Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial

Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial Ameldina Ceric, Josef Dankiewicz, Tobias Cronberg, Joachim Düring, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6155229/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jun, 2025 Read the published version in Critical Care → Version 1 posted 6 You are reading this latest preprint version Abstract Background : The routine use of sedation and analgesia during post-cardiac arrest care and its association with clinical outcomes remain unclear. This study aimed to describe the use of sedatives and analgesics in post-cardiac arrest care, and evaluate associations with good functional outcome, survival, clinical seizures, and late awakening. Methods : This was a post hoc analysis of the TTM2-trial, which randomised 1900 out-of-hospital cardiac arrest patients to either normothermia or hypothermia. In both groups, deep sedation (Richmond Agitation and Sedation Scale ≤-4) was mandatory during the 40-hour intervention. Cumulative doses of sedatives and analgesic drugs were recorded within the first 72 hours from randomization. Outcomes were functional outcome (modified Rankin Scale) and survival status at 6 months, occurrence of clinical seizures during the intensive care stay, and late awakening (Full outline of unresponsiveness motor score of four 96 hours after randomization). Cumulative propofol doses were divided into quartiles (Q1-Q4). Logistic regression models were used to assess associations between sedative doses and functional outcome and survival, clinical seizures, and late awakening, adjusting for the severity of illness and other clinical factors influencing sedation. Results : A total of 1861 patients were analysed. In a multivariable logistic regression model, higher propofol doses (Q3, 100.7-153.6 mg/kg) were associated with good functional outcome (OR 1.62, 95%CI 1.12 - 2.34) and (Q2 and Q3, 43.9-153.6 mg/kg) with survival (OR 1.49, 95%CI 1.05 - 2.12 and OR 1.84, 95%CI 1.27 - 2.65, respectively). Receiving fentanyl and remifentanil were associated with good functional outcome (OR 1.69, 95%CI 1.27 - 2.26 and OR 1.50, 95%CI 1.11 - 2.02) and survival (OR 1.80, 95%CI 1.35 - 2.40 and OR 1.56, 95%CI 1.16 - 2.10). Receiving fentanyl (OR 0.64, 95%CI 0.48 - 0.86) and higher propofol doses (Q2-4 (43.9-669.4 mg/kg) were associated with the occurrence of clinical seizures. The highest quartile of propofol dose (153.7-669.4 mg/kg, OR 3.19, 95%CI 1.91 - 5.42) was associated with late awakening. Conclusions : In this study, higher doses of propofol and the use of remifentanil and fentanyl were associated with good functional outcome and survival, occurrence of clinical seizures, and late awakening. Cardiac arrest Targeted temperature management Sedation Seizures Propofol Midazolam Figures Figure 1 Introduction The majority of patients unconscious after out-of-hospital cardiac arrest (OHCA) receive intensive care treatment and targeted temperature management (TTM) [ 1 , 2 ]. TTM and fever management are recommended to mitigate hypoxic-ischemic brain injury and improve functional outcomes, with sedation and analgesia provided during post-cardiac arrest care to reduce discomfort induced by lowering the body temperature, facilitate therapy, reduce shivering, and prevent awareness during neuromuscular blockade [ 3 – 5 ]. About one third of cardiac arrest patients develop seizures, which are associated with poor outcomes, however, causal relationship with the degree of hypoxic-ischemic brain injury has not been established [ 6 , 7 ]. Sedatives, some of which are also potent antiepileptic agents, may mitigate secondary brain injury and optimize neurological recovery by lowering metabolic rate and intracranial pressure [ 8 , 9 ]. Thus, in clinical practice, sedation is often increased when a patient is having clinical seizures or shows signs of pain and agitation. Sedation carries inherent risks, including compromised circulatory and respiratory functions, increased risk of delirium, prolonged mechanical ventilation, and intensive care stay [ 10 – 13 ]. Importantly, for patients with cardiac arrest, sedation may confound neurological prognostication, influencing the decision on withdrawal of life-sustaining therapies [ 14 , 15 ]. This study investigates the association between the use of sedatives and analgesics and outcomes, including functional, mortality, clinical seizure, and time to awakening in a large multicenter trial. We hypothesized that there is an association between higher doses of sedatives and analgesics and long-term good functional outcome, survival, occurrence of clinical seizures, and late awakening. Methods Setting and participants The TTM2-trial (Clinicaltrials.gov NCT02908308) was an international, multicenter, parallel group, investigator-initiated trial randomizing 1900 adult patients between November 2017 and January 2020, with an OHCA of presumed cardiac cause to targeted hypothermia (33°C) (hypothermia) or normothermia with early treatment of fever ( 18 years) patients with a presumed cardiac cause and ROSC were eligible for inclusion. The main exclusion criteria were time from ROSC to screening of more than 180 minutes, unwitnessed cardiac arrest with asystole as the initial rhythm and limitations in care [ 16 ]. This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (Supplement Table 1 ) [ 17 ]. Table 1 Background and cardiac arrest characteristics. Overall Comatose patients at 96 hours without clinical seizures n 1861 463 Male (%) 1477 (79.4) 378 (81.6) Age (mean (SD)) 63.8 (13.6) 65.5 (12.5) Frailty score (median (IQR)) 2 (1) 2.8 (1.3) Body mass index (mean (SD)) 27.5 (5.7) 27.8 (5.7) Circulatory shock on admission 1 (%) 536 (28.8) 143 (30.9) Minutes to ROSC (mean (SD)) 31 (20) 30 (18) Initial shockable rhythm (%) 1371 (73.7) 351 (75.8) Bystander CPR (%) 1487 (79.9) 372 (80.3) Previous liver disease (%) 43 (2.3) 15 (3.2) Previous renal disease (%) 92 (4.9) 32 (6.9) Previous cerebrovascular disease (%) 120 (6.4) 29 (6.3) Admission FOUR motor (%) 0 No response to pain 1463 (86.3) 374 (86.6) 1 Extension response to pain 54 (3.2) 11 (2.5) 2 Flexion response to pain 113 (6.7) 30 (6.9) 3 Localizes pain 61 (3.6) 16 (3.7) 4 Awake and obeying commands 5 (0.3) 1 (0.2) 1 Circulatory shock at admission was defined as a systolic blood pressure of 30 minutes or end-organ hypoperfusion (cool arms and legs, urine output < 30 ml/hour, and heart rate < 60 beats/minute). Patient management Patients assigned to hypothermia were cooled to 33°C, and this temperature was maintained for 28 hours, followed by rewarming to 37°C for 12 hours (intervention period). In the normothermia group, the aim was to maintain a temperature of 37.5°C or less. After the intervention period, normothermia was maintained until 72 hours after randomization in all patients who remained unconscious, and sedation was discontinued or tapered according to clinical state. Extubation and wake-up test was attempted at the earliest time possible after the intervention period (40 hours), based on standard protocols for discontinuation of mechanical ventilation [ 18 ]. Multimodal neurological prognostication was performed by a physician blinded to the intervention no earlier than 96 hours after randomization, with strict criteria according to the TTM2-trial study protocol [ 18 ]. Decision of withdrawal of life-sustaining therapy (WLST) was at the discretion of the treating physician [ 18 ]. Neuron-specific enolase (NSE) sampling was optional and conducted at sites with relevant expertise. The highest NSE value was recorded. Bilirubin and glomerular filtration rate (GFR) were measured daily during the first week of intensive care. Sedative and analgesic drugs During the intervention period of 40 hours, deep sedation, defined as Richmond Agitation and Sedation Scale (RASS) -4 to -5, was mandatory in both groups and provided similar treatment in both groups [ 19 ] (Supplement Table 2 ). The trial protocol recommended short-acting drugs, but to comply with the pragmatic nature of the trial was left to the treating physician's discretion or local protocol. Type of drug and cumulative dosing of each sedative and analgesic drug administered up to 72 hours after randomization were recorded as follows: midazolam (mg), propofol (mg), dexmedetomidine (mcg), clonidine (mcg), esketamine (mg), ketamine (mg), fentanyl (mcg), morphine (mg), remifentanil (mcg) and oxycodone (mg). In patients in whom neurological prognostication was performed, time of discontinuation of sedatives was recorded. Table 2 Clinical variables and outcomes. Overall Comatose patients at 96 hours without clinical seizures n 1861 463 Normothermia (%) 931 (50.0) 228 (49) Early discontinuation of TTM (%) 300 (16.6) 21 (4.6) Shivering 2 (%) 632 (34.9) 157 (34.7) Clinical seizures (%) 3 464 (25.1) 0 (0.0) Highest NSE 3 (mean (SD)) 88.5 (161.5) 74.4 (114.5) Lowest GFR (mean (SD)) 57.7 (26.8) 54.5 (25.8) Highest bilirubin (mean (SD)) 20.4 (27.6) 21.3 (30.0) Time to extubation, days (median (IQR)) 3.5 (1.9, 5.9) 6.6 (4.7, 11.1) Time to wake-up, days 4 (median (IQR)) 2.5 (1.8, 4.4) 5.6 (4.4, 8.2) Neurological prognostication performed according to protocol (%) 883 (47.5) 359 (77.5) Poor prognosis likely at time of neurological prognostication (%) 264 (29.5) 90 (24.9) Time of sedation discontinued before prognostication, hours (median (IQR)) 14.0 (1.0, 48.0) 6.0 (1.0, 46.5) ICU length of stay, days (median (IQR)) 4.9 (2.9, 8.1) 8.7 (5.8, 13.8) Good neurological outcome (mRS 4–6), n (%) 873 (47.0) 177 (38.2) Survival at six months, n (%) 950 (50.8) 262 (56.8) 1 Discontinuation of TTM any time during the intervention period of 40 hours. 2 The occurrence of shivering during up to 72 hours. 3 Highest NSE measurement during the ICU stay. Measured in 1018 out of 1861 patients. 4 Data available in 979 patients out of 1861. Abbreviations: TTM = Target temperature management, NSE = Neuron specific enolase, GFR = Glomerular filtration rate, ICU = intensive care unit, SD = standard deviation. Shivering was assessed daily during the intensive care stay using the bedside shivering assessment scale (BSAS) [ 20 ] (Supplement Table 3 ). Shivering was defined as BSAS > 1 anytime up to 72 hours after randomization. Prophylactic acetaminophen/paracetamol was recommended. In response to a BSAS > 1, the first measure taken was to increase sedation, and secondarily to administer neuromuscular blocking agent at the discretion of the treating physician The goal was to maintain BSAS 0–1. Table 3 Total doses of sedatives, analgesics, and neuromuscular blockade up to 72 hours Good Poor 841 988 Propofol, mg/kg (mean (SD)) 115.0 (72.2) 98.0 (79.3) Propofol, n (%) 767 (91%) 815 (82%) Midazolam, mg/kg (mean (SD)) 2.9 (3.4) 2.7 (6.2) Midazolam, n (%) 324 (38%) 372 (38%) Midazolam and propofol, n (%) 272 (32%) 271 (27%) Midazolam only, n (%) 52 (6%) 101 (10%) Remifentanil, mcg/kg (mean (SD)) 1.2 (3.92) 0.7 (2.33) Remifentanil, n (%) 297 (35%) 335 (34%) Fentanyl, mcg/kg (mean (SD)) 0.4 (3.94) 0.3 (2.91) Fentanyl, n (%) 494 (60%) 456 (47%) Dexmedetomidine, mcg/kg (mean (SD)) 0.02 (0.04) 0.02 (0.02) Dexmedetomidine, n (%) 113 (14%) 26 (3%) Oxycodone, mg/kg (mean (SD)) 0.3 (0.37) 0.3 (0.41) Oxycodone, n (%) 77 (9%) 35 (4%) Morphine, mg/kg (mean (SD)) 0.8 (1.5) 1.2 (2.3) Morphine, n (%) 101 (12%) 120 (12%) Any neuromuscular blockade, n (%) 483 (57%) 529 (53%) Primary outcome A good functional outcome was defined as a modified Rankin Scale (mRS) 0–3 at six months. The mRS ranges from 0 to 6, with 0 representing no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death [ 21 ]. Secondary outcomes Survival Survival status was recorded by six months follow-up. Clinical seizures Clinical seizures were defined as myoclonus or tonic-clonic seizures, which were assessed daily and recorded as present or absent during the intensive care stay up to seven days after randomization. Seizures were managed according to local protocols, at the discretion of the treating physician. Time to awakening Awakening was defined as obeying commands, i.e. Full Outline of Unresponsiveness (FOUR) (Supplement Table 4 ) score motor component of four [ 22 ]. FOUR score was recorded daily during the first seven days of intensive care. Time to awakening was recorded, with late awakening defined as occurring after 96 hours. Table 4 Multivariable logistic regression and chi-square analysis of clinical factors, sedation, and analgesics on functional outcome, survival, clinical seizures, and late awakening. Association of clinical factors, TTM, and total dose of propofol up to 72 hrs with good functional outcome (mRS 0–3) at six months follow up, survival at six months, clinical seizures, and late awakening in multivariate regression model. Good functional outcome Survival Variable OR CI p OR CI p Normothermia 0.84 0.65–1.08 0.176 0.98 0.76–1.26 0.872 Propofol dose (mg/kg)* 0.01 0.001 Propofol quartile 1 (0.01–43.8 mg/kg) - - - - - - Propofol quartile 2 (43.9-100.6 mg/kg) 1.38 0.96–2.00 0.08 1.49 1.05–2.12 0.025 Propofol quartile 3 (100.7-153.6 mg/kg) 1.62 1.12–2.34 0.01 1.84 1.27–2.65 0.001 Propofol quartile 4 (153.7-669.4 mg/kg) 1.04 0.71–1.51 0.825 1.28 0.88–1.85 0.192 Midazolam 1.01 0.77–1.33 0.943 1.10 0.84–1.45 0.49 Fentanyl 1.69 1.27–2.26 < 0.001 1.80 1.35–2.40 < 0.001 Remifentanil 1.50 1.11–2.02 0.008 1.56 1.16–2.10 0.003 Clinical seizures Late awakening Normothermia 0.75 0.58–0.96 0.022 0.57 0.40–0.81 0.002 Propofol dose (mg/kg)* < 0.001 < 0.001 Propofol quartile 1 (0.01–43.8 mg/kg) - - - - - - Propofol quartile 2 (43.9-100.6 mg/kg) 1.53 1.06–2.2 0.022 0.78 0.46–1.34 0.369 Propofol quartile 3 (100.7-153.6 mg/kg) 1.56 1.06–2.29 0.023 1.33 0.80–2.23 0.279 Propofol quartile 4 (153.7-669.4 mg/kg) 2.82 1.94–4.11 < 0.001 3.19 1.91–5.42 < 0.001 Midazolam 1.99 1.52–2.61 < 0.001 1.98 1.38–2.86 < 0.001 Fentanyl 0.64 0.48–0.86 0.003 1.26 0.86–1.86 0.246 Remifentanil 1.19 0.89–1.59 0.245 1.20 0.82–1.77 0.352 The multivariable regression model is including variables: age, male sex, time to return of spontaneous circulation, witnessed arrest, shock on admission, shockable rhythm, normothermia, shivering or neuromuscular blockade, lowest glomerular filtration rate, and highest bilirubin. Abbreviations: OR = Odds ratio, conf = Confidence interval, p = p-value. *Analysed using Analysis of Variance (ANOVA) Statistical analyses Patient and cardiac arrest characteristics were used to describe the study cohort. Clinical variables such as temperature management strategy, sedation and analgesia use, intensive care interventions, and outcomes, including a figure describing numbers of patients awake, dead, and comatose from day 1 to 7 post randomization, were also presented to describe the post–cardiac arrest care. Cumulative total doses of sedatives and analgesics were adjusted for body weight, expressed as mg or mcg per kg as appropriate. Continuous variables are presented as median and interquartile range (IQR) or mean and standard deviation (SD). Categorical variables are reported using numbers and percentages. Propofol doses were divided into quartiles (Q1-Q4) to explore dose-response relationships, given observed non-linearity, while administration of midazolam, fentanyl, and remifentanil were evaluated as binary variables (yes/no). Associations between sedative and analgesic use and outcomes: Justification for variables in the multivariable model We evaluated propofol doses using chi-square statistics to test the associations with outcomes (good functional outcome (mRS 0–3) at 6 months, survival at 6 months, clinical seizures, and late awakening). The association of propofol quartiles, midazolam, fentanyl, remifentanil, and outcomes were also evaluated in an univariable and multivariable logistic regression model with odds ratio (OR with 95% confidence intervals (CI)). The overall test of propofol chi-square test and the multiple logistic regression model, including propofol dose, midazolam, fentanyl, and remifentanil, were adjusted for baseline severity of illness, clinically important variables, and design variables of the TTM2-trial to account for severity of illness and clinical factors potentially influencing the choice and dosage of sedative and analgesics. These included: age, sex, witnessed arrest, shockable rhythm, minutes to ROSC, shock on admission, body mass index (BMI), TTM allocation, shivering or administration of any neuromuscular blockade agent (recorded as yes/no), lowest GFR, and highest bilirubin. Sedation/analgesia by temperature group Sedative and analgesic doses and proportion of patients in the hypothermia versus the normothermia group were analyzed using Wilcoxon rank sum test or Wilcoxon rank rum exact test and using Pearson’s chi-square test. Sensitivity analysis Patients comatose at 96 hours without clinical seizures were included in ta sensitivity analysis, as they would be the population most likely to benefit from optimized sedation strategies. Patients with clinical seizures during intensive care stay were excluded, as their convulsions could significantly impact sedation management and confound the analysis. For the patients who underwent neurological prognostication, the time of sedation discontinuation was recorded, allowing for the calculation of the duration of sedation and the average dose of sedatives and analgesics as dose per kilogram per hour. Results The TTM2 trial enrolled 1900 patients, with 37 patients withdrawing or unable to provide consent, and 2 patients undergoing randomization twice. This resulted in 1861 patients being included in the intention-to-treat analyses. Detailed patient and cardiac arrest characteristics are summarized in Table 1 . Clinical variables and outcomes are presented in Table 2 , while Fig. 1 describes the proportion of patients awake, comatose, and dead during the first seven days after cardiac arrest. The rate of good functional outcomes (mRS 0–3) at six months was 47.0%, while the six-month survival rate was 50.8%. Clinical seizures were observed in 25% of patients during the intensive care stay. The median time until awakening was 2.5 (IQR 1.8–4.4) days. Total sedative and analgesic doses up to 72 hours post-randomization are outlined in Table 3 . Propofol was the most used sedative, with higher mean doses (115.0 mg/kg vs. 98.0 mg/kg) and proportions of use (91% vs. 82%) in patients with good versus poor outcome, followed by midazolam, which showed similar usage between the two groups (mean dosages 2.9 mg/kg vs. 2.7 mg/kg and both 38%, p = 0.737). Among analgesics, fentanyl was the most frequently, with more frequent use in good outcome patients (mean dosages 0.4 mcg/kg vs 0.3 mcg/kg, proportion of use 60% vs. 47%), followed by remifentanil, which also had a higher mean dosage in good outcome patients (mean dosages 1.2 mcg/kg vs. 0.7 mcg/kg, proportion of use 35% vs. 34%). There were no significant differences in average doses or proportion of patients receiving any sedative or analgesics between the hypothermia and the normothermia group, as shown in Supplement table 5. However, significantly more patients received a neuromuscular blockade in the hypothermia group, 614 (66.0%) compared to 418 (44.9%) (p < 0.001). Associations between sedatives and outcomes Exploratory analyses indicated a non-linear relationship between propofol dose and outcomes (good functional outcome, survival, clinical seizures, and delayed awakening) in logistic regression models, as illustrated in Supplementary Figs. 1–4. Consequently, propofol doses were categorized into quartiles for subsequent analyses to better assess associations with outcomes. Proportion of patients alive at 72 hours in each propofol quartile group were: 67.7% (Q1), 88.0% (Q2), 97.0% (Q3), and 99.3% (Q4). Chi-square analyses showed a significant association between propofol dose and good functional outcome (p < 0.01) and survival at six months (p = 0.001), as well as clinical seizures (p < 0.001), and late awakening (p < 0.001), also after adjusting for confounding factors. Univariable analyses of clinical variables and sedatives and analgesics are shown in Supplement Table 6. The results of the multivariable logistic regression models are presented in Table 4 . In a multivariable regression model, higher propofol doses (Q3, 100.7-153.6 mg/kg) were associated with good functional outcome (OR 1.62 CI 1.12–2.34), and Q2 and Q3 (43.9-153.6 mg/kg) with survival (OR 1.49 95%CI 1.05–2.12 and OR 1.84 95%CI 1.27–2.65, respectively). Fentanyl and remifentanil were associated with good functional outcome (OR 1.69 95% CI 1.27–2.26 and OR 1.50 95% CI 1.11–2.02) and survival at six months follow-up (OR 1.80 95%CI 1.35–2.40 and OR 1.56 95%CI 1.16–2.10). Additionally, fentanyl (OR 0.64 95%CI 0.48–0.86) and higher propofol doses (Q2-4, 43.9-669.4 mg/kg) were associated with clinical seizures. Higher doses of propofol (Q4, 153.7-669.4 mg/kg) were associated with late awakening (OR 3.19 95%CI 1.91–5.42). Furthermore, midazolam was associated with clinical seizures (OR 1.99, CI 95% 1.52–2.61) and with late awakening (OR 1.98, CI 95% 1.38–2.86). In the sensitivity analysis including 463 patients unconscious at 96 hours and without any clinical seizures, 359 (78%) patients had neurological prognostication performed, 90 (25%) patients had a poor neurological prognosis, and median duration without sedatives before neurological prognostication was 6.0 hours (IQR 1.0, 46.5). Clinical variables and outcomes are presented in Table 2 , and doses of sedative and analgesic are outlined in Supplement table 7. Chi-square analyses showed no significant association of propofol dose and good functional outcome was observed, while high dose propofol were significantly associated with survival (Supplement Table 8). In a multivariable regression model, higher propofol doses (Q3 and Q4, 1.86–38.86 mg/kg) were associated with good functional outcome (OR 3.15 95%CI 1.29–8.06 and OR 2.78 95%CI 1.15–6.99, respectively), and survival (OR 3.43 95%CI 1.43–8.59 and OR 3.27 95%CI 1.38–8.00, respectively). Receiving fentanyl and remifentanil were associated with good functional outcome (OR 2.16 95% CI 1.10–4.39 and OR 2.25 95% CI 1.14–4.52, respectively) and survival (OR 2.65 95%CI 1.35–5.40 and OR 2.25 95%CI 1.15–4.49, respectively). Discussion In this post-hoc analysis of a large multicentered trial comparing hypothermia with normothermia in out of hospital cardiac arrest, including 40 hours of protocolized deep sedation, we found a significant association between higher total doses of propofol and good functional outcome and survival at 6 months. Notably, proportion of patients alive at 72 hours increased across quartiles of total propofol dose, suggesting a dose-response relationship between higher propofol exposure and early survival. Additionally, higher total doses of propofol over the first 72 hours after randomization were associated with a higher frequency of clinical seizures, with high total doses also associated with late awakening. In addition, we found that the use of the two analgesics remifentanil and fentanyl was associated with good functional outcome and survival at 6 months follow-up. In a subgroup of patients without clinically observed seizures and remaining comatose at the time of earliest neurological prognostication (96 hours), we found that higher hourly doses of propofol were associated with good functional outcome and survival at 6 months follow-up. Our results also indicate that the use of fentanyl and remifentanil is associated with good functional outcomes and survival, further emphasizing that patients with milder injuries tend to need more sedatives and analgesics for therapeutic comfort. Seizures are often observed after cardiac arrest as a result of neuronal excitation due to brain injury [ 6 ]. Seizures are strongly associated with poor outcomes and if left untreated, can potentially exacerbate brain injury by increasing metabolic demand, disruption of cerebral autoregulation, and excitotoxicity [ 23 – 27 ]. Since the causality cannot be known, it is unclear whether a higher dose of propofol is neuroprotective and reduces the risk of seizures or if this only reflects the clinical practice of increasing the sedation when a patient is having clinical seizures or shows signs of pain and agitation. Thus, in patients without seizures, higher doses of propofol were associated with improved outcomes, aligning with the observation that patients with less severe brain injuries often require more sedatives for comfort. Alternatively, this may suggest that sedation itself has neuroprotective effects. However, the direction of this relationship remains uncertain, highlighting the need for further investigation. Shivering is another common reason for increased sedation in clinical practice, and in the main trial, it was recommended that shivering be treated with increased sedation as first-line therapy. A shivering response may indicate preserved thermoregulation and less severe brain injury and has been previously associated with improved outcomes after cardiac arrest [ 28 – 30 ]. Higher doses of sedatives and analgesics observed in patients with good functional outcomes may be partly explained by the higher incidence of shivering in patients with good functional outcome and survival [ 31 – 33 ]. In concordance with our findings that midazolam was associated with late awakening, a small randomized clinical trial comparing sedation regimens during hypothermia after cardiac arrest found that propofol and remifentanil significantly reduced time to extubation compared to midazolam and fentanyl [ 34 ]. Another trial with 460 participants demonstrated that the use of propofol and remifentanil compared to midazolam and fentanyl resulted in significantly earlier awakening and more ventilator-free days, however, with no differences in survival nor neurological outcomes at hospital discharge [ 35 ]. There were no statistically significant differences in sedation or analgesia dosing between patients treated with hypothermia or normothermia. This suggests that doses to keep the patients at deep sedation during TTM were similar. However, after adjusting for sedation and analgesia, severity of illness, and clinical factors, we found normothermia to be associated with a reduced risk of late awakening compared to hypothermia. Hypothermia has previously been shown to be associated with late awakening [ 36 ]. Hypothermia decreases drug metabolism and elimination and increases the risk of lingering sedation, which consequently may delay awakening [ 37 – 40 ]. Current guidelines favor the use of short-acting sedatives and analgesics during TTM, specifically propofol, remifentanil, and fentanyl, over midazolam and morphine, and recommend stopping sedatives as soon as possible to assess the level of consciousness and to facilitate neurological prognostication [ 3 – 5 ]. However, limited evidence supports these recommendations, reflected in the variability in clinical practice [ 41 – 44 ]. In this study propofol was the most used sedative agent, however, midazolam was also commonly used. Our multivariable regression model showed no association between midazolam use and good functional outcomes or survival. Instead, midazolam use was associated with seizures and delayed awakening, even after adjusting for illness severity and clinical factors. Other studies have similarly reported significant use of long-acting drugs [ 45 – 48 ]. While causality cannot be established in this study, the use of long-acting sedatives may reflect patient-specific challenges, such as hemodynamic instability or clinical seizures, which influence sedative choice. Alternatively, the selection of sedatives may depend on physician preference or institutional practices [ 48 , 49 ]. Strengths and limitations This study provides the to date most comprehensive evaluation of sedation and analgesia management after out-of-hospital cardiac arrest, with robust adjustments for illness severity. By examining individual patient data, the study identifies factors influencing outcome. The large, diverse patient cohort from international centers further strengthens the generalizability of the findings. Nevertheless, as with all observational analyses, particularly post-hoc studies, there is a risk of confounding bias. Although we adjusted for key clinical variables and illness severity in the multivariable analysis, there may still be residual confounding. For instance, while use of neuromuscular blockade was included in the multivariable models to account for their potential impact, the depth and duration of neuromuscular blockade were not recorded, limiting our ability to assess their relationship with sedation depth, neurological status, or outcomes. Additionally, EEG recordings were not uniformly available across participating centers and were therefor not included in this study which may have introduced heterogeneity in seizure detection. Moreover, variation in sedation and analgesia practices across the 61 participating centers may represent a source of residual confounding not fully captured by the current multivariable model. Although the TTM2-trial protocol was standardized across sites, recommending a target for sedation depth (RASS − 4 to − 5) and the use of short-acting agents, differences in clinical practice may still have influenced drug choice and dosing, and are not fully accounted for in this analysis. Furthermore, sedation and analgesia management were not primary outcomes of the original TTM2 trial. As such, there is a risk of post-randomization bias, particularly related to differences in clinical management not captured by available data. To mitigate potential information bias, data was collected prospectively using standardized case report forms across all sites. However, with the post-hoc nature of the study, further investigation to establish the causality of the associations found, and findings should be interpreted as hypothesis-generating. Additionally, while sedation was mandatory up to 40 hours, data on sedative and analgesic cumulative doses were collected at 72 hours. The reasons for prolonged sedation or titration of sedation were not recorded. To address this, we conducted subgroup analyses, analyzing those comatose at 96 hours and with known sedation duration, to improve our understanding of sedation and analgesia management in post-cardiac arrest care. Future aspects The findings in this study and the possible impact of sedation strategies on patient outcomes, will be further investigated in the Sedation after Cardiac Arrest and Resuscitation (SED-CARE) trial (clinicaltrials.gov no NCT05564754, 2022-10-03). The SED-CARE trial is a part of the CARE platform trial and is essential in addressing the knowledge gap in a randomized and prospective manner, allowing for a more robust assessment of the causal effects of sedation strategies on seizures, neurological outcome, and survival. Conclusions In this post-hoc analysis of a large multicenter cardiac arrest trial, we found that higher doses of propofol were significantly associated with good functional outcomes and survival at six months, clinical seizures, and late awakening. Remifentanil and fentanyl were both associated with good functional outcomes and survival, while midazolam was associated with clinical seizures and delayed awakening. These findings partially support our hypothesis, suggesting that the type and dosage of sedatives and analgesics during post-cardiac arrest care may reflect the severity of illness, with higher doses in patients with less severe brain injury and better outcomes. In comparison, higher doses of sedatives in the presence of seizures are not associated with improve outcomes. Clinical trials are needed to establish causality and optimizing sedation strategies. Abbreviations SD standard deviation BMI Body mass index CPR Cardiopulmonary resuscitation FOUR Full Outline of Unresponsiveness ROSC Return of spontaneous circulation. Declarations Ethics approval and consent to participate The TTM2-trial was approved by Regional Ethical Review Board in Lund, Sweden (Nr 2015/228 and 2017/36) and in all participating countries and was carried out in accordance with the World Medical Association’s Declaration of Helsinki. Written informed consent was waived, deferred, or obtained from a legal surrogate, depending on the circumstances, and was obtained from each patient who regained mental capacity. For this sub analysis, no further ethical approval was required. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Supported by independent research grants from nonprofit or governmental agencies (the Swedish Research Council [Vetenskapsrådet], Swedish Heart–Lung Foundation, Stig and Ragna Gorthon Foundation, Knutsson Foundation, Laerdal Foundation, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, and Regional Research Support in Region Skåne) and by governmental funding of clinical research within the Swedish National Health Service. Authors’ contributions All authors have substantially contributed to the conception of the work and substantially contributed to the conception, interpretation of data, and substantially revised the manuscript. All authors also have approved the submitted version and agreed both to be personally accountable for their contribution and to ensure accuracy and integrity of all parts of the work. AC has drafted the work, substantially contributed to the design of the work, the analysis, and the interpretation of data. 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Celis-Rodríguez E, Díaz Cortés JC, Cárdenas Bolívar YR et al : Evidence-based clinical practice guidelines for the management of sedoanalgesia and delirium in critically ill adult patients. Med Intensiva (Engl Ed) 2020 Apr, 44(3):171–184. DAS-Taskforce 2015; Baron R, Binder A, Biniek R et al : Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) - short version. Ger Med Sci 2015 Nov 12, 13(Coc19). Devlin JW, Skrobik Y, Gelinas C et al : Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med 2018, 46(9):e825-e873. Gonzalez D, Dahiya G, Mutirangura P et al : Post Cardiac Arrest Care in the Cardiac Intensive Care Unit. Curr Cardiol Rep 2024, 26(2):35–49. 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J Intensive Care Med 2023, 38(12):1143–1150. Additional Declarations No competing interests reported. Supplementary Files TTM2sedsupplement.docx Cite Share Download PDF Status: Published Journal Publication published 17 Jun, 2025 Read the published version in Critical Care → Version 1 posted Editorial decision: Revision requested 14 Apr, 2025 Reviews received at journal 13 Apr, 2025 Reviewers agreed at journal 11 Apr, 2025 Reviewers invited by journal 11 Apr, 2025 Submission checks completed at journal 11 Apr, 2025 First submitted to journal 09 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Data were collected in hour and days from randomization to awakening or death. Patients awake were defined as FOUR motor \u0026gt;4 (obeying commands). Comatose was defined as any patient FOUR motor \u0026lt; 4. The days are defined as every 24 hours period after randomisation: day 1 (0-24 hours), day 2 (24-48 hours), day 3 (48-72 hours), day 4 (72-96 hours), day 5 (96-120 hours), day 6 (120-144 hours), and day 7 (144-168 hours).