Pancreatic stone protein as a biomarker for the early diagnosis of post-operative peritonitis, intra-abdominal infection and sepsis.

The diagnosis of intra-abdominal infection and post-operative peritonitis based on clinical examination, biomarkers and radiological signs, should be made as early as possible to improve outcomes and decrease mortality through early and optimal source control, adequate surgery and appropriate antibiotic therapy (Montravers et al. Therapeutic management of peritonitis: a comprehensive guide for intensivists. Intensive Care Med 2016;42:1234-47). However, the indication and the timing of the surgery is often not an easy decision. This case presents the use of a novel early biomarker of infection and sepsis, pancreatic stone protein (Fidalgo et al. Pancreatic stone protein: review of a new biomarker in sepsis. J Clin Med 2022;11:1085), as a tool to aid in the diagnosis of intra-abdominal infection and post-operative peritonitis and to help guide the decision for adequate surgeries in a patient with intra-abdominal infection and post radical prostatectomy peritonitis.

Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS).

BACKGROUND AND PURPOSE: The purpose of this study was to assess nationwide incidence and outcomes of aneurysmal subarachnoid hemorrhage (aSAH). The Swiss SOS (Swiss Study on Subarachnoid Hemorrhage) was established in 2008 and offers the unique opportunity to provide this data from the point of care on a nationwide level. METHODS: All patients with confirmed aneurysmal subarachnoid hemorrhage admitted between January 1, 2009 and December 31, 2014, within Switzerland were recorded in a prospective registry. Incidence rates were calculated based on time-matched population data. Admission parameters and outcomes at discharge and at 1 year were recorded. RESULTS: We recorded data of 1787 consecutive patients. The incidence of aneurysmal subarachnoid hemorrhage in Switzerland was 3.7 per 100 000 persons/y. The number of female patients was 1170 (65.5%). With a follow-up rate of 91.3% at 1 year, 1042 patients (58.8%) led an independent life according to the modified Rankin Scale (0-2). About 1 in 10 patients survived in a dependent state (modified Rankin Scale, 3-5; n=185; 10.4%). Case fatality was 20.1% (n=356) at discharge and 22.1% (n=391) after 1 year. CONCLUSIONS: The current incidence of aneurysmal subarachnoid hemorrhage in Switzerland is lower than expected and an indication of a global trend toward decreasing admissions for ruptured intracranial aneurysms. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03245866.

Protein S100 as outcome predictor after out-of-hospital cardiac arrest and targeted temperature management at 33 °C and 36 °C.

BACKGROUND: We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 °C and 36 °C) on serum levels of S100. METHODS: This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1-2 = good outcome, CPC 3-5 = poor outcome). RESULTS: We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10-0.49) versus 0.08 (IQR 0.06-0.11) µg/ml, 0.16 (IQR 0.10-0.44) versus 0.07 (IQR 0.06-0.11) µg/L, and 0.13 (IQR 0.08-0.26) versus 0.06 (IQR 0.05-0.09) µg/L (p < 0.001), respectively. The ability to predict outcome was best at 24 h with an AUC of 0.80 (95% CI 0.77-0.83). S100 values were higher at 24 and 72 h in the 33 °C group than in the 36 °C group (0.12 [0.07-0.22] versus 0.10 [0.07-0.21] µg/L and 0.09 [0.06-0.17] versus 0.08 [0.05-0.10], respectively) (p < 0.02). In multivariable analyses including baseline variables and the allocated target temperature, the addition of S100 improved the AUC from 0.80 to 0.84 (95% CI 0.81-0.87) (p < 0.001), but S100 was not an independent outcome predictor. Adding S100 to the same model including neuron-specific enolase (NSE) did not further improve the AUC. CONCLUSIONS: The allocated target temperature did not affect S100 to a clinically relevant degree. High S100 values are predictive of poor outcome but do not add value to present prognostication models with or without NSE. S100 measured at 24 h and afterward is of limited value in clinical outcome prediction after OHCA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01020916 . Registered on 25 November 2009.

Single versus Serial Measurements of Neuron-Specific Enolase and Prediction of Poor Neurological Outcome in Persistently Unconscious Patients after Out-Of-Hospital Cardiac Arrest - A TTM-Trial Substudy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. TRIAL REGISTRATION: NCT01020916.

Infectious complications after out-of-hospital cardiac arrest-A comparison between two target temperatures.

