Design paper of the "Blood pressure targets in post-resuscitation care and bedside monitoring of cerebral energy state: a randomized clinical trial".
ABSTRACT: BACKGROUND:Neurological injuries remain the leading cause of death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Adequate blood pressure is of paramount importance to optimize cerebral perfusion and to minimize secondary brain injury. Markers measuring global cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic variations after successful resuscitation are needed to assist a more individualized post-resuscitation care. Currently, no technique is available for bedside evaluation of global cerebral energy state, and until now blood pressure targets have been based on limited clinical evidence. Recent experimental and clinical studies indicate that it might be possible to evaluate cerebral oxidative metabolism from measuring the lactate-to-pyruvate (LP) ratio of the draining venous blood. In this study, jugular bulb microdialysis and immediate bedside biochemical analysis are introduced as new diagnostic tools to evaluate the effect of higher mean arterial blood pressure on global cerebral metabolism and the degree of cellular damage after OHCA. METHODS/DESIGN:This is a single-center, randomized, double-blinded, superiority trial. Sixty unconscious patients with sustained return of spontaneous circulation after OHCA will be randomly assigned in a one-to-one fashion to low (63?mm Hg) or high (77?mm Hg) mean arterial blood pressure target. The primary end-point will be a difference in mean LP ratio within 48?h between blood pressure groups. Secondary end-points are (1) association between LP ratio and all-cause intensive care unit (ICU) mortality and (2) association between LP ratio and survival to hospital discharge with poor neurological function. DISCUSSION:Markers measuring cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic changes after successful resuscitation are urgently needed to enable a more personalized post-resuscitation care and prognostication. Jugular bulb microdialysis may provide a reliable global estimate of cerebral metabolic state and can be implemented as an entirely new and less invasive diagnostic tool for ICU patients after OHCA and has implications for early prognosis and treatment. TRIAL REGISTRATION:ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT03095742 ). Registered March 30, 2017.
Project description:PURPOSE:We aimed to determine the feasibility of targeting low-normal or high-normal mean arterial pressure (MAP) after out-of-hospital cardiac arrest (OHCA) and its effect on markers of neurological injury. METHODS:In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial, we used a 23 factorial design to randomly assign patients after OHCA and resuscitation to low-normal or high-normal levels of arterial carbon dioxide tension, to normoxia or moderate hyperoxia, and to low-normal or high-normal MAP. In this paper we report the results of the low-normal (65-75 mmHg) vs. high-normal (80-100 mmHg) MAP comparison. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest. The feasibility outcome was the difference in MAP between the groups. Secondary outcomes included S100B protein and cardiac troponin (TnT) concentrations, electroencephalography (EEG) findings, cerebral oxygenation and neurological outcome at 6 months after cardiac arrest. RESULTS:We recruited 123 patients and included 120 in the final analysis. We found a clear separation in MAP between the groups (p?<?0.001). The median (interquartile range) NSE concentration at 48 h was 20.6 µg/L (15.2-34.9 µg/L) in the low-normal MAP group and 22.0 µg/L (13.6-30.9 µg/L) in the high-normal MAP group, p?=?0.522. We found no differences in the secondary outcomes. CONCLUSIONS:Targeting a specific range of MAP was feasible during post-resuscitation intensive care. However, the blood pressure level did not affect the NSE concentration at 48 h after cardiac arrest, nor any secondary outcomes.
