen for the limited pulmonary blood ow, and the relatively low alveolar partial pressure of carbon ioxide allows for adequate unloading of carbon dioxide. Thereore, arterial partial pressure of oxygen, partial pressure of carbon ioxide, and pH can be adequate for several minutes, even with irway obstruction.5,12,13 In addition, substantial active ventilaion (gasping) is common during CPR, which provides additional as exchange.12–14 Finally, animal studies indicate that significant hest compression-induced gas exchange can occur because of the egative intrathoracic pressure associated with chest recoil in the elaxation phase of external chest compressions.5 In this issue of Resuscitation, Tsui and colleagues evaluated gas xchange with gentle chest compressions in children.15 In their rospective cohort pilot study, 116 children undergoing general

Electroencephalographic Response to Deep Hypothermic Circulatory Arrest in Neonatal Swine and Humans

BACKGROUND Piglets are used to study neurologic effects of deep hypothermic circulatory arrest (DHCA), but no studies have compared human and swine electroencephalogram (EEG) responses to DHCA. The importance of isoelectricity before circulatory arrest is not fully known in neonates. We compared the EEG response to DHCA in human neonates and piglets. METHODS We recorded 2 channel, left and right centroparietal, subdermal EEG in 10 neonatal patients undergoing operations involving DHCA and 10 neonatal piglets that were placed on cardiopulmonary bypass and underwent a simulated procedure using DHCA. EEG waveforms were analyzed for the presence and extent of burst suppression and isoelectricity by automated moving window analysis. The patients were monitored with 16-channel array EEG for 48 hours postoperatively and underwent postoperative brain magnetic resonance imaging. RESULTS After induction of anesthesia, humans and piglets both displayed slowing or brief suppression, then mild burst suppression, and then severe burst suppression during cooling. All piglets subsequently achieved isoelectricity at 22.4° ± 6.9°C, whereas only 1 human did at 20.2°C. Piglets and humans emerged from severe, mild, and then brief suppression patterns during rewarming. Among the patients, there were no seizures during postoperative monitoring and 1 instance of increased white matter injury on postoperative magnetic resonance imaging. CONCLUSIONS Our data suggest that current cooling strategies may not be sufficient to eliminate all EEG activity before circulatory arrest in humans but are sufficient in swine. This important difference between the swine and human response to DHCA should be considered when using this model.

353: HEMODYNAMIC EFFECTS OF CHEST COMPRESSION INTERRUPTIONS DURING CARDIAC ARREST RESUSCITATION

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Animal studies established that interruptions in chest compressions (pauses) have deleterious hemodynamic effects. The objective of this study was to evaluate the effect of pauses on invasively measured blood pressures during actual pediatric In-Hospital Cardiac Arrest (p-IHCA). We hypothesized that invasively measured blood pressures would be higher pre vs. post chest compression pauses. Methods: This was a prospective, single-center, observational study of pediatric (≤18 years) intensive care unit CA events. All subjects had an invasive arterial line in place at the time of arrest. A pause was defined as an interruption in chest compressions of ≥1s. Systolic and Diastolic Blood Pressures (SBP, DBP) were determined for individual compressions. For the primary analysis, the average SBP and DBP of the last three compressions preceding each pause were compared to the first 3 compressions following each pause using a paired t-test. Secondary analyses were conducted for pauses of ≥2s, ≥3s, and ≥6s. Results: Between 9/2013 and 4/2016, there were 20 events with complete data among 18 subjects, yielding 79 evaluable pauses. The median age at arrest was 3 yrs (IQR 1 – 15yrs). Return of circulation was achieved in 15 (75%) events. The median pause length was 3.5s (IQR 1.5 – 7.6s). SBP and DBP were not significantly different pre vs. post pause: SBP 93.5 ± 4.6 vs. 93.3 ± 4.4mmHg, p = 0.96; DBP 31.6 ± 1.6 vs. 31.9 ± 1.8mmHg, p = 0.72. Subgroup analyses considering rhythm (shockable vs. non-shockable), pause number, and time from start of event to pause (s) had similar results. Secondary analyses showed no significant difference for pauses of ≥2s, ≥3s, and ≥6s (p> 0.05). Conclusions: In this single center study at a hospital that focuses on titrating chest compressions to invasive blood pressure targets, chest compression pauses of up to 6 seconds did not result in statistically significant lower systolic or diastolic blood pressures.