BACKGROUND: It has been suggested that target temperature management (TTM) increases the probability of infectious complications after cardiac arrest. We aimed to compare the incidence of pneumonia, severe sepsis and septic shock after out-of-hospital cardiac arrest (OHCA) in patients with two target temperatures and to describe changes in biomarkers and possible mortality associated with these infectious complications. METHODS: Post-hoc analysis of the TTM-trial which randomized patients resuscitated from OHCA to a target temperature of 33°C or 36°C. Prospective data on infectious complications were recorded daily during the ICU-stay. Pneumonia, severe sepsis and septic shock were considered infectious complications. Procalcitonin (PCT) and C-reactive-protein (CRP) levels were measured at 24h, 48h and 72h after cardiac arrest. RESULTS: There were 939 patients in the modified intention-to-treat population. Five-hundred patients (53%) developed pneumonia, severe sepsis or septic shock which was associated with mortality in multivariate analysis (Hazard ratio [HR] 1.39; 95%CI 1.13-1.70; p=0.001). There was no statistically significant difference in the incidence of infectious complications between temperature groups (sub-distribution hazard ratio [SHR] 0.88; 95%CI 0.75-1.03; p=0.12). PCT and CRP were significantly higher for patients with infections at all times (p<0.001), but there was considerable overlap. CONCLUSIONS: Patients who develop pneumonia, severe sepsis or septic shock after OHCA might have an increased mortality. A target temperature of 33°C after OHCA was not associated with an increased risk of infectious complications compared to a target temperature of 36°C. PCT and CRP are of limited value for diagnosing infectious complications after cardiac arrest.

Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest - an analysis of the TTM trial data.

BACKGROUND: Targeted temperature management is recommended after out-of-hospital cardiac arrest and may be achieved using a variety of cooling devices. This study was conducted to explore the performance and outcomes for intravascular versus surface devices for targeted temperature management after out-of-hospital cardiac arrest. METHOD: A retrospective analysis of data from the Targeted Temperature Management trial. N = 934. A total of 240 patients (26%) managed with intravascular versus 694 (74%) with surface devices. Devices were assessed for speed and precision during the induction, maintenance and rewarming phases in addition to adverse events. All-cause mortality, as well as a composite of poor neurological function or death, as evaluated by the Cerebral Performance Category and modified Rankin scale were analysed. RESULTS: For patients managed at 33 °C there was no difference between intravascular and surface groups in the median time taken to achieve target temperature (210 [interquartile range (IQR) 180] minutes vs. 240 [IQR 180] minutes, p = 0.58), maximum rate of cooling (1.0 [0.7] vs. 1.0 [0.9] °C/hr, p = 0.44), the number of patients who reached target temperature (within 4 hours (65% vs. 60%, p = 0.30); or ever (100% vs. 97%, p = 0.47), or episodes of overcooling (8% vs. 34%, p = 0.15). In the maintenance phase, cumulative temperature deviation (median 3.2 [IQR 5.0] °C hr vs. 9.3 [IQR 8.0] °C hr, p = <0.001), number of patients ever out of range (57.0% vs. 91.5%, p = 0.006) and median time out of range (1 [IQR 4.0] hours vs. 8.0 [IQR 9.0] hours, p = <0.001) were all significantly greater in the surface group although there was no difference in the occurrence of pyrexia. Adverse events were not different between intravascular and surface groups. There was no statistically significant difference in mortality (intravascular 46.3% vs. surface 50.0%; p = 0.32), Cerebral Performance Category scale 3-5 (49.0% vs. 54.3%; p = 0.18) or modified Rankin scale 4-6 (49.0% vs. 53.0%; p = 0.48). CONCLUSIONS: Intravascular and surface cooling was equally effective during induction of mild hypothermia. However, surface cooling was associated with less precision during the maintenance phase. There was no difference in adverse events, mortality or poor neurological outcomes between patients treated with intravascular and surface cooling devices. TRIAL REGISTRATION: TTM trial ClinicalTrials.gov number https://clinicaltrials.gov/ct2/show/NCT01020916 NCT01020916; 25 November 2009.

Usefulness of Serum B-Type Natriuretic Peptide Levels in Comatose Patients Resuscitated from Out-of-Hospital Cardiac Arrest to Predict Outcome.