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6155229/v1/a2d3c7ad01f5f48b8dbc986e.jpg"},{"id":85231237,"identity":"a3825d0e-7358-4830-be9d-37f82912d25c","added_by":"auto","created_at":"2025-06-23 15:58:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2122627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6155229/v1/14b4140b-be72-462d-864f-511bf1ce82fb.pdf"},{"id":80805068,"identity":"3ed78d58-666f-42a0-8f23-97f2b0b3da01","added_by":"auto","created_at":"2025-04-17 09:18:41","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":315500,"visible":true,"origin":"","legend":"","description":"","filename":"TTM2sedsupplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-6155229/v1/86281fdb4bb541c99913951f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe majority of patients unconscious after out-of-hospital cardiac arrest (OHCA) receive intensive care treatment and targeted temperature management (TTM) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. TTM and fever management are recommended to mitigate hypoxic-ischemic brain injury and improve functional outcomes, with sedation and analgesia provided during post-cardiac arrest care to reduce discomfort induced by lowering the body temperature, facilitate therapy, reduce shivering, and prevent awareness during neuromuscular blockade [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. About one third of cardiac arrest patients develop seizures, which are associated with poor outcomes, however, causal relationship with the degree of hypoxic-ischemic brain injury has not been established [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Sedatives, some of which are also potent antiepileptic agents, may mitigate secondary brain injury and optimize neurological recovery by lowering metabolic rate and intracranial pressure [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Thus, in clinical practice, sedation is often increased when a patient is having clinical seizures or shows signs of pain and agitation.\u003c/p\u003e \u003cp\u003eSedation carries inherent risks, including compromised circulatory and respiratory functions, increased risk of delirium, prolonged mechanical ventilation, and intensive care stay [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Importantly, for patients with cardiac arrest, sedation may confound neurological prognostication, influencing the decision on withdrawal of life-sustaining therapies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study investigates the association between the use of sedatives and analgesics and outcomes, including functional, mortality, clinical seizure, and time to awakening in a large multicenter trial. We hypothesized that there is an association between higher doses of sedatives and analgesics and long-term good functional outcome, survival, occurrence of clinical seizures, and late awakening.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSetting and participants\u003c/h2\u003e \u003cp\u003eThe TTM2-trial (Clinicaltrials.gov NCT02908308) was an international, multicenter, parallel group, investigator-initiated trial randomizing 1900 adult patients between November 2017 and January 2020, with an OHCA of presumed cardiac cause to targeted hypothermia (33\u0026deg;C) (hypothermia) or normothermia with early treatment of fever (\u0026lt;\u0026thinsp;37.8\u0026deg;C) (normothermia) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. As previously reported, unconscious adult (\u0026gt;\u0026thinsp;18 years) patients with a presumed cardiac cause and ROSC were eligible for inclusion. The main exclusion criteria were time from ROSC to screening of more than 180 minutes, unwitnessed cardiac arrest with asystole as the initial rhythm and limitations in care [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (Supplement Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBackground and cardiac arrest characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eComatose patients at 96 hours without clinical seizures\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e463\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1477 (79.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e378\u0026nbsp;(81.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.8 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.5\u0026nbsp;(12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFrailty score (median (IQR))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8\u0026nbsp;(1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBody mass index (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.5 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.8\u0026nbsp;(5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCirculatory shock on admission\u003c/b\u003e\u003csup\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e536 (28.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143\u0026nbsp;(30.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMinutes to ROSC (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u0026nbsp;(18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInitial shockable rhythm (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1371 (73.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e351\u0026nbsp;(75.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBystander CPR (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1487 (79.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u0026nbsp;(80.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious liver disease (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u0026nbsp;(3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious renal disease (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u0026nbsp;(6.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious cerebrovascular disease (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120 (6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u0026nbsp;(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdmission FOUR motor (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0 No response to pain\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1463 (86.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e374\u0026nbsp;(86.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1 Extension response to pain\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u0026nbsp;(2.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2 Flexion response to pain\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u0026nbsp;(6.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3 Localizes pain\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u0026nbsp;(3.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4 Awake and obeying commands\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u0026nbsp;(0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e1\u003c/sup\u003e Circulatory shock at admission was defined as a systolic blood pressure of \u0026lt;\u0026thinsp;90 mmHg for \u0026gt;\u0026thinsp;30 minutes or end-organ hypoperfusion (cool arms and legs, urine output\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/hour, and heart rate\u0026thinsp;\u0026lt;\u0026thinsp;60 beats/minute).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient management\u003c/h3\u003e\n\u003cp\u003ePatients assigned to hypothermia were cooled to 33\u0026deg;C, and this temperature was maintained for 28 hours, followed by rewarming to 37\u0026deg;C for 12 hours (intervention period). In the normothermia group, the aim was to maintain a temperature of 37.5\u0026deg;C or less. After the intervention period, normothermia was maintained until 72 hours after randomization in all patients who remained unconscious, and sedation was discontinued or tapered according to clinical state. Extubation and wake-up test was attempted at the earliest time possible after the intervention period (40 hours), based on standard protocols for discontinuation of mechanical ventilation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMultimodal neurological prognostication was performed by a physician blinded to the intervention no earlier than 96 hours after randomization, with strict criteria according to the TTM2-trial study protocol [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Decision of withdrawal of life-sustaining therapy (WLST) was at the discretion of the treating physician [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeuron-specific enolase (NSE) sampling was optional and conducted at sites with relevant expertise. The highest NSE value was recorded. Bilirubin and glomerular filtration rate (GFR) were measured daily during the first week of intensive care.\u003c/p\u003e\n\u003ch3\u003eSedative and analgesic drugs\u003c/h3\u003e\n\u003cp\u003eDuring the intervention period of 40 hours, deep sedation, defined as Richmond Agitation and Sedation Scale (RASS) -4 to -5, was mandatory in both groups and provided similar treatment in both groups [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] (Supplement Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The trial protocol recommended short-acting drugs, but to comply with the pragmatic nature of the trial was left to the treating physician's discretion or local protocol. Type of drug and cumulative dosing of each sedative and analgesic drug administered up to 72 hours after randomization were recorded as follows: midazolam (mg), propofol (mg), dexmedetomidine (mcg), clonidine (mcg), esketamine (mg), ketamine (mg), fentanyl (mcg), morphine (mg), remifentanil (mcg) and oxycodone (mg). In patients in whom neurological prognostication was performed, time of discontinuation of sedatives was recorded.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical variables and outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eComatose patients at 96 hours without clinical seizures\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e463\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNormothermia (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e931 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e228\u0026nbsp;(49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEarly discontinuation of TTM (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e300 (16.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u0026nbsp;(4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eShivering\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e632 (34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157\u0026nbsp;(34.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical seizures (%)\u003c/b\u003e\u003csup\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e464 (25.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u0026nbsp;(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHighest NSE\u003c/b\u003e\u003csup\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e(mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88.5 (161.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.4\u0026nbsp;(114.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLowest GFR (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.7 (26.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.5\u0026nbsp;(25.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHighest bilirubin (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.4 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.3\u0026nbsp;(30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to extubation, days (median (IQR))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5\u0026nbsp;(1.9,\u0026nbsp;5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6 (4.7, 11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to wake-up, days\u003c/b\u003e\u003csup\u003e\u003cb\u003e4\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e(median (IQR))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5\u0026nbsp;(1.8,\u0026nbsp;4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.6\u0026nbsp;(4.4,\u0026nbsp;8.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeurological prognostication performed according to protocol (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e883 (47.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e359\u0026nbsp;(77.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePoor prognosis likely at time of neurological prognostication (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e264 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90\u0026nbsp;(24.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime of sedation discontinued before prognostication, hours (median (IQR))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.0 (1.0, 48.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0\u0026nbsp;(1.0,\u0026nbsp;46.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICU length of stay, days (median (IQR))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.9 (2.9, 8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.7\u0026nbsp;(5.8,\u0026nbsp;13.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGood neurological outcome (mRS 4\u0026ndash;6), n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e873 (47.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e177\u0026nbsp;(38.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurvival at six months, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e950 (50.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e262\u0026nbsp;(56.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e1\u003c/sup\u003e Discontinuation of TTM any time during the intervention period of 40 hours.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e2\u003c/sup\u003e The occurrence of shivering during up to 72 hours.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e3\u003c/sup\u003e Highest NSE measurement during the ICU stay. Measured in 1018 out of 1861 patients.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e4\u003c/sup\u003e Data available in 979 patients out of 1861.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: TTM\u0026thinsp;=\u0026thinsp;Target temperature management, NSE\u0026thinsp;=\u0026thinsp;Neuron specific enolase, GFR\u0026thinsp;=\u0026thinsp;Glomerular filtration rate, ICU\u0026thinsp;=\u0026thinsp;intensive care unit, SD\u0026thinsp;=\u0026thinsp;standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eShivering was assessed daily during the intensive care stay using the bedside shivering assessment scale (BSAS) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] (Supplement Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Shivering was defined as BSAS\u0026thinsp;\u0026gt;\u0026thinsp;1 anytime up to 72 hours after randomization. Prophylactic acetaminophen/paracetamol was recommended. In response to a BSAS\u0026thinsp;\u0026gt;\u0026thinsp;1, the first measure taken was to increase sedation, and secondarily to administer neuromuscular blocking agent at the discretion of the treating physician The goal was to maintain BSAS 0\u0026ndash;1.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTotal doses of sedatives, analgesics, and neuromuscular blockade up to 72 hours\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePoor\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e988\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol, mg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115.0 (72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98.0 (79.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e767\u0026nbsp;(91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e815\u0026nbsp;(82%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMidazolam, mg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.9 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7 (6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMidazolam, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e324\u0026nbsp;(38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372\u0026nbsp;(38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMidazolam and propofol, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e272\u0026nbsp;(32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e271\u0026nbsp;(27%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMidazolam only, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u0026nbsp;(6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101\u0026nbsp;(10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRemifentanil, mcg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2 (3.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7 (2.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRemifentanil, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e297\u0026nbsp;(35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e335\u0026nbsp;(34%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFentanyl, mcg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.4 (3.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3 (2.91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFentanyl, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e494\u0026nbsp;(60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e456\u0026nbsp;(47%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDexmedetomidine, mcg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.02 (0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02 (0.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDexmedetomidine, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113\u0026nbsp;(14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u0026nbsp;(3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOxycodone, mg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3 (0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3 (0.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOxycodone, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77\u0026nbsp;(9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u0026nbsp;(4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMorphine, mg/kg (mean (SD))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMorphine, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101\u0026nbsp;(12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120\u0026nbsp;(12%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAny neuromuscular blockade, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e483 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e529 (53%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePrimary outcome\u003c/h3\u003e\n\u003cp\u003eA good functional outcome was defined as a modified Rankin Scale (mRS) 0\u0026ndash;3 at six months. The mRS ranges from 0 to 6, with 0 representing no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSecondary outcomes\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSurvival\u003c/h2\u003e \u003cp\u003eSurvival status was recorded by six months follow-up.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical seizures\u003c/h3\u003e\n\u003cp\u003eClinical seizures were defined as myoclonus or tonic-clonic seizures, which were assessed daily and recorded as present or absent during the intensive care stay up to seven days after randomization. Seizures were managed according to local protocols, at the discretion of the treating physician.\u003c/p\u003e\n\u003ch3\u003eTime to awakening\u003c/h3\u003e\n\u003cp\u003eAwakening was defined as obeying commands, i.e. Full Outline of Unresponsiveness (FOUR) (Supplement Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) score motor component of four [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. FOUR score was recorded daily during the first seven days of intensive care. Time to awakening was recorded, with late awakening defined as occurring after 96 hours.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eMultivariable logistic regression and chi-square analysis of clinical factors, sedation, and analgesics on functional outcome, survival, clinical seizures, and late awakening.\u003c/b\u003e Association of clinical factors, TTM, and total dose of propofol up to 72 hrs with good functional outcome (mRS 0\u0026ndash;3) at six months follow up, survival at six months, clinical seizures, and late awakening in multivariate regression model.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eGood functional outcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eSurvival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNormothermia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.65\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.76\u0026ndash;1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol dose (mg/kg)*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 1 (0.01\u0026ndash;43.8 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 2 (43.9-100.6 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96\u0026ndash;2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.05\u0026ndash;2.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 3 (100.7-153.6 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.12\u0026ndash;2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.27\u0026ndash;2.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 4 (153.7-669.4 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.71\u0026ndash;1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.88\u0026ndash;1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.192\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMidazolam\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.77\u0026ndash;1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.84\u0026ndash;1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFentanyl\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.27\u0026ndash;2.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.35\u0026ndash;2.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRemifentanil\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.11\u0026ndash;2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.16\u0026ndash;2.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eClinical seizures\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e\u003cb\u003eLate awakening\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNormothermia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.58\u0026ndash;0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.40\u0026ndash;0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol dose (mg/kg)*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 1 (0.01\u0026ndash;43.8 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 2 (43.9-100.6 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.06\u0026ndash;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.46\u0026ndash;1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.369\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 3 (100.7-153.6 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.06\u0026ndash;2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.80\u0026ndash;2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePropofol quartile 4 (153.7-669.4 mg/kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.94\u0026ndash;4.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.91\u0026ndash;5.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMidazolam\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.52\u0026ndash;2.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.38\u0026ndash;2.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFentanyl\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.48\u0026ndash;0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.86\u0026ndash;1.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRemifentanil\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.89\u0026ndash;1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.245\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.82\u0026ndash;1.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.352\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eThe multivariable regression model is including variables: age, male sex, time to return of spontaneous circulation, witnessed arrest, shock on admission, shockable rhythm, normothermia, shivering or neuromuscular blockade, lowest glomerular filtration rate, and highest bilirubin. Abbreviations: OR\u0026thinsp;=\u0026thinsp;Odds ratio, conf\u0026thinsp;=\u0026thinsp;Confidence interval, p\u0026thinsp;=\u0026thinsp;p-value.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003e*Analysed using Analysis of Variance (ANOVA)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003ePatient and cardiac arrest characteristics were used to describe the study cohort. Clinical variables such as temperature management strategy, sedation and analgesia use, intensive care interventions, and outcomes, including a figure describing numbers of patients awake, dead, and comatose from day 1 to 7 post randomization, were also presented to describe the post\u0026ndash;cardiac arrest care. Cumulative total doses of sedatives and analgesics were adjusted for body weight, expressed as mg or mcg per kg as appropriate. Continuous variables are presented as median and interquartile range (IQR) or mean and standard deviation (SD). Categorical variables are reported using numbers and percentages. Propofol doses were divided into quartiles (Q1-Q4) to explore dose-response relationships, given observed non-linearity, while administration of midazolam, fentanyl, and remifentanil were evaluated as binary variables (yes/no).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between sedative and analgesic use and outcomes: Justification for variables in the multivariable model\u003c/h2\u003e \u003cp\u003eWe evaluated propofol doses using chi-square statistics to test the associations with outcomes (good functional outcome (mRS 0\u0026ndash;3) at 6 months, survival at 6 months, clinical seizures, and late awakening). The association of propofol quartiles, midazolam, fentanyl, remifentanil, and outcomes were also evaluated in an univariable and multivariable logistic regression model with odds ratio (OR with 95% confidence intervals (CI)). The overall test of propofol chi-square test and the multiple logistic regression model, including propofol dose, midazolam, fentanyl, and remifentanil, were adjusted for baseline severity of illness, clinically important variables, and design variables of the TTM2-trial to account for severity of illness and clinical factors potentially influencing the choice and dosage of sedative and analgesics. These included: age, sex, witnessed arrest, shockable rhythm, minutes to ROSC, shock on admission, body mass index (BMI), TTM allocation, shivering or administration of any neuromuscular blockade agent (recorded as yes/no), lowest GFR, and highest bilirubin.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSedation/analgesia by temperature group\u003c/h2\u003e \u003cp\u003eSedative and analgesic doses and proportion of patients in the hypothermia versus the normothermia group were analyzed using Wilcoxon rank sum test or Wilcoxon rank rum exact test and using Pearson\u0026rsquo;s chi-square test.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003ePatients comatose at 96 hours without clinical seizures were included in ta sensitivity analysis, as they would be the population most likely to benefit from optimized sedation strategies. Patients with clinical seizures during intensive care stay were excluded, as their convulsions could significantly impact sedation management and confound the analysis. For the patients who underwent neurological prognostication, the time of sedation discontinuation was recorded, allowing for the calculation of the duration of sedation and the average dose of sedatives and analgesics as dose per kilogram per hour.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe TTM2 trial enrolled 1900 patients, with 37 patients withdrawing or unable to provide consent, and 2 patients undergoing randomization twice. This resulted in 1861 patients being included in the intention-to-treat analyses. Detailed patient and cardiac arrest characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eClinical variables and outcomes are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, while Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e describes the proportion of patients awake, comatose, and dead during the first seven days after cardiac arrest. The rate of good functional outcomes (mRS 0\u0026ndash;3) at six months was 47.0%, while the six-month survival rate was 50.8%. Clinical seizures were observed in 25% of patients during the intensive care stay. The median time until awakening was 2.5 (IQR 1.8\u0026ndash;4.4) days.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTotal sedative and analgesic doses up to 72 hours post-randomization are outlined in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Propofol was the most used sedative, with higher mean doses (115.0 mg/kg vs. 98.0 mg/kg) and proportions of use (91% vs. 82%) in patients with good versus poor outcome, followed by midazolam, which showed similar usage between the two groups (mean dosages 2.9 mg/kg vs. 2.7 mg/kg and both 38%, p\u0026thinsp;=\u0026thinsp;0.737). Among analgesics, fentanyl was the most frequently, with more frequent use in good outcome patients (mean dosages 0.4 mcg/kg vs 0.3 mcg/kg, proportion of use 60% vs. 47%), followed by remifentanil, which also had a higher mean dosage in good outcome patients (mean dosages 1.2 mcg/kg vs. 0.7 mcg/kg, proportion of use 35% vs. 34%).\u003c/p\u003e \u003cp\u003eThere were no significant differences in average doses or proportion of patients receiving any sedative or analgesics between the hypothermia and the normothermia group, as shown in Supplement table 5. However, significantly more patients received a neuromuscular blockade in the hypothermia group, 614 (66.0%) compared to 418 (44.9%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between sedatives and outcomes\u003c/h2\u003e \u003cp\u003eExploratory analyses indicated a non-linear relationship between propofol dose and outcomes (good functional outcome, survival, clinical seizures, and delayed awakening) in logistic regression models, as illustrated in Supplementary Figs.\u0026nbsp;1\u0026ndash;4. Consequently, propofol doses were categorized into quartiles for subsequent analyses to better assess associations with outcomes. Proportion of patients alive at 72 hours in each propofol quartile group were: 67.7% (Q1), 88.0% (Q2), 97.0% (Q3), and 99.3% (Q4).\u003c/p\u003e \u003cp\u003eChi-square analyses showed a significant association between propofol dose and good functional outcome (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and survival at six months (p\u0026thinsp;=\u0026thinsp;0.001), as well as clinical seizures (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and late awakening (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), also after adjusting for confounding factors. Univariable analyses of clinical variables and sedatives and analgesics are shown in Supplement Table\u0026nbsp;6. The results of the multivariable logistic regression models are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In a multivariable regression model, higher propofol doses (Q3, 100.7-153.6 mg/kg) were associated with good functional outcome (OR 1.62 CI 1.12\u0026ndash;2.34), and Q2 and Q3 (43.9-153.6 mg/kg) with survival (OR 1.49 95%CI 1.05\u0026ndash;2.12 and OR 1.84 95%CI 1.27\u0026ndash;2.65, respectively). Fentanyl and remifentanil were associated with good functional outcome (OR 1.69 95% CI 1.27\u0026ndash;2.26 and OR 1.50 95% CI 1.11\u0026ndash;2.02) and survival at six months follow-up (OR 1.80 95%CI 1.35\u0026ndash;2.40 and OR 1.56 95%CI 1.16\u0026ndash;2.10). Additionally, fentanyl (OR 0.64 95%CI 0.48\u0026ndash;0.86) and higher propofol doses (Q2-4, 43.9-669.4 mg/kg) were associated with clinical seizures. Higher doses of propofol (Q4, 153.7-669.4 mg/kg) were associated with late awakening (OR 3.19 95%CI 1.91\u0026ndash;5.42). Furthermore, midazolam was associated with clinical seizures (OR 1.99, CI 95% 1.52\u0026ndash;2.61) and with late awakening (OR 1.98, CI 95% 1.38\u0026ndash;2.86).\u003c/p\u003e \u003cp\u003eIn the sensitivity analysis including 463 patients unconscious at 96 hours and without any clinical seizures, 359 (78%) patients had neurological prognostication performed, 90 (25%) patients had a poor neurological prognosis, and median duration without sedatives before neurological prognostication was 6.0 hours (IQR 1.0, 46.5). Clinical variables and outcomes are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and doses of sedative and analgesic are outlined in Supplement table 7. Chi-square analyses showed no significant association of propofol dose and good functional outcome was observed, while high dose propofol were significantly associated with survival (Supplement Table\u0026nbsp;8). In a multivariable regression model, higher propofol doses (Q3 and Q4, 1.86\u0026ndash;38.86 mg/kg) were associated with good functional outcome (OR 3.15 95%CI 1.29\u0026ndash;8.06 and OR 2.78 95%CI 1.15\u0026ndash;6.99, respectively), and survival (OR 3.43 95%CI 1.43\u0026ndash;8.59 and OR 3.27 95%CI 1.38\u0026ndash;8.00, respectively). Receiving fentanyl and remifentanil were associated with good functional outcome (OR 2.16 95% CI 1.10\u0026ndash;4.39 and OR 2.25 95% CI 1.14\u0026ndash;4.52, respectively) and survival (OR 2.65 95%CI 1.35\u0026ndash;5.40 and OR 2.25 95%CI 1.15\u0026ndash;4.49, respectively).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this post-hoc analysis of a large multicentered trial comparing hypothermia with normothermia in out of hospital cardiac arrest, including 40 hours of protocolized deep sedation, we found a significant association between higher total doses of propofol and good functional outcome and survival at 6 months. Notably, proportion of patients alive at 72 hours increased across quartiles of total propofol dose, suggesting a dose-response relationship between higher propofol exposure and early survival. Additionally, higher total doses of propofol over the first 72 hours after randomization were associated with a higher frequency of clinical seizures, with high total doses also associated with late awakening. In addition, we found that the use of the two analgesics remifentanil and fentanyl was associated with good functional outcome and survival at 6 months follow-up. In a subgroup of patients without clinically observed seizures and remaining comatose at the time of earliest neurological prognostication (96 hours), we found that higher hourly doses of propofol were associated with good functional outcome and survival at 6 months follow-up. Our results also indicate that the use of fentanyl and remifentanil is associated with good functional outcomes and survival, further emphasizing that patients with milder injuries tend to need more sedatives and analgesics for therapeutic comfort.\u003c/p\u003e \u003cp\u003eSeizures are often observed after cardiac arrest as a result of neuronal excitation due to brain injury [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Seizures are strongly associated with poor outcomes and if left untreated, can potentially exacerbate brain injury by increasing metabolic demand, disruption of cerebral autoregulation, and excitotoxicity [\u003cspan additionalcitationids=\"CR24 CR25 CR26\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Since the causality cannot be known, it is unclear whether a higher dose of propofol is neuroprotective and reduces the risk of seizures or if this only reflects the clinical practice of increasing the sedation when a patient is having clinical seizures or shows signs of pain and agitation. Thus, in patients without seizures, higher doses of propofol were associated with improved outcomes, aligning with the observation that patients with less severe brain injuries often require more sedatives for comfort. Alternatively, this may suggest that sedation itself has neuroprotective effects. However, the direction of this relationship remains uncertain, highlighting the need for further investigation.\u003c/p\u003e \u003cp\u003eShivering is another common reason for increased sedation in clinical practice, and in the main trial, it was recommended that shivering be treated with increased sedation as first-line therapy. A shivering response may indicate preserved thermoregulation and less severe brain injury and has been previously associated with improved outcomes after cardiac arrest [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Higher doses of sedatives and analgesics observed in patients with good functional outcomes may be partly explained by the higher incidence of shivering in patients with good functional outcome and survival [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn concordance with our findings that midazolam was associated with late awakening, a small randomized clinical trial comparing sedation regimens during hypothermia after cardiac arrest found that propofol and remifentanil significantly reduced time to extubation compared to midazolam and fentanyl [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Another trial with 460 participants demonstrated that the use of propofol and remifentanil compared to midazolam and fentanyl resulted in significantly earlier awakening and more ventilator-free days, however, with no differences in survival nor neurological outcomes at hospital discharge [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere were no statistically significant differences in sedation or analgesia dosing between patients treated with hypothermia or normothermia. This suggests that doses to keep the patients at deep sedation during TTM were similar. However, after adjusting for sedation and analgesia, severity of illness, and clinical factors, we found normothermia to be associated with a reduced risk of late awakening compared to hypothermia. Hypothermia has previously been shown to be associated with late awakening [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Hypothermia decreases drug metabolism and elimination and increases the risk of lingering sedation, which consequently may delay awakening [\u003cspan additionalcitationids=\"CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent guidelines favor the use of short-acting sedatives and analgesics during TTM, specifically propofol, remifentanil, and fentanyl, over midazolam and morphine, and recommend stopping sedatives as soon as possible to assess the level of consciousness and to facilitate neurological prognostication [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, limited evidence supports these recommendations, reflected in the variability in clinical practice [\u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In this study propofol was the most used sedative agent, however, midazolam was also commonly used. Our multivariable regression model showed no association between midazolam use and good functional outcomes or survival. Instead, midazolam use was associated with seizures and delayed awakening, even after adjusting for illness severity and clinical factors. Other studies have similarly reported significant use of long-acting drugs [\u003cspan additionalcitationids=\"CR46 CR47\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. While causality cannot be established in this study, the use of long-acting sedatives may reflect patient-specific challenges, such as hemodynamic instability or clinical seizures, which influence sedative choice. Alternatively, the selection of sedatives may depend on physician preference or institutional practices [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThis study provides the to date most comprehensive evaluation of sedation and analgesia management after out-of-hospital cardiac arrest, with robust adjustments for illness severity. By examining individual patient data, the study identifies factors influencing outcome. The large, diverse patient cohort from international centers further strengthens the generalizability of the findings. Nevertheless, as with all observational analyses, particularly post-hoc studies, there is a risk of confounding bias. Although we adjusted for key clinical variables and illness severity in the multivariable analysis, there may still be residual confounding. For instance, while use of neuromuscular blockade was included in the multivariable models to account for their potential impact, the depth and duration of neuromuscular blockade were not recorded, limiting our ability to assess their relationship with sedation depth, neurological status, or outcomes. Additionally, EEG recordings were not uniformly available across participating centers and were therefor not included in this study which may have introduced heterogeneity in seizure detection. Moreover, variation in sedation and analgesia practices across the 61 participating centers may represent a source of residual confounding not fully captured by the current multivariable model. Although the TTM2-trial protocol was standardized across sites, recommending a target for sedation depth (RASS \u0026minus;\u0026thinsp;4 to \u0026minus;\u0026thinsp;5) and the use of short-acting agents, differences in clinical practice may still have influenced drug choice and dosing, and are not fully accounted for in this analysis.\u003c/p\u003e \u003cp\u003eFurthermore, sedation and analgesia management were not primary outcomes of the original TTM2 trial. As such, there is a risk of post-randomization bias, particularly related to differences in clinical management not captured by available data. To mitigate potential information bias, data was collected prospectively using standardized case report forms across all sites. However, with the post-hoc nature of the study, further investigation to establish the causality of the associations found, and findings should be interpreted as hypothesis-generating.\u003c/p\u003e \u003cp\u003eAdditionally, while sedation was mandatory up to 40 hours, data on sedative and analgesic cumulative doses were collected at 72 hours. The reasons for prolonged sedation or titration of sedation were not recorded. To address this, we conducted subgroup analyses, analyzing those comatose at 96 hours and with known sedation duration, to improve our understanding of sedation and analgesia management in post-cardiac arrest care.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFuture aspects\u003c/b\u003e The findings in this study and the possible impact of sedation strategies on patient outcomes, will be further investigated in the Sedation after Cardiac Arrest and Resuscitation (SED-CARE) trial (clinicaltrials.gov no NCT05564754, 2022-10-03). The SED-CARE trial is a part of the CARE platform trial and is essential in addressing the knowledge gap in a randomized and prospective manner, allowing for a more robust assessment of the causal effects of sedation strategies on seizures, neurological outcome, and survival.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this post-hoc analysis of a large multicenter cardiac arrest trial, we found that higher doses of propofol were significantly associated with good functional outcomes and survival at six months, clinical seizures, and late awakening. Remifentanil and fentanyl were both associated with good functional outcomes and survival, while midazolam was associated with clinical seizures and delayed awakening. These findings partially support our hypothesis, suggesting that the type and dosage of sedatives and analgesics during post-cardiac arrest care may reflect the severity of illness, with higher doses in patients with less severe brain injury and better outcomes. In comparison, higher doses of sedatives in the presence of seizures are not associated with improve outcomes. Clinical trials are needed to establish causality and optimizing sedation strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCPR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCardiopulmonary resuscitation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFOUR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFull Outline of Unresponsiveness\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReturn of spontaneous circulation.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003cbr /\u003e The TTM2-trial was approved by Regional Ethical Review Board in Lund, Sweden (Nr 2015/228 and 2017/36) and in all participating countries and was carried out in accordance with the World Medical Association\u0026rsquo;s Declaration of Helsinki. Written informed consent was waived, deferred, or obtained from a legal surrogate, depending on the circumstances, and was obtained from each patient who regained mental capacity. For this sub analysis, no further ethical approval was required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u003cbr /\u003e \u003c/em\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003cbr /\u003e \u003c/em\u003e\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003cbr /\u003e \u003c/em\u003e\u003c/strong\u003e\u003cem\u003eThe authors declare that they have no competing interests.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003cbr /\u003e \u003c/em\u003e\u003c/strong\u003eSupported by independent research grants from nonprofit or governmental agencies (the Swedish Research Council [Vetenskapsr\u0026aring;det], Swedish Heart\u0026ndash;Lung Foundation, Stig and Ragna Gorthon Foundation, Knutsson Foundation, Laerdal Foundation, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, and Regional Research Support in Region Sk\u0026aring;ne) and by governmental funding of clinical research within the Swedish National Health Service.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003cbr /\u003e \u003c/em\u003e\u003c/strong\u003eAll authors have substantially contributed to the conception of the work and substantially contributed to the conception, interpretation of data, and substantially revised the manuscript. All authors also have approved the submitted version and agreed both to be personally accountable for their contribution and to ensure accuracy and integrity of all parts of the work. AC has drafted the work, substantially contributed to the design of the work, the analysis, and the interpretation of data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThomassen A WM: Prevalence and prognostic significance of coma after cardiac arrest outside intensive care and coronary units. Acta Anaesthesiol Scand 1979 Apr, 23(2):143\u0026ndash;148.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDragancea I, Horn J, Kuiper M \u003cem\u003eet al\u003c/em\u003e: Neurological prognostication after cardiac arrest and targeted temperature management 33 degrees C versus 36 degrees C: Results from a randomised controlled clinical trial. Resuscitation 2015, 93:164\u0026ndash;170.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandroni C, Nolan JP, Andersen LW \u003cem\u003eet al\u003c/em\u003e: ERC-ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Medicine 2022, 48(3):261\u0026ndash;269.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNolan JP SC, Bottiger BW, et al.: European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med 2021 47(4):369\u0026ndash;421.