A metabolic profile of xenon and metabolite associations with 6-month mortality after out-of-hospital cardiac arrest: A post-hoc study of the randomised Xe-Hypotheca trial.

PURPOSE: Out-of-hospital cardiac arrest (OHCA) carries a relatively poor prognosis and requires multimodal prognostication to guide clinical decisions. Identification of previously unrecognized metabolic routes associated with patient outcome may contribute to future biomarker discovery. In OHCA, inhaled xenon elicits neuro- and cardioprotection. However, the metabolic effects remain unknown. MATERIALS AND METHODS: In this post-hoc study of the randomised, 2-group, single-blind, phase 2 Xe-Hypotheca trial, 110 OHCA survivors were randomised 1:1 to receive targeted temperature management (TTM) at 33°C with or without inhaled xenon during 24 h. Blood samples for nuclear magnetic resonance spectroscopy metabolic profiling were drawn upon admission, at 24 and 72 h. RESULTS: At 24 h, increased lactate, adjusted hazard-ratio 2.25, 95% CI [1.53; 3.30], p<0.001, and decreased branched-chain amino acids (BCAA) leucine 0.64 [0.5; 0.82], p = 0.007, and valine 0.37 [0.22; 0.63], p = 0.003, associated with 6-month mortality. At 72 h, increased lactate 2.77 [1.76; 4.36], p<0.001, and alanine 2.43 [1.56; 3.78], p = 0.001, and decreased small HDL cholesterol ester content (S-HDL-CE) 0.36 [0.19; 0.68], p = 0.021, associated with mortality. No difference was observed between xenon and control groups. CONCLUSIONS: In OHCA patients receiving TTM with or without xenon, high lactate and alanine and decreased BCAAs and S-HDL-CE associated with increased mortality. It remains to be established whether current observations on BCAAs, and possibly alanine and lactate, could reflect neural damage via their roles in the metabolism of the neurotransmitter glutamate. Xenon did not significantly alter the measured metabolic profile, a potentially beneficial attribute in the context of compromised ICU patients. TRIAL REGISTRATION: Trial Registry number: ClinicalTrials.gov Identifier: NCT00879892.

Dysnatremia at ICU admission and functional outcome of cardiac arrest: insights from four randomised controlled trials.

PURPOSE: To evaluate the potential association between early dysnatremia and 6-month functional outcome after cardiac arrest. METHODS: We pooled data from four randomised clinical trials in post-cardiac-arrest patients admitted to the ICU with coma after stable return of spontaneous circulation (ROSC). Admission natremia was categorised as normal (135-145 mmol/L), low, or high. We analysed associations between natremia category and Cerebral Performance Category (CPC) 1 or 2 at 6 months, with and without adjustment on the modified Cardiac Arrest Hospital Prognosis Score (mCAHP). RESULTS: We included 1163 patients (581 from HYPERION, 352 from TTH48, 120 from COMACARE, and 110 from Xe-HYPOTHECA) with a mean age of 63 ± 13 years and a predominance of males (72.5%). A cardiac cause was identified in 63.6% of cases. Median time from collapse to ROSC was 20 [15-29] minutes. Overall, mean natremia on ICU admission was 137.5 ± 4.7 mmol/L; 211 (18.6%) and 31 (2.7%) patients had hyponatremia and hypernatremia, respectively. By univariate analysis, CPC 1 or 2 at 6 months was significantly less common in the group with hyponatremia (50/211 [24%] vs. 363/893 [41%]; P = 0.001); the mCAHP-adjusted odds ratio was 0.45 (95%CI 0.26-0.79, p = 0.005). The number of patients with hypernatremia was too small for a meaningful multivariable analysis. CONCLUSIONS: Early hyponatremia was common in patients with ROSC after cardiac arrest and was associated with a poorer 6-month functional outcome. The mechanisms underlying this association remain to be elucidated in order to determine whether interventions targeting hyponatremia are worth investigating. Registration ClinicalTrial.gov, NCT01994772, November 2013, 21.