N-terminal pro-B-type natriuretic (NT-proBNP) is expressed in the heart and brain, and serum levels are elevated in acute heart and brain diseases. We aimed to assess the possible association between serum levels and neurological outcome and death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Of the 939 comatose OHCA patients enrolled and randomized in the Targeted Temperature Management (TTM) trial to TTM at 33°C or 36°C for 24 hours, 700 were included in the biomarker substudy. Of these, 647 (92%) had serum levels of NT-proBNP measured 24, 48, and 72 hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by the Cerebral Performance Category (CPC) score and modified Rankin Scale (mRS) at 6 months. Six hundred thirty-eight patients (99%) had serum NT-proBNP levels ≥125 pg/ml. Patients with TTM at 33°C had significantly lower NT-proBNP serum levels (median 1,472 pg/ml) than those in the 36°C group (1,914 pg/ml) at 24 hours after ROSC, p <0.01 but not at 48 and 72 hours. At 24 hours, an increase in NT-proBNP quartile was associated with death (Plogrank <0.0001). In addition, NT-proBNP serum levels > median were independently associated with poor neurological outcome (odds ratio, ORCPC 2.02, CI 1.34 to 3.05, p <0.001; ORmRS 2.28, CI 1.50 to 3.46, p <0.001) adjusted for potential confounders. The association was diminished at 48 and 72 hours after ROSC. In conclusion, NT-proBNP serum levels are increased in comatose OHCA patients. Furthermore, serum NT-proBNP levels are affected by level of TTM and are associated with death and poor neurological outcome.

A low body temperature on arrival at hospital following out-of-hospital-cardiac-arrest is associated with increased mortality in the TTM-study.

AIM: To investigate the association of temperature on arrival to hospital after out-of-hospital-cardiac arrest (OHCA) with the primary outcome of mortality, in the targeted temperature management (TTM) trial. METHODS: The TTM trial randomized 939 patients to TTM at 33 or 36°C for 24h. Patients were categorized according to their recorded body temperature on arrival and also categorized to groups of patients being actively cooled or passively rewarmed. RESULTS: OHCA patients having a temperature ≤34.0°C on arrival at hospital had a significantly higher mortality compared to the OHCA patients with a higher temperature on arrival. A low body temperature on arrival was associated with a longer time to return of spontaneous circulation (ROSC) and duration of transport time to hospital. Patients who were actively cooled or passively rewarmed during the first 4h had similar mortality. In a multivariate logistic regression model mortality was significantly related to time from OHCA to ROSC, time from OHCA to advanced life support (ALS), age, sex and first registered rhythm. None of the temperature related variables (included the TTM-groups) were significantly related to mortality. CONCLUSION: OHCA patients with a temperature ≤34.0°C on arrival have a higher mortality than patients with a temperature ≥34.1°C on arrival. A low temperature on arrival is associated with a long time to ROSC. Temperature changes and TTM-groups were not associated with mortality in a regression model.

Standardized EEG interpretation accurately predicts prognosis after cardiac arrest.

OBJECTIVE: To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society. METHODS: In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3-5 until 180 days. RESULTS: Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG feature had a low specificity to predict poor prognosis (48%) but if 2 malignant EEG features were present specificity increased to 96% (p < 0.001). Specificity and sensitivity were not significantly affected by targeted temperature or sedation. A benign EEG was found in 1% of the patients with a poor outcome. CONCLUSIONS: Highly malignant EEG after rewarming reliably predicted poor outcome in half of patients without false predictions. An isolated finding of a single malignant feature did not predict poor outcome whereas a benign EEG was highly predictive of a good outcome.

Predictive value of interleukin-6 in post-cardiac arrest patients treated with targeted temperature management at 33 °C or 36 °C.

AIM: Post-cardiac arrest syndrome (PCAS) is characterized by systemic inflammation, however data on the prognostic value of inflammatory markers is sparse. We sought to investigate the importance of systemic inflammation, assessed by interleukin-6 (IL-6) in comatose survivors of out-of-hospital cardiac arrest. METHODS: A total of 682 patients enrolled in the Target Temperature Management (TTM) trial, surviving >24h with available IL-6 data were included. IL-6 was measured on days 1, 2 and 3 after return of spontaneous circulation. Severity of PCAS was assessed daily by the Sequential Organ Failure Assessment score. Survival status was recorded at 30 days. RESULTS: High levels of IL-6 at day 1-3 (all p<0.0001) were independently associated with severity of PCAS with no interaction of target temperature (all p=NS). IL-6 levels did not differ between temperature groups (p(interaction)=0.99). IL-6 levels at day 2 (p<0.0001) and day 3 (p<0.0001) were associated with crude mortality. Adjusted Cox proportional-hazards analysis showed that a two-fold increase of IL-6 levels at day 2 (HR=1.15 (95% CI: 1.07-1.23), p=0.0002) and day 3 (HR=1.18 (95% CI: 1.09-1.27), p<0.0001) were associated with mortality. IL-6 levels at day 3 had the highest discriminative value in predicting mortality (AUC=0.66). IL-6 did not significantly improve 30-day mortality prediction compared to traditional prognostic factors (p=0.08). CONCLUSIONS: In patients surviving >24h following cardiac arrest, IL-6 levels were significantly elevated and associated with severity of PCAS with no significant influence of target temperature. High IL-6 levels were associated with increased mortality. Measuring levels of IL-6 did not provide incremental prognostic value.