Project description:BACKGROUND:Patients resuscitated from cardiac arrest have brain and cardiac injury. Recent animal studies suggest that the administration of sodium nitrite after resuscitation from 12min of asystole limits acute cardiac dysfunction and improves survival and neurologic outcomes. It has been hypothesized that low doses of IV sodium nitrite given during resuscitation of out of hospital cardiac arrest (OHCA) will improve survival. Low doses of sodium nitrite (e.g., 9.6mg of sodium nitrite) are safe in healthy individuals, however the effect of nitrite on blood pressure in resuscitated cardiac arrest patients is unknown. METHODS:We performed a single-center, pilot trial of low dose sodium nitrite (1 or 9.6mg dose) vs. placebo in hospitalized out-of-hospital cardiac arrest patient to determine whether nitrite administration reduced blood pressure and whether whole blood nitrite levels increased in response to nitrite administration. RESULTS:This is the first reported study of sodium nitrite in cardiac arrest patients. Infusion of low doses of sodium nitrite in comatose survivors of OHCA (n=7) compared to placebo (n=4) had no significant effects on heart rate within 30min after infusion (70±20 vs. 78±3 beats per minute, p=0.18), systolic blood pressure (103±20 vs 108±15mmHg, p=0.3), or methemoglobin levels (0.92±0.33 vs. 0.70±0.26, p=0.45). Serum nitrite levels of 2-4?M were achieved within 15min of a 9.6mg nitrite infusion. CONCLUSIONS:Low dose sodium nitrite does not cause significant hemodynamic effect in patients with OHCA, which suggests that nitrite can be delivered safely in this critically ill patient population. Higher doses of sodium nitrite are necessary in order to achieve target serum level of 10?M.
Project description:BACKGROUND:Cerebral hypoperfusion may aggravate neurological damage after cardiac arrest. Near-infrared spectroscopy (NIRS) provides information on cerebral oxygenation but its relevance during post-resuscitation care is undefined. We investigated whether cerebral oxygen saturation (rSO2) measured with NIRS correlates with the serum concentration of neuron-specific enolase (NSE), a marker of neurological injury, and with clinical outcome in out-of-hospital cardiac arrest (OHCA) patients. METHODS:We performed a post hoc analysis of a randomised clinical trial (COMACARE, NCT02698917) comparing two different levels of carbon dioxide, oxygen and arterial pressure after resuscitation from OHCA with ventricular fibrillation as the initial rhythm. We measured rSO2 in 118 OHCA patients with NIRS during the first 36?h of intensive care. We determined the NSE concentrations from serum samples at 48?h after cardiac arrest and assessed neurological outcome with the Cerebral Performance Category (CPC) scale at 6?months. We evaluated the association between rSO2 and serum NSE concentrations and the association between rSO2 and good (CPC 1-2) and poor (CPC 3-5) neurological outcome. RESULTS:The median (inter-quartile range (IQR)) NSE concentration at 48?h was 17.5 (13.4-25.0) ?g/l in patients with good neurological outcome and 35.2 (22.6-95.8) ?g/l in those with poor outcome, p?<?0.001. We found no significant correlation between median rSO2 and NSE at 48?h, rs?=?-?0.08, p?=?0.392. The median (IQR) rSO2 during the first 36?h of intensive care was 70.0% (63.5-77.0%) in patients with good outcome and 71.8% (63.3-74.0%) in patients with poor outcome, p?=?0.943. There was no significant association between rSO2 over time and neurological outcome. In a binary logistic regression model, rSO2 was not a statistically significant predictor of good neurological outcome (odds ratio 0.99, 95% confidence interval 0.94-1.04, p?=?0.635). CONCLUSIONS:We found no association between cerebral oxygenation measured with NIRS and NSE concentrations or outcome in patients resuscitated from OHCA. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02698917 . Registered on 26 January 2016.
Project description:It is hypothesized that intravenous (IV) sodium nitrite given during resuscitation of out-of-hospital cardiac arrest (OHCA) will improve survival. We performed a phase 1 open-label study of IV sodium nitrite given during resuscitation of 120 patents with OHCA from ventricular fibrillation or nonventricular fibrillation initial rhythms by Seattle Fire Department paramedics. A total of 59 patients received 25 mg (low) and 61 patients received 60 mg (high) of sodium nitrite during resuscitation from OHCA. Treatment effects were compared between high- and low-dose nitrite groups, and all patients in a concurrent local Emergency Medical Services registry of OHCA. Whole blood nitrite levels were measured in 97 patients. The rate of return of spontaneous circulation (48% vs 49%), rearrest in the field (15% vs 25%), use of norepinephrine (12% vs 12%), first systolic blood pressure (124 ± 32 vs 125 ± 38 mm Hg), survival to discharge (23.7% vs 16.4%), and neurologically favorable survival (18.6% vs 11.5%) were not significantly different in the low and high nitrite groups. There were no significant differences in these outcomes among patients who received IV nitrite compared with concurrent registry controls. We estimate that 60 mg achieves whole blood nitrite levels of 22 to 38 ?M 10 minutes after administration, whereas 25 mg achieves a level of 9 to 16 ?M 10 minutes after delivery. In conclusion, administration of IV nitrite is feasible and appears to be safe in patients with OHCA, permitting subsequent evaluation of the effectiveness of IV nitrite for the treatment of OHCA.