Effect of xenon on brain injury, neurological outcome, and survival in patients after aneurysmal subarachnoid hemorrhage-study protocol for a randomized clinical trial.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a neurological emergency, affecting a younger population than individuals experiencing an ischemic stroke; aSAH is associated with a high risk of mortality and permanent disability. The noble gas xenon has been shown to possess neuroprotective properties as demonstrated in numerous preclinical animal studies. In addition, a recent study demonstrated that xenon could attenuate a white matter injury after out-of-hospital cardiac arrest. METHODS: The study is a prospective, multicenter phase II clinical drug trial. The study design is a single-blind, prospective superiority randomized two-armed parallel follow-up study. The primary objective of the study is to explore the potential neuroprotective effects of inhaled xenon, when administered within 6 h after the onset of symptoms of aSAH. The primary endpoint is the extent of the global white matter injury assessed with magnetic resonance diffusion tensor imaging of the brain. DISCUSSION: Despite improvements in medical technology and advancements in medical science, aSAH mortality and disability rates have remained nearly unchanged for the past 10 years. Therefore, new neuroprotective strategies to attenuate the early and delayed brain injuries after aSAH are needed to reduce morbidity and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT04696523. Registered on 6 January 2021. EudraCT, EudraCT Number: 2019-001542-17. Registered on 8 July 2020.

Decreased Thalamic Activity Is a Correlate for Disconnectedness during Anesthesia with Propofol, Dexmedetomidine and Sevoflurane But Not S-Ketamine.

Establishing the neural mechanisms responsible for the altered global states of consciousness during anesthesia and dissociating these from other drug-related effects remains a challenge in consciousness research. We investigated differences in brain activity between connectedness and disconnectedness by administering various anesthetics at concentrations designed to render 50% of the subjects unresponsive. One hundred and sixty healthy male subjects were randomized to receive either propofol (1.7 µg/ml; n = 40), dexmedetomidine (1.5 ng/ml; n = 40), sevoflurane (0.9% end-tidal; n = 40), S-ketamine (0.75 µg/ml; n = 20), or saline placebo (n = 20) for 60 min using target-controlled infusions or vaporizer with end-tidal monitoring. Disconnectedness was defined as unresponsiveness to verbal commands probed at 2.5-min intervals and unawareness of external events in a postanesthesia interview. High-resolution positron emission tomography (PET) was used to quantify regional cerebral metabolic rates of glucose (CMRglu) utilization. Contrasting scans where the subjects were classified as connected and responsive versus disconnected and unresponsive revealed that for all anesthetics, except S-ketamine, the level of thalamic activity differed between these states. A conjunction analysis across the propofol, dexmedetomidine and sevoflurane groups confirmed the thalamus as the primary structure where reduced metabolic activity was related to disconnectedness. Widespread cortical metabolic suppression was observed when these subjects, classified as either connected or disconnected, were compared with the placebo group, suggesting that these findings may represent necessary but alone insufficient mechanisms for the change in the state of consciousness.SIGNIFICANCE STATEMENT Experimental anesthesia is commonly used in the search for measures of brain function which could distinguish between global states of consciousness. However, most previous studies have not been designed to separate effects related to consciousness from other effects related to drug exposure. We employed a novel study design to disentangle these effects by exposing subjects to predefined EC50 doses of four commonly used anesthetics or saline placebo. We demonstrate that state-related effects are remarkably limited compared with the widespread cortical effects related to drug exposure. In particular, decreased thalamic activity was associated with disconnectedness with all used anesthetics except for S-ketamine.

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest-a substudy of the XeHypotheca trial.

PURPOSE: We compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA). METHODS: The predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72 h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 - 6) in 92 comatose OHCA patients at 6 months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory. RESULTS: The predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62-0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 - 0.88)), or NSE at 72 h (0.85 (0.76 - 0.93)) was not significantly better than motor score at 72 h (0.88 (95% CI 0.80-0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85-0.98) vs 0.98 (0.96-1.00), p = 0.037). CONCLUSION: None of the variables (FA, tNAA/tCr, ES, NSE at 72 h, and motor score at 72 h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use. TRIAL REGISTRATION: ClinicalTrials.gov NCT00879892, April 13, 2009.

Electrolyte profiles with induced hypothermia: A sub study of a clinical trial evaluating the duration of hypothermia after cardiac arrest.

