Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial.
ABSTRACT: 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?
Project description:PURPOSE:We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury. METHODS:Using a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5-4.7 kPa) or high-normal (5.8-6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10-15 kPa) or moderate hyperoxia (PaO2 20-25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months. RESULTS:In total 120 patients were included in the analyses. There was a clear separation in PaCO2 (p?<?0.001) and PaO2 (p?<?0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9-28.3 µg/l) in the low-normal PaCO2 group and 22.5 µg/l (14.2-34.9 µg/l) in the high-normal PaCO2 group, p?=?0.400; and 22.3 µg/l (14.8-27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2-34.9 µg/l) in the moderate hyperoxia group, p?=?0.594). High-normal PaCO2 and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes. CONCLUSIONS:Both high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected. REGISTRATION:ClinicalTrials.gov, NCT02698917. Registered on January 26, 2016.
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.
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:This study aimed to identify neurological and pathophysiological factors that predicted return of spontaneous circulation (ROSC) among patients with out-of-hospital cardiac arrest (OHCA). This prospective 1-year observational study evaluated patients with cardiogenic OHCA who were admitted to a tertiary medical center, Nippon Medical School Hospital. Physiological and neurological examinations were performed at admission for quantitative infrared pupillometry (measured with NPi-200, NeurOptics, CA, USA), arterial blood gas, and blood chemistry. Simultaneous blood samples were also collected to determine levels of neuron-specific enolase (NSE), S-100b, phosphorylated neurofilament heavy subunit, and interleukin-6. In-hospital standard advanced cardiac life support was performed for 30?minutes.The ROSC (n?=?26) and non-ROSC (n?=?26) groups were compared, which a revealed significantly higher pupillary light reflex ratio, which was defined as the percent change between maximum pupil diameter before light stimuli and minimum pupil diameter after light stimuli, in the ROSC group (median: 1.3% [interquartile range (IQR): 0.0-2.0%] vs. non-ROSC: (median: 0%), (Cut-off: 0.63%). Furthermore, NSE provided the great sensitivity and specificity for predicting ROSC, with an area under the receiver operating characteristic curve of 0.86, which was created by plotting sensitivity and 1-specificity. Multivariable logistic regression analyses revealed that the independent predictors of ROSC were maximum pupillary diameter (odds ratio: 0.25, 95% confidence interval: 0.07-0.94, P?=?0.04) and NSE at admission (odds ratio: 0.96, 95% confidence interval: 0.93-0.99, P?=?0.04). Pupillary diameter was also significantly correlated with NSE concentrations (r?=?0.31, P?=?0.027). Conclusively, the strongest predictors of ROSC among patients with OHCA were accurate pupillary diameter and a neuronal biomarker, NSE. Quantitative pupillometry may help guide the decision to terminate resuscitation in emergency departments using a neuropathological rationale. Further large-scale studies are needed.
Project description: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: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: Mild therapeutic hypothermia alters the validity of a number of parameters currently used to predict neurological outcome after cardiac arrest and resuscitation. Thus, additional parameters are needed to increase certainty of early prognosis in these patients. A promising new approach is the determination of the gray-white-matter ratio (GWR) in cranial computed tomography (CCT) obtained early after resuscitation. It is not known how GWR relates to established outcome parameters such as neuron specific enolase (NSE) or somatosensory evoked potentials (SSEP). METHODS: Cardiac arrest patients (n?=?98) treated with hypothermia were retrospectively analyzed with respect to the prognostic value of GWR, NSE and SSEP. RESULTS: A GWR?<?1.16 predicted poor outcome with 100% specificity and 38% sensitivity. In 62 patients NSE, SSEP and CCT were available. The sensitivity of poor outcome prediction by both NSE?>?97 ?g/L and bilateral absent SSEP was 43%. The sensitivity increased to 53% in a multi-parameter approach predicting poor outcome using at least two of the three parameters (GWR, NSE and SSEP). CONCLUSION: Our results suggest a strong association of a low GWR with poor outcome following cardiac arrest. Determination of the GWR increases the sensitivity in a multi-parameter approach for prediction of poor outcome after cardiac arrest.
Project description:<h4>Background</h4>Prediction of neurological outcome is a crucial part of post cardiac arrest care and prediction in patients remaining unconscious and/or sedated after rewarming from targeted temperature management (TTM) remains difficult. Current guidelines suggest the use of serial measurements of the biomarker neuron-specific enolase (NSE) in combination with other predictors of outcome in patients admitted after out-of-hospital cardiac arrest (OHCA). This study sought to investigate the ability of NSE to predict poor outcome in patients remaining unconscious at day three after OHCA. In addition, this study sought to investigate if serial NSE measurements add incremental prognostic information compared to a single NSE measurement at 48 hours in this population.<h4>Methods</h4>This study is a post-hoc sub-study of the TTM trial, randomizing OHCA patients to a course of TTM at either 33°C or 36°C. Patients were included from sites participating in the TTM-trial biobank sub study. NSE was measured at 24, 48 and 72 hours after ROSC and follow-up was concluded after 180 days. The primary end point was poor neurological function or death defined by a cerebral performance category score (CPC-score) of 3 to 5.<h4>Results</h4>A total of 685 (73%) patients participated in the study. At day three after OHCA 63 (9%) patients had died and 473 (69%) patients were not awake. In these patients, a single NSE measurement at 48 hours predicted poor outcome with an area under the receiver operating characteristics curve (AUC) of 0.83. A combination of all three NSE measurements yielded the highest discovered AUC (0.88, p = .0002). Easily applicable combinations of serial NSE measurements did not significantly improve prediction over a single measurement at 48 hours (AUC 0.58-0.84 versus 0.83).<h4>Conclusion</h4>NSE is a strong predictor of poor outcome after OHCA in persistently unconscious patients undergoing TTM, and NSE is a promising surrogate marker of outcome in clinical trials. While combinations of serial NSE measurements may provide an increase in overall prognostic information, it is unclear whether actual clinical prognostication with low false-positive rates is improved by application of serial measurements in persistently unconscious patients. The findings of this study should be confirmed in another prospective cohort.<h4>Trial registration</h4>NCT01020916.
Project description:Neuron specific enolase (NSE) and astroglial protein S100B are associated with outcome following resuscitation from cardiac arrest. We tested whether NSE and S100B levels are associated with illness severity on hospital arrival, and whether levels are independently associated with survival to hospital discharge after adjusting for initial illness severity.Levels of NSE and S100B were obtained at arrival, 6, 12, 24, 48, and 72h after successful resuscitation from cardiac arrest. Clinical data included demographics, Pittsburgh Cardiac Arrest Category (PCAC I-IV) and survival to hospital discharge. Univariable and multivariable predictive models including NSE and S-100B were created to predict survival. ROC analyses were performed to determine sensitivity and specificity of NSE and S-100B at each time interval.Of 77 comatose subjects, 5 did not receive therapeutic hypothermia and were excluded. Mean age was 59 (SD 16) years, with 58% male (N=42), 72% out-of-hospital arrest (N=52), and 43% VF/VT. Survival was 36% (N=26). PCAC IV was associated with higher levels of NSE at 24h (p=0.001) and S100B at 24h (p=0.005). In the multivariate analysis, survival was associated with initial S100B level (OR 0.24; 95% CI 0.07-0.86). NSE values>49.5ng/mL at 48h and NSE values>10.59ng/mL at 72h predicted mortality. S100B levels>0.414ng/mL at 72h predicted mortality.More severe neurologic injury on initial examination is associated with higher levels of NSE and S100B. Elevated levels of S100B immediately following resuscitation were associated with death. Persistently elevated levels of NSE and S100B at 48 and 72h were associated with death.
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.