Time to start of cardiopulmonary resuscitation and the effect of target temperature management at 33°C and 36°C.

INTRODUCTION: The optimal temperature during targeted temperature management (TTM) for comatose patients resuscitated from out-of-hospital cardiac arrest is unknown. It has been hypothesized that patients with long no-flow times, for example those without bystander CPR would have the most to gain from temperature management at lower temperatures. METHODS: We analysed data from an international clinical trial randomizing cardiac arrest patients to targeted temperature management at 33°C and 36°C for an interaction between no-flow time and intervention group, with neurological function at six months after cardiac arrest as the primary outcome. A cerebral performance category (CPC) score of 1 or 2 was considered a good outcome. RESULTS: No-flow time (min) was associated with poor neurological outcome (OR 1.13, 95% confidence interval 1.06-1.20, p<0.001). There was no statistically significant interaction between no flow-time and intervention group (p=0.11), which may imply that the non-superior effect of 33°C was consistent for all no-flow times. Bystander CPR was not independently associated with neurological function. CONCLUSIONS: TTM at 33°C compared to 36°C was not associated with an increased probability of a good neurological function for patients with longer no-flow times.

Successful heart transplantation after prolonged cardiac arrest and extracorporeal life support in organ donor-a case report.

BACKGROUND: Although heart transplantation is a successful therapy for patients suffering from end-stage heart failure, the therapeutic is limited by the lack of organs. Donor cardiac arrest is a classic hindrance to heart retrieval as it raises issues on post-transplant outcomes. CASE PRESENTATION: The present case reports a successful heart transplantation after prolonged donor cardiac arrest (total lowflow time of 95 minutes) due to anaphylactic shock necessitating extracorporeal life support. We further provide an overview of the current evidence and outcomes of heart transplantation in cases of donor cardiac arrest. CONCLUSION: Providing that donor and recipient criteria are respected, donor cardiac arrest does not seem to be an adverse predictor in heart transplantation.

No difference in mortality between men and women after out-of-hospital cardiac arrest.

AIM: Comparing the outcome after out-of-hospital cardiac arrest (OHCA) in men and women and to determine whether sex modifies the effect of targeted temperature management (TTM) at 33 or 36°C. METHODS: The TTM trial randomized 950 patients to TTM at 33 or 36°C for 24h. This predefined sub-study of the TTM trial assessed survival and neurological outcome defined as Cerebral Performance Category (CPC) and modified Rankin Scale (mRS) using female sex as main predictor of outcome, in relation to level of TTM and other confounding factors. RESULTS: Compared to men, women more often had OHCA at home, p=0.04 and less often had bystander defibrillation, p=0.01. No other differences in arrest circumstances were found. Coronary angiography (CAG) and percutaneous coronary intervention (PCI) <24h after ROSC was less often performed in women, both: p=0.02. Female sex was associated with higher mortality in univariate analysis, hazard ratio (HR)=1.29, CI=1.04-1.61, p=0.02 compared to men. Adjusting for demographic factors (age and comorbidity), arrest circumstances, pre-hospital findings, inclusion sites, treatments and status at admission reduced this: HR=1.11, CI=0. 87-1.41, p=0.42, and sex was no longer an independent risk factor for death. The effect of sex did not modify the effect of TTM at 33 and 36°C, pinteraction=0.73. CONCLUSION: Female sex seems associated with adverse outcome, but this association is largely explained by differences in arrest circumstances and in-hospital treatment. Our data shows no interaction between sex and the effect of targeting 33 vs. 36°C.

Clinical features and viral kinetics in a rapidly cured patient with Ebola virus disease: a case report.

BACKGROUND: A detailed description of viral kinetics, duration of virus shedding, and intraviral evolution in different body sites is warranted to understand Ebola virus pathogenesis. Patients with Ebola virus infections admitted to university hospitals provide a unique opportunity to do such in-depth virological investigations. We describe the clinical, biological, and virological follow-up of a case of Ebola virus disease. METHODS: A 43-year-old medical doctor who contracted an Ebola virus infection in Sierra Leone on Nov 16, 2014 (day 1), was airlifted to Geneva University Hospitals, Geneva, Switzerland, on day 5 after disease onset. The patient received an experimental antiviral treatment of monoclonal antibodies (ZMAb) and favipiravir. We monitored daily viral load kinetics, estimated viral clearance, calculated the half-life of the virus in plasma, and analysed the viral genome via high-throughput sequencing, in addition to clinical and biological signs. FINDINGS: The patient recovered rapidly, despite an initial high viral load (about 1 × 10(7) RNA copies per mL 24 h after onset of fever). We noted a two-phase viral decay. The virus half-life decreased from about 26 h to 9·5 h after the experimental antiviral treatment. Compared with a consensus sequence of June 18, 2014, the isolate that infected this patient displayed only five synonymous nucleotide substitutions on the full genome (4901A→C, 7837C→T, 8712A→G, 9947T→C, 16201T→C) despite 5 months of human-to-human transmission. INTERPRETATION: This study emphasises the importance of virological investigations to fully understand the course of Ebola virus disease and adaptation of the virus. Whether the viral decay was caused by the effects of the immune response alone, an additional benefit from the antiviral treatment, or a combination of both is unclear. In-depth virological analysis and randomised controlled trials are needed before any conclusion on the potential effect of antiviral treatment can be drawn. FUNDING: Geneva University Hospitals, Swiss Office of Public Health, Swiss Agency for Development and Cooperation, and Swiss National Science Foundation.

Percutaneous Aortic Balloon Valvuloplasty and Intracardiac Adrenaline in Electromechanical Dissociation as Bridge to Transcatheter Aortic Valve Implantation.

This report describes an emergent balloon aortic valvuloplasty (BAV) procedure performed under cardiopulmonary resuscitation in a 79-year-old man with severe symptomatic aortic stenosis (mean gradient 78 mm Hg, valve area 0.71 cm, and left ventricular ejection fraction 40%) awaiting surgery and who was admitted for heart failure rapidly evolving to cardiogenic shock and multiorgan failure. Decision was made to perform emergent BAV. After crossing the valve with a 6 French catheter, the patient developed an electromechanical dissociation confirmed at transesophageal echocardiography and cardiac arrest. Manual chest compressions were initiated along with the application of high doses of intravenous adrenaline, and BAV was performed under ongoing resuscitation. Despite BAV, transoesophageal echocardiography demonstrated no cardiac activity. At this point, it was decided to advance a pigtail catheter over the wire already in place in the left ventricle and to inject intracardiac adrenaline (1 mg, followed by 5 mg). Left ventricular contraction progressively resumed and, in the absence of aortic regurgitation, an intraaortic balloon pump was inserted. The patient could be weaned from intraaortic balloon pump and vasopressors on day 1, extubated on day 6, and recovered from multiorgan failure. In the absence of neurologic deficits, he underwent uneventful transcatheter aortic valve implantation on day 12 and was discharged to a cardiac rehabilitation program on day 30. At 3-month follow-up, he reported dyspnea NYHA class II as the only symptom.This case shows that severe aortic stenosis leading to electromechanical dissociation may be treated by emergent BAV and intracardiac administration of high-dose adrenaline. Intracardiac adrenaline may be considered in case of refractory electromechanical dissociation occurring in the cardiac catheterization laboratory.

Impact of time to return of spontaneous circulation on neuroprotective effect of targeted temperature management at 33 or 36 degrees in comatose survivors of out-of hospital cardiac arrest.

AIM: Time to Return of Spontaneous Circulation (ROSC) has a plausible relation to severity of hypoxic injury before and during resuscitation in Out-of-Hospital Cardiac Arrest (OHCA), and has consistently been associated with adverse outcome. The effect of Targeted Temperature Management (TTM) may not be similar over the full spectrum of time to ROSC. This study investigated the possible beneficial effect of targeting 33°C over 36°C on the prognostic importance of time to ROSC. METHODS: In predefined sub-study of the TTM-trial (NEJM 2013) we investigated the relationship between time to ROSC, level of TTM and mortality and neurological outcome as assessed by the Cerebral Performance Category (CPC) scale and modified Rankin Scale (mRS) after 180 days. RESULTS: Prolonged time to ROSC was significantly associated with increased mortality with a hazard ratio (HR) of 1.02 per minute (95% CI 1.01-1.02). Level of TTM did not modify the association of time to ROSC and mortality, pinteraction=0.85. Prolonged time to ROSC was associated with reduced odds of surviving with a favorable neurological outcome for CPC (p=0.008 for CPC 1-2) and mRS (p=0.17, mRS 0-3) with no significant interaction with level of TTM. CONCLUSION: Time to ROSC remains a significant prognostic factor in comatose OHCA patients with regards to risk of death and risk of adverse neurological outcome. For any time to ROSC, targeting 33°C in TTM was not associated with benefit with regards to reducing mortality or risk of adverse neurological outcome compared to targeting 36°C.

Neuron-Specific Enolase as a Predictor of Death or Poor Neurological Outcome After Out-of-Hospital Cardiac Arrest and Targeted Temperature Management at 33°C and 36°C.

BACKGROUND: Neuron-specific enolase (NSE) is a widely-used biomarker for prognostication of neurological outcome after cardiac arrest, but the relevance of recommended cutoff values has been questioned due to the lack of a standardized methodology and uncertainties over the influence of temperature management. OBJECTIVES: This study investigated the role of NSE as a prognostic marker of outcome after out-of-hospital cardiac arrest (OHCA) in a contemporary setting. METHODS: A total of 686 patients hospitalized after OHCA were randomized to targeted temperature management at either 33°C or 36°C. NSE levels were assessed in blood samples obtained 24, 48, and 72 h after return of spontaneous circulation. The primary outcome was neurological outcome at 6 months using the cerebral performance category score. RESULTS: NSE was a robust predictor of neurological outcome in a baseline variable-adjusted model, and target temperature did not significantly affect NSE values. Median NSE values were 18 ng/ml versus 35 ng/ml, 15 ng/ml versus 61 ng/ml, and 12 ng/ml versus 54 ng/ml for good versus poor outcome at 24, 48, and 72 h, respectively (p < 0.001). At 48 and 72 h, NSE predicted neurological outcome with areas under the receiver-operating curve of 0.85 and 0.86, respectively. High NSE cutoff values with false positive rates ≤5% and tight 95% confidence intervals were able to reliably predict outcome. CONCLUSIONS: High, serial NSE values are strong predictors of poor outcome after OHCA. Targeted temperature management at 33°C or 36°C does not significantly affect NSE levels. (Target Temperature Management After Cardiac Arrest [TTM]; NCT01020916).

Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

IMPORTANCE: Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE: To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS: Targeted temperature management at 33°C vs 36°C. MAIN OUTCOMES AND MEASURES: Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS: In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE: Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales. TRIAL REGISTRATION: ClinicalTrials.gov NCT01020916.

Target temperature management of 33°C and 36°C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm - a TTM sub-study.

PURPOSE: Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR. METHODS: Hundred and seventy-eight patients out of 950 in the TTM trial with an initial NSR were randomly assigned to targeted temperature management at either 33°C (TTM33, n=96) or 36°C (TTM36, n=82). We assessed mortality, neurologic function (Cerebral Performance Score (CPC) and modified Rankin Scale (mRS)), and organ dysfunction (Sequential Organ Failure Assessment (SOFA) score). RESULTS: Patients with NSR were older, had longer time to ROSC, less frequently had bystander CPR and had higher lactate levels at admission compared to patients with shockable rhythm, p<0.001 for all. Mortality in patients with NSR was 84% in both temperature groups (unadjusted HR 0.92, adjusted HR 0.75; 95% CI 0.53-1.08, p=0.12). In the TTM33 group 3% survived with poor neurological outcome (CPC 3-4, mRS 4-5), compared to 2% in the TTM36 group (adjusted OR 0.67; 95% CI 0.08-4.73, p=0.69 for both). Thirteen percent in the TTM33 group and 15% in the TTM36 group had good neurologic outcome (CPC 1-2, mRS 0-3, OR 1.5, CI 0.21-12.5, p=0.69). The SOFA-score did not differ between temperature groups. CONCLUSION: Comatose patients after OHCA with initial NSR continue to have a poor prognosis. We found no effect of targeted temperature management at 33°C compared to 36°C in these patients.