Project description:Extracorporeal cardiopulmonary resuscitation (ECPR) followed by targeted temperature management has been demonstrated to significantly improve the outcomes of out-of-hospital cardiac arrest (OHCA) in adult patients. Although recent narrative and systematic reviews on extracorporeal life support in the emergency department are available in the literature, they are focused on the efficacy of ECPR, and no comprehensively summarized review on ECPR for OHCA in adult patients is available. In this review, we aimed to clarify the prevalence, pathophysiology, predictors, management, and details of the complications of ECPR for OHCA, all of which have not been reviewed in previous literature, with the aim of facilitating understanding among acute care physicians. The leading countries in the field of ECPR are those in East Asia followed by those in Europe and the United States. ECPR may reduce the risks of reperfusion injury and deterioration to secondary brain injury. Unlike conventional cardiopulmonary resuscitation, however, no clear prognostic markers have been identified for ECPR for OHCA. Bleeding was identified as the most common complication of ECPR in patients with OHCA. Future studies should combine ECPR with intra-aortic balloon pump, extracorporeal membrane oxygenation flow, target blood pressure, and seizure management in ECPR.
Project description:In spite of many years of development and implementation of pre-hospital advanced life support programmes, the survival rate of out-of-hospital cardiac arrest (OHCA) used to be very poor. Neurologic injury from cerebral hypoxia is the most common cause of death in patients with OHCA. In the past two decades, post-resuscitation care has developed many new concepts aimed at improving the neurological outcome and survival rate of patients after cardiac arrest. Systematic post-cardiac arrest care after the return of spontaneous circulation, including induced mild therapeutic hypothermia (TH) in selected patients, is aimed at significantly improving rates of long-term neurologically intact survival. This review summarises the history and current knowledge in the field of mild TH after OHCA.
Project description:Survival from out-of-hospital cardiac arrest (OHCA) has remained low despite advances in resuscitation science. Hospital-based extra-corporeal cardiopulmonary resuscitation (ECPR) is a novel use of an established technology that provides greater blood flow and oxygen delivery during cardiac arrest than closed chest compressions. Hospital-based ECPR is currently offered to selected OHCA patients in specialized centres. The interval between collapse and restoration of circulation is inversely associated with good clinical outcomes after ECPR. Pre-hospital delivery of ECPR concurrent with conventional resuscitation is one approach to shortening this interval and improving outcomes after OHCA. This article examines the background and rationale for pre-hospital ECPR; summarises the findings of a literature search for published evidence; and considers candidate selection, logistics, and complications for this complex intervention.
Project description:Background We sought to evaluate the effect of mild hypercapnia on brain tissue oxygen tension (Pbto2) and diffusion limitation (impaired ability of oxygen extraction) in a porcine post asphyxial cardiac arrest model. Methods In 16 Bama pigs, asphyxial cardiac arrest was induced by endotracheal tube clamping and remained untreated for another 4?min. After return of spontaneous circulation (ROSC), animals were randomly assigned to mild hypercapnia (end-tidal carbon dioxide (EtCO2): 45?~?50?mmHg) and normocapnia (EtCO2: 35?~?40?mmHg) groups for 12?h. Intracranial pressure (ICP), Pbto2, and brain tissue temperature were invasively measured by multimodality monitors. Blood gas analysis, neuron specific enolase (NSE), and S100? were tested at baseline, ROSC 1?h, 6?h, and 12?h. Generalized mixed model with a compound symmetry covariance matrix was used to compare the time-variables of the two groups. Results Twelve (75%) pigs had ROSC and 11 pigs survived for the study period, with 6 pigs in mild hypercapnia group and 5 in the normocapnia group. The mean EtCO2 in the mild hypercapnia was significantly higher than normocapnia group (48 vs 38?mmHg, p?<? 0.001). Compared with normocapnia, mild hypercapnia group had higher Pbto2 (p?<? 0.001), slightly higher mean arterial pressure (p?=?0.012) and ICP (p?=?0.009). There were no differences in cerebral perfusion pressure (p?=?0.106), gradient of partial pressure of jugular venous bulb oxygen (Pjvo2) and Pbto2 (p?=?0.262), difference of partial pressure of jugular venous CO2 and arterial CO2 (p?=?0.546), cardiac output (p?=?0.712), NSE (p?=?0.822), and S100? (p?=?0.759) between the two groups. Conclusions Short term mild hypercapnia post-resuscitation could improve Pbto2. However, no corresponding improvements in the gradient of Pjvo2 to Pbto2 and biomarkers of neurological recovery were observed in the porcine asphyxial cardiac arrest model.