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirsch KG, Abella BS, Amorim E \u003cem\u003eet al\u003c/em\u003e: Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society. 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Am Heart J 2019 Nov, 217:23\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSessler CN, Gosnell MS, Grap MJ \u003cem\u003eet al\u003c/em\u003e: The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002, 166(10):1338\u0026ndash;1344.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadjatia N, Strongilis E, Gordon E \u003cem\u003eet al\u003c/em\u003e: Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke 2008, 39(12):3242\u0026ndash;3247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J: Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988 may, 19(5):604\u0026ndash;607.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL: Validation of a new coma scale: The FOUR score. Ann Neurol 2005, 58(4):585\u0026ndash;593.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRossetti AO, Oddo M, Logroscino G, Kaplan PW: Prognostication after cardiac arrest and hypothermia: a prospective study. Ann Neurol 2010, 67:301\u0026ndash;307.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouwes A, van Poppelen D, Koelman JH et al: Acute posthypoxic myoclonus after cardiopulmonary resuscitation. BMC Neurol 2012, 12:63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeder DB, Sunde K, Rubertsson S \u003cem\u003eet al\u003c/em\u003e: Neurologic Outcomes and Postresuscitation Care of Patients With Myoclonus Following Cardiac Arrest. Crit Care Med 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElmer J, Rittenberger JC, Faro J \u003cem\u003eet al\u003c/em\u003e: Clinically distinct electroencephalographic phenotypes of early myoclonus after cardiac arrest. Ann Neurol 2016, 80:175\u0026ndash;184.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBackman S, Westhall E, Dragancea I \u003cem\u003eet al\u003c/em\u003e: Electroencephalographic characteristics of status epilepticus after cardiac arrest. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 2017, 128:681\u0026ndash;688.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee DH, Lee BK, Cho YS \u003cem\u003eet al\u003c/em\u003e: High heat generation is associated with good neurologic outcome in out-of-hospital cardiac arrest survivors underwent targeted temperature management at 33 degrees C. Resuscitation 2020, 153:187\u0026ndash;194.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNair SU, Lundbye JB: The occurrence of shivering in cardiac arrest survivors undergoing therapeutic hypothermia is associated with a good neurologic outcome. Resuscitation 2013, 84(5):626\u0026ndash;629.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHovdenes J, Roysland K, Nielsen N \u003cem\u003eet al\u003c/em\u003e: A low body temperature on arrival at hospital following out-of-hospital-cardiac-arrest is associated with increased mortality in the TTM-study. Resuscitation 2016, 107:102\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee DH, Lee BK, Cho YS \u003cem\u003eet al\u003c/em\u003e: High heat generation is associated with good neurologic outcome in out-of-hospital cardiac arrest survivors underwent targeted temperature management at 33\u0026deg;C. Resuscitation 2020, 153:187\u0026ndash;194.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMay TL, Riker RR, Fraser GL \u003cem\u003eet al\u003c/em\u003e: Variation in Sedation and Neuromuscular Blockade Regimens on Outcome After Cardiac Arrest. Crit Care Med 2018, 46(10):e975-e980.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeller BJ, Maciel CB, May TL, Jentzer JC: Sedation and shivering management after cardiac arrest. Eur Heart J Acute Cardiovasc Care 2023, 12(8):518\u0026ndash;524.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBjelland TW, Dale O, Kaisen K \u003cem\u003eet al\u003c/em\u003e: Propofol and remifentanil versus midazolam and fentanyl for sedation during therapeutic hypothermia after cardiac arrest: a randomised trial. Intensive Care Med 2012, 38(6):959\u0026ndash;967.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaul M, Bougouin W, Dumas F \u003cem\u003eet al\u003c/em\u003e: Comparison of two sedation regimens during targeted temperature management after cardiac arrest. Resuscitation 2018, 128:204\u0026ndash;210.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLybeck A, Cronberg T, Aneman A \u003cem\u003eet al\u003c/em\u003e: Time to awakening after cardiac arrest and the association with target temperature management. Resuscitation 2018, 126:166\u0026ndash;171.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan den Broek MP, Groenendaal F, Egberts AC, Rademaker CM: Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet 2010, 49(5):277\u0026ndash;294.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeslie K, Sessler DI, Bjorksten AR, Moayeri A: Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesth Analg 1995, 80(5):1007\u0026ndash;1014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTortorici MA, Kochanek PM, Poloyac SM: Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 2007, 35(9):2196\u0026ndash;2204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVarghese JM, Roberts JA, Lipman J: Pharmacokinetics and pharmacodynamics in critically ill patients. Curr Opin Anaesthesiol 2010, 23(4):472\u0026ndash;478.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCelis-Rodr\u0026iacute;guez E, D\u0026iacute;az Cort\u0026eacute;s JC, C\u0026aacute;rdenas Bol\u0026iacute;var YR \u003cem\u003eet al\u003c/em\u003e: Evidence-based clinical practice guidelines for the management of sedoanalgesia and delirium in critically ill adult patients. Med Intensiva (Engl Ed) 2020 Apr, 44(3):171\u0026ndash;184.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDAS-Taskforce 2015; Baron R, Binder A, Biniek R \u003cem\u003eet al\u003c/em\u003e: Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) - short version. \u003cem\u003eGer Med Sci\u003c/em\u003e 2015 Nov 12, 13(Coc19).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDevlin JW, Skrobik Y, Gelinas C \u003cem\u003eet al\u003c/em\u003e: Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. \u003cem\u003eCrit Care Med\u003c/em\u003e 2018, 46(9):e825-e873.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGonzalez D, Dahiya G, Mutirangura P \u003cem\u003eet al\u003c/em\u003e: Post Cardiac Arrest Care in the Cardiac Intensive Care Unit. Curr Cardiol Rep 2024, 26(2):35\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrban JC, Cattet F, Lefrant JY \u003cem\u003eet al\u003c/em\u003e: The practice of therapeutic hypothermia after cardiac arrest in France: a national survey. PLoS One 2012, 7(9):e45284.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeye N, Cariou A, Girardie P \u003cem\u003eet al\u003c/em\u003e: Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study. Circulation 2015, 132(3):182\u0026ndash;193.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamps MJ, Horn J, Oddo M \u003cem\u003eet al\u003c/em\u003e: Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature. Intensive Care Med 2013, 39(10):1671\u0026ndash;1682.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCeric A, May TL, Lybeck A \u003cem\u003eet al\u003c/em\u003e: Cardiac Arrest Treatment Center Differences in Sedation and Analgesia Dosing During Targeted Temperature Management. Neurocrit Care 2023, 38(1):16\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDolmans RGF, Nahed BV, Robertson FC, Peul WC, Rosenthal ES, Broekman MLD: Practice-Pattern Variation in Sedation of Neurotrauma Patients in the Intensive Care Unit: An International Survey. J Intensive Care Med 2023, 38(12):1143\u0026ndash;1150.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cardiac arrest, Targeted temperature management, Sedation, Seizures, Propofol, Midazolam ","lastPublishedDoi":"10.21203/rs.3.rs-6155229/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6155229/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The routine use of sedation and analgesia during post-cardiac arrest care and its association with clinical outcomes remain unclear. This study aimed to describe the use of sedatives and analgesics in post-cardiac arrest care, and evaluate associations with good functional outcome, survival, clinical seizures, and late awakening.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This was a \u003cem\u003epost hoc\u003c/em\u003e analysis of the TTM2-trial, which randomised 1900 out-of-hospital cardiac arrest patients to either normothermia or hypothermia. In both groups, deep sedation (Richmond Agitation and Sedation Scale ≤-4) was mandatory during the 40-hour intervention. Cumulative doses of sedatives and analgesic drugs were recorded within the first 72 hours from randomization. Outcomes were functional outcome (modified Rankin Scale) and survival status at 6 months, occurrence of clinical seizures during the intensive care stay, and late awakening (Full outline of unresponsiveness motor score of four 96 hours after randomization). Cumulative propofol doses were divided into quartiles (Q1-Q4). Logistic regression models were used to assess associations between sedative doses and functional outcome and survival, clinical seizures, and late awakening, adjusting for the severity of illness and other clinical factors influencing sedation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 1861 patients were analysed. In a multivariable logistic regression model, higher propofol doses (Q3, 100.7-153.6 mg/kg) were associated with good functional outcome (OR 1.62, 95%CI 1.12 - 2.34) and (Q2 and Q3, 43.9-153.6 mg/kg) with survival (OR 1.49, 95%CI 1.05 - 2.12 and OR 1.84, 95%CI 1.27 - 2.65, respectively). Receiving fentanyl and remifentanil were associated with good functional outcome (OR 1.69, 95%CI 1.27 - 2.26 and OR 1.50, 95%CI 1.11 - 2.02) and survival (OR 1.80, 95%CI 1.35 - 2.40 and OR 1.56, 95%CI 1.16 - 2.10). Receiving fentanyl (OR 0.64, 95%CI 0.48 - 0.86) and higher propofol doses (Q2-4 (43.9-669.4 mg/kg) were associated with the occurrence of clinical seizures. The highest quartile of propofol dose (153.7-669.4 mg/kg, OR 3.19, 95%CI 1.91 - 5.42) was associated with late awakening.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: In this study, higher doses of propofol and the use of remifentanil and fentanyl were associated with good functional outcome and survival, occurrence of clinical seizures, and late awakening.\u003c/p\u003e","manuscriptTitle":"Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 09:02:36","doi":"10.21203/rs.3.rs-6155229/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-14T09:18:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-13T17:28:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"13652657358060370100784739976323473455","date":"2025-04-11T16:29:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-11T14:02:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-11T11:55:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2025-04-09T19:50:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cc7aab71-18d9-46c5-9708-313ccd6cdd83","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-23T15:58:03+00:00","versionOfRecord":{"articleIdentity":"rs-6155229","link":"https://doi.org/10.1186/s13054-025-05461-0","journal":{"identity":"critical-care","isVorOnly":false,"title":"Critical Care"},"publishedOn":"2025-06-17 15:56:50","publishedOnDateReadable":"June 17th, 2025"},"versionCreatedAt":"2025-04-17 09:02:36","video":"","vorDoi":"10.1186/s13054-025-05461-0","vorDoiUrl":"https://doi.org/10.1186/s13054-025-05461-0","workflowStages":[]},"version":"v1","identity":"rs-6155229","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6155229","identity":"rs-6155229","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}