BACKGROUND: Electrolyte disturbances can result from targeted temperature treatment (TTM) in out-of-hospital cardiac arrest (OHCA) patients. This study explores electrolyte changes in blood and urine in OHCA patients treated with TTM. METHODS: This is a sub-study of the TTH48 trial, with the inclusion of 310 unconscious OHCA patients treated with TTM at 33°C for 24 or 48 h. Over a three-day period, serum concentrations were obtained on sodium potassium, chloride, ionized calcium, magnesium and phosphate, as were results from a 24-h diuresis and urine electrolyte concentration and excretion. Changes over time were analysed with a mixed-model multivariate analysis of variance with repeated measurements. RESULTS: On admission, mean ± SD sodium concentration was 138 ± 3.5 mmol/l, which increased slightly but significantly (p < .05) during the first 24 h. Magnesium concentration stayed within the reference interval. Median ionized calcium concentration increased from 1.11 (IQR 1.1-1.2) mmol/l during the first 24 h (p < .05), whereas median phosphate concentration dropped to 1.02 (IQR 0.8-1.2) mmol/l (p < .05) and stayed low. During rewarming, potassium concentrations increased, and magnesium and ionizes calcium concentration decreased (p < .05). Median 24-h diuresis results on days one and two were 2198 and 2048 ml respectively, and the electrolyte excretion mostly stayed low in the reference interval. CONCLUSIONS: Electrolytes mostly remained within the reference interval. A temporal change occurred in potassium, magnesium and calcium concentrations with TTM's different phases. No hypothermia effect on diuresis was detected, and urine excretion of electrolytes mostly stayed low.

Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine: a randomised controlled trial using tandem mass spectrometry.

Background: This exploratory study aimed to investigate whether dexmedetomidine, propofol, sevoflurane, and S-ketamine affect oxylipins and bile acids, which are functionally diverse molecules with possible connections to cellular bioenergetics, immune modulation, and organ protection. Methods: In this randomised, open-label, controlled, parallel group, Phase IV clinical drug trial, healthy male subjects (n=160) received equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml-1; n=40), propofol (1.7 µg ml-1; n=40), sevoflurane (0.9% end-tidal; n=40), S-ketamine (0.75 µg ml-1; n=20), or placebo (n=20). Blood samples for tandem mass spectrometry were obtained at baseline, after study drug administration at 60 and 130 min from baseline; 40 metabolites were analysed. Results: Statistically significant changes vs placebo were observed in 62.5%, 12.5%, 5.0%, and 2.5% of analytes in dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively. Data are presented as standard deviation score, 95% confidence interval, and P-value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) -1.19 (-1.6; -0.78), P<0.001 and 12,13-DiHOME -1.22 (-1.66; -0.77), P<0.001 were affected. Propofol elevated 9,10-DiHOME 2.29 (1.62; 2.96), P<0.001 and 12,13-DiHOME 2.13 (1.42; 2.84), P<0.001. Analytes were mostly unaffected by S-ketamine. Sevoflurane decreased tauroursodeoxycholic acid (TUDCA) -2.7 (-3.84; -1.55), P=0.015. Conclusions: Dexmedetomidine-induced oxylipin alterations may be connected to pathways associated with organ protection. In contrast to dexmedetomidine, propofol emulsion elevated DiHOMEs, oxylipins associated with acute respiratory distress syndrome, and mitochondrial dysfunction in high concentrations. Further research is needed to establish the behaviour of DIHOMEs during prolonged propofol/dexmedetomidine infusions and to verify the sevoflurane-induced reduction in TUDCA, a suggested neuroprotective agent. Clinical trial registration: NCT02624401.

Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome: A randomised trial using nuclear magnetic resonance spectroscopy.

BACKGROUND: Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE: We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN: Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING: The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS: One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS: Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml-1; n  = 40), propofol (1.7 µg ml-1; n  = 40), sevoflurane (0.9% end-tidal; n  = 39), S-ketamine (0.75 µg ml-1; n  = 20) or placebo (n = 20). MAIN OUTCOME MEASURES: Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia. RESULTS: All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased. CONCLUSION: A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624401.

On no man's land: Subjective experiences during unresponsive and responsive sedative states induced by four different anesthetic agents.

To understand how anesthetics with different molecular mechanisms affect consciousness, we explored subjective experiences recalled after responsive and unresponsive sedation induced with equisedative doses of dexmedetomidine, propofol, sevoflurane, and S-ketamine in healthy male participants (N = 140). The anesthetics were administered in experimental setting using target-controlled infusion or vapouriser for one hour. Interviews conducted after anesthetic administration revealed that 46.9% (n = 46) of arousable participants (n = 98) reported experiences, most frequently dreaming or memory incorporation of the setting. Participants receiving dexmedetomidine reported experiences most often while S-ketamine induced the most multimodal experiences. Responsiveness at the end of anesthetic administration did not affect the prevalence or content of reported experiences. These results demonstrate that subjective experiences during responsive and unresponsive sedation are common and anesthetic agents with different molecular mechanisms of action may have different effects on the prevalence and complexity of the experiences, albeit in the present sample the differences between drugs were minute.

Effect of Inhaled Xenon on Cardiac Function in Comatose Survivors of Out-of-Hospital Cardiac Arrest-A Substudy of the Xenon in Combination With Hypothermia After Cardiac Arrest Trial.

This explorative substudy aimed at determining the effect of inhaled xenon on left ventricular function by echocardiography in comatose survivors of out-of-hospital cardiac arrest. DESIGN: A randomized two-group single-blinded phase 2 clinical drug trial. SETTING: A multipurpose ICU in two university hospitals. PATIENTS: Of the 110 randomized comatose survivors after out-of-hospital cardiac arrest with a shockable rhythm in the xenon in combination with hypothermia after cardiac arrest trial, 38 patients (24-76 yr old) with complete echocardiography were included in this study. INTERVENTIONS: Patients were randomized to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours or hypothermia treatment alone. Echocardiography was performed at hospital admission and 24 ± 4 hours after hypothermia. MEASUREMENTS AND MAIN RESULTS: Left ventricular ejection fraction, myocardial longitudinal systolic strain, and diastolic function were analyzed blinded to treatment. There were 17 xenon and 21 control patients in whom echocardiography was completed. Clinical characteristics did not differ significantly between the groups. At admission, ejection fraction was similar in xenon and control patients (39% ± 10% vs 38% ± 11%; p = 0.711) but higher in xenon than control patients after hypothermia (50% ± 10% vs 42% ± 10%; p = 0.014). Global longitudinal systolic strain was similar in xenon and control patients at admission (-9.0% ± 3.8% vs -8.1% ± 3.6%; p = 0.555) but better in xenon than control patients after hypothermia (-14.4.0% ± 4.0% vs -10.5% ± 4.0%; p = 0.006). In patients with coronary artery disease, longitudinal strain improved in the nonischemic myocardial segments in xenon patients. There were no changes in diastolic function between the groups. CONCLUSIONS: Among comatose survivors of a cardiac cause out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia was associated with greater recovery of left ventricular systolic function in comparison with hypothermia alone.

Factors Associated With Rebound Hyperthermia After Targeted Temperature Management in Out-of-Hospital Cardiac Arrest Patients: An Explorative Substudy of the Time-Differentiated Therapeutic Hypothermia in Out-of-Hospital Cardiac Arrest Survivors Trial.