Project description:In a prior study of seven North American cities Pittsburgh had the highest crude rate of cardiac arrest deaths in patients 18 to 64 years of age, particularly in neighborhoods with lower socioeconomic status (SES). We hypothesized that lower SES, associated poor health behaviors (e.g., illicit drug use) and pre-existing comorbid conditions (grouped as socioeconomic factors [SE factors]) could affect the type and severity of cardiac arrest, thus outcomes.We retrospectively identified patients aged 18 to 64 years treated for in-hospital (IHCA) and out-of hospital arrest (OHCA) at two Pittsburgh hospitals between January 2010 and July 2012. We abstracted data on baseline demographics and arrest characteristics like place of residence, insurance and employment status. Favorable cerebral performance category [CPC] (1 or 2) was our primary outcome. We examined the associations between SE factors, cardiac arrest variables and outcome as well as post-resuscitation care.Among 415 subjects who met inclusion criteria, unfavorable CPC were more common in patients who were unemployed, had a history of drug abuse or hypertension. In OHCA, favorable CPC was more often associated with presentation with ventricular fibrillation/tachycardia (OR 3.53, 95% CI 1.43-8.74, p = 0.006) and less often associated with non-cardiovascular arrest etiology (OR 0.22, 95% CI 0.08-0.62, p = 0.004). We found strong associations between specific SE factors and arrest factors associated with outcome in OHCA patients only. Significant differences in post-resuscitation care existed based on injury severity, not on SES.SE factors strongly influence type and severity of OHCA but not IHCA resulting in an association with outcomes.
Project description:Arterial carbon dioxide tension (PaCO2), oxygen tension (PaO2), and mean arterial pressure (MAP) are modifiable factors that affect cerebral blood flow (CBF), cerebral oxygen delivery, and potentially the course of brain injury after cardiac arrest. No evidence regarding optimal treatment targets exists.The Carbon dioxide, Oxygen, and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial is a pilot multi-center randomized controlled trial (RCT) assessing the feasibility of targeting low- or high-normal PaCO2, PaO2, and MAP in comatose, mechanically ventilated patients after out-of-hospital cardiac arrest (OHCA), as well as its effect on brain injury markers. Using a 23 factorial design, participants are randomized upon admission to an intensive care unit into one of eight groups with various combinations of PaCO2, PaO2, and MAP target levels for 36 h after admission. The primary outcome is neuron-specific enolase (NSE) serum concentration at 48 h after cardiac arrest. The main feasibility outcome is the between-group differences in PaCO2, PaO2, and MAP during the 36 h after ICU admission. Secondary outcomes include serum concentrations of NSE, S100 protein, and cardiac troponin at 24, 48, and 72 h after cardiac arrest; cerebral oxygenation, measured with near-infrared spectroscopy (NIRS); potential differences in epileptic activity, monitored via continuous electroencephalogram (EEG); and neurological outcomes at six months after cardiac arrest.The trial began in March 2016 and participant recruitment has begun in all seven study sites as of March 2017. Currently, 115 of the total of 120 patients have been included. When completed, the results of this trial will provide preliminary clinical evidence regarding the feasibility of targeting low- or high-normal PaCO2, PaO2, and MAP values and its effect on developing brain injury, brain oxygenation, and epileptic seizures after cardiac arrest. The results of this trial will be used to evaluate whether a larger RCT on this subject is justified.ClinicalTrials.gov, NCT02698917 . Registered on 26 January 2016.