Targeted temperature management and cardiac arrest after the TTM-2 study

Non peer reviewe

Neuromuscular blockade during therapeutic hypothermia after cardiac arrest: Observational study of neurological and infectious outcomes

AbstractIntroductionNeuromuscular blockade (NMB) is widely used during therapeutic hypothermia (TH) after cardiac arrest but its effect on patient outcomes is unclear. We compared the effects of NMB on neurological outcomes and frequency of early-onset pneumonia in cardiac-arrest survivors managed with TH.MethodsWe retrospectively studied consecutive adult cardiac-arrest survivors managed with TH in a tertiary-level intensive care unit between January 2008 and July 2013. Patients given continuous NMB for persistent shivering were compared to those managed without NMB. Cases of early-onset pneumonia and vital status at ICU discharge were recorded. To avoid bias due to between-group baseline differences, we adjusted the analysis on a propensity score.ResultsOf 311 cardiac-arrest survivors, 144 received TH, including 117 with continuous NMB and 27 without NMBs. ICU mortality was lower with NMB (hazard ratio [HR], 0.54 [0.32; 0.89], p=0.016) but the difference was not significant after adjustment on the propensity score (HR, 0.70 [0.39; 1.25], p=0.22). The proportion of patients with good neurological outcomes was not significantly different (36% with and 22% without NMB, p=0.16). Early-onset pneumonia was more common with NMB (HR, 2.36 [1.24; 4.50], p=0.009) but the difference was not significant after adjustment on the propensity score (HR, 1.68 [0.90; 3.16], p=0.10).ConclusionsContinuous intravenous NMB during TH after cardiac arrest has potential owns effects on ICU survival with a trend increase in the frequency of early-onset pneumonia. Randomised controlled trials are needed to define the role for NMB among treatments for TH-induced shivering

Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest : a systematic review and meta-analysis

Background Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA. Methods We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality. Results Our search identified 6886 studies; 22 studies (n = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75-0.96]; p = 0.008) but not mortality (OR 0.88 [95% CIs 0.62-1.25]; p = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs. Conclusions Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).Peer reviewe

Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial

Background: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. Methods: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale). Results: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26). Conclusions: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever. Keywords: Hypothermia; Out of hospital cardiac arrest; Temperature management; Time to target temperature

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest

ImportanceThe Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens.ObjectivesTo investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA.Design, Setting, and ParticipantsThis study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing.InterventionsRandomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher).Main outcomes and measuresFunctional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes.ResultsAt 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,−0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,−0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%).ConclusionsIn this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common.Trial RegistrationClinicalTrials.gov Identifier: NCT0290830

Epidemiology and outcome predictors in 450 patients with hanging-induced cardiac arrest: a retrospective study

BackgroundCardiac arrest is the most life-threatening complication of attempted suicide by hanging. However, data are scarce on its characteristics and outcome predictors.MethodsThis retrospective observational multicentre study in 31 hospitals included consecutive adults admitted after cardiac arrest induced by suicidal hanging. Factors associated with in-hospital mortality were identified by multivariate logistic regression with multiple imputations for missing data and adjusted to the temporal trends over the study period.ResultsOf 450 patients (350 men, median age, 43 [34–52] years), 305 (68%) had a psychiatric history, and 31 (6.9%) attempted hanging while hospitalized. The median time from unhanging to cardiopulmonary resuscitation was 0 [0–5] min, and the median time to return of spontaneous circulation (ROSC) was 20 [10–30] min. Seventy-nine (18%) patients survived to hospital discharge. Three variables were independently associated with higher in-hospital mortality: time from collapse or unhanging to ROSC>20 min (odds ratio [OR], 4.71; 95% confidence intervals [95%CIs], 2.02–10.96; p = 0.0004); glycaemia >1.4 g/L at admission (OR, 6.38; 95%CI, 2.60–15.66; p < 0.0001); and lactate >3.5 mmol/L at admission (OR, 6.08; 95%CI, 1.71–21.06; p = 0.005). A Glasgow Coma Scale (GCS) score of >5 at admission was associated with lower in-hospital mortality (OR, 0.009; 95%CI, 0.02–0.37; p = 0.0009).ConclusionIn patients with hanging-induced cardiac arrest, time from collapse or unhanging to return of spontaneous circulation, glycaemia, arterial lactate, and coma depth at admission were independently associated with survival to hospital discharge. Knowledge of these risk factors may help guide treatment decisions in these patients at high risk of hospital mortality

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)

Purpose Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Non-AIDS-, non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.publishedVersio

Targeted temperature management after cardiac arrest : better define indications and modalities of implementation

La prise en charge de l’arrêt cardiaque (AC) repose sur les 4 maillons de la chaîne de survie. Le 4ème maillon : la prise en charge spécialisée, correspond aux soins prodigués après la reprise d’activité circulatoire spontanée: l’élément essentiel de la prise en charge consiste alors à limiter le risque de progression des lésions cérébrales, notamment au travers de la mise en œuvre d’un contrôle ciblé de la température (CCT) corporelle. La place et les modalités d’emploi de ce traitement nécessitent néanmoins d’être mieux précisées. Premièrement, nos objectifs étaient de rapporter la fréquence d’utilisation, son évolution au cours du temps ainsi que la possible association avec les modifications du pronostic à la sortie de l’hôpital en fonction de la réalisation ou non d’un CCT. Deuxièmement, notre objectif était de tester l’hypothèse selon laquelle la réalisation d’un CCT à 33°C améliorerait le pronostic neurologique à 3 mois chez des patients victimes d’AC en rythme non choquable en comparaison à un CCT à 37°C. Troisièmement, notre objectif était de rechercher l’existence d’une variation de l’effet du CCT sur le pronostic neurologique à la sortie d’hôpital en fonction de la gravité initiale du patient, appréciée à l’admission en réanimation à l’aide d’un score spécifique. Nous avons inclus les patients victimes d’un AC et admis en réanimation, à partir du registre régional du Centre d’Expertise de la Mort Subite entre 2011 et 2017. L’évolution temporelle des circonstances de survenue et des caractéristiques de prise en charge a été étudiée. L’association entre les variables caractérisant l’AC (notamment CCT) et le pronostic neurologique à la sortie de réanimation a été étudiée à l’aide d’un modèle de régression logistique en incluant l’année de survenue dans le modèle. Puis, nous avons construit, conduit et analysé une étude randomisée contrôlée et ouverte comparant deux stratégies de CCT (33°C versus 37°C) pendant les premières 24 heures chez des patients ayant présenté un AC en rythme non choquable. Enfin, nous avons inclus les patients victimes d’un AC admis vivants en réanimation à partir de 2 cohortes différentes (française et nord-américaine). L’étude de l’association entre le pronostic neurologique à la sortie de réanimation et les circonstances initiales de survenue de l’AC a été réalisée à l’aide d’un modèle de régression logistique stratifié selon 3 classes de gravité distinctes identifiées à l’aide d’un score pronostique. Premièrement, parmi les 3925 patients inclus, on observe que la fréquence d’utilisation du CCT a diminuée au cours de la période d’étude (33% en 2011 vs 15% en 2017; p<0,001). Nous n’avons pas observé d’amélioration du pronostic neurologique au cours de la période d’étude malgré une amélioration de la prise en charge pré-hospitalière de ces patients. Deuxièmement, nous avons inclus 584 patients ayant présenté un AC en rythme non choquable. La réalisation d’un CCT à 33°C a conduit à une amélioration du pronostic neurologique à 3 mois par rapport à une normothermie thérapeutique (évolution favorable : 10,2% vs 5,7% ; p=0,04). Troisièmement, parmi les 2723 patients inclus dans la cohorte française et les 4202 dans la cohorte nord-américaine, on observe une association positive entre la réalisation d’un CCT et le pronostic neurologique à la sortie de l’hôpital. Cette association est statistiquement significative dans les sous-groupes de patients les moins sévères et les plus sévères avec un bénéfice maximal chez les patients les plus sévères (OR 1,94 ; P=0,026 et OR 2,42 ; p=0,021). Nous avons identifié une baisse de la fréquence d’utilisation du CCT depuis 2011. Cette baisse pourrait expliquer l’absence d’amélioration du pronostic neurologique des patients inclus. Cette hypothèse est renforcée par les résultats de notre essai randomisé qui une amélioration significative du pronostic neurologique à 3 mois grâce à la réalisation d’un CCT à 33° après un AC en rythme non choquable.The management of cardiac arrest (CA) is based on a survival chain that includes 4 links. The last link corresponds to the care provided during the first hours after return of spontaneous circulation. During this phase, the essential element of management consists of limiting the risk of progression and aggravation of brain damage, in particular through the implementation of targeted temperature management (TTM). However, the place and modalities of use of this treatment need to be better specified. First, our objectives were to report the frequency of use of TTM, its evolution over time as well as the possible association with changes in neurological prognosis at hospital discharge depending on whether or not a TTM procedure has been carried out. Second, our objective was to test the hypothesis that performing a TTM at 33°C would improve the neurological prognosis at 3 months in patients with CA in non-shockable rhythm compared to TTM at 37°C. Third, our objective was to investigate the existence of a variation in the effect of TTM on neurological prognosis at hospital discharge according to the initial severity of the patient, assessed at admission to intensive care using a specific score. First, we included patients with CA and admitted in intensive care unit, from the Great Paris registry of the Sudden Death Expertise Center between 2011 and 2017. The temporal evolution of the circumstances and the characteristics of management of patients were studied. The association between the variables characterizing the CA and the neurological prognosis at hospital discharge was studied using a logistic regression model including the year of occurrence in the model. Second, we constructed and analyzed a randomized controlled trial conducted in France comparing two strategies of TTM (33°C vs 37°C) in patients suffering from CA with a non-shockable rhythm. Third, we included CA patients admitted alive to resuscitation from 2 different datasets (French regional registry and North American ROC-CCC study). The study of the association between neurological prognosis at hospital discharge and the initial circumstances of CA was conducted using a stratified logistic regression model according to 3 distinct severity classes using a developed and validated prognostic score. First, among 3925 included patients, the frequency of TTM use decreased over the study period (33% in 2011 vs. 15% in 2017; p<0.001). At the same time, we did not observe any improvement in neurological prognosis during the study period (19% vs 23%; p=0.76) despite an improvement in pre-hospital management of these patients. Second, we included 584 patients with non-shockable rhythm over a 4-year period. Achieving a TTM at 33°C led to an improvement in the neurological prognosis at 3 months compared to therapeutic normothermia (favorable neurological evolution 10.2% vs. 5.7%; p=0.04). Third, among 2723 patients and the 4202 included respectively in the French and North American dataset, a positive association was observed between TTM and the neurological prognosis at hospital discharge: this association was statistically significant in the less severe and in the most severe patient subgroups (OR 1.94; P=0.026 and OR 2.42; p=0.021 for each dataset for most severe patients). We have identified a decrease in TTM use since 2011. It could explain the lack of improvement in the neurological prognosis of patients included despite the enhancement in certain elements of pre-hospital management observed. This hypothesis is reinforced by the results of our randomized trial which shows that performing a TTM at 33° after a non-shockable rhythm CA significantly improves the neurological prognosis at 3 months for patients suffering from non-shockable rhythm CA. Last, association between TTM use and neurological prognosis vary depending of initial severity