To investigate rebound hyperthermia following targeted temperature management after cardiac arrest and its impact on functional outcome. DESIGN: Post hoc analysis. SETTING: Ten European ICUs. PATIENTS: Patients included in the time-differentiated therapeutic hypothermia in out-of-hospital cardiac arrest survivors trial treated with targeted temperature management at 33°C for 48 or 24 hours. Favorable functional outcome was defined as a Cerebral Performance Category of 1 or 2 at 6 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 338 included patients, 103 (30%) experienced rebound hyperthermia defined as a maximum temperature after targeted temperature management and rewarming exceeding 38.5°C. Using multivariate logistic regression analysis, increasing age (odds ratio, 0.97; 95% CI, 0.95-0.99; p = 0.02) and severe acute kidney injury within 72 hours of ICU admission (odds ratio, 0.35; 95% CI, 0.13-0.91; p = 0.03) were associated with less rebound hyperthermia, whereas male gender (odds ratio, 3.94; 95% CI, 1.34-11.57; p = 0.01), highest C-reactive protein value (odds ratio, 1.04; 95% CI, 1.01-1.07; p = 0.02), and use of mechanical chest compression during cardiopulmonary resuscitation (odds ratio, 2.00; 95% CI, 1.10-3.67; p = 0.02) were associated with more rebound hyperthermia. Patients with favorable functional outcome spent less time after rewarming over 38.5°C (2.5% vs 6.3%; p = 0.03), 39°C (0.14% vs 2.7%; p < 0.01), and 39.5°C (0.03% vs 0.71%; p < 0.01) when compared with others. Median time to rebound hyperthermia was longer in the unfavorable functional outcome group (33.2 hr; interquartile range, 14.3-53.0 hr vs 6.5 hr; interquartile range, 2.2-34.1; p < 0.01). In a predefined multivariate binary logistic regression model, rebound hyperthermia was associated with decreased odds of favorable functional outcome (odds ratio, 0.42; 95% CI, 0.22-0.79). CONCLUSIONS: One-third of targeted temperature management patients experience rebound hyperthermia, and it is more common in younger male patients with an aggravated inflammatory response and those treated with a mechanical chest compression device. Later onset of rebound hyperthermia and temperatures exceeding 38.5°C associate with unfavorable outcome.

Quality of targeted temperature management and outcome of out-of-hospital cardiac arrest patients: A post hoc analysis of the TTH48 study.

BACKGROUND: No data are available on the quality of targeted temperature management (TTM) provided to out-of-hospital cardiac arrest (OHCA) patients and its association with outcome. METHODS: Post hoc analysis of the TTH48 study (NCT01689077), which compared the effects of prolonged TTM at 33 °C for 48 h to standard 24-h TTM on neurologic outcome. Admission temperature, speed of cooling, rewarming rates, precision (i.e. temperature variability), overcooling and overshooting as post-cooling fever (i.e. >38.0 °C) were collected. A specific score, ranging from 1 to 9, was computed to define the "quality of TTM". RESULTS: On a total of 352 patients, most had a moderate quality of TTM (n = 217; 62% - score 4-6), while 80 (23%) patients had a low quality of TTM (score 1-3) and only 52 (16%) a high quality of TTM (score 7-9). The proportion of patients with unfavorable neurological outcome (UO; Cerebral Performance Category of 3-5 at 6 months) was similar between the different quality of TTM groups (p = 0.90). Although a shorter time from arrest to target temperature and a lower proportion of time outside the target ranges in the TTM 48-h than in the TTM 24-h group, quality of TTM was similar between groups. Also, the proportion of patients with UO was similar between the different quality of TTM groups when TTM 48-h and TTM 24-h were compared. CONCLUSIONS: In this study, high quality of TTM was provided to a small proportion of patients. However, quality of TTM was not associated with patients' outcome.

Severe or critical hypotension during post cardiac arrest care is associated with factors available on admission - a post hoc analysis of the TTH48 trial.

PURPOSE: We explored whether severe or critical hypotension can be predicted, based on patient and resuscitation characteristics in out-of-hospital cardiac arrest (OHCA) patients. We also explored the association of hypotension with mortality and neurological outcome. MATERIALS AND METHODS: We conducted a post hoc analysis of the TTH48 study (NCT01689077), where 355 out-of-hospital cardiac arrest (OHCA) patients were randomized to targeted temperature management (TTM) treatment at 33 °C for either 24 or 48 h. We recorded hypotension, according to four severity categories, within four days from admission. We used multivariable logistic regression analysis to test association of admission data with severe or critical hypotension. RESULTS: Diabetes mellitus (OR 3.715, 95% CI 1.180-11.692), longer ROSC delay (OR 1.064, 95% CI 1.022-1.108), admission MAP (OR 0.960, 95% CI 0.929-0.991) and non-shockable rhythm (OR 5.307, 95% CI 1.604-17.557) were associated with severe or critical hypotension. Severe or critical hypotension was associated with increased mortality and poor neurological outcome at 6 months. CONCLUSIONS: Diabetes, non-shockable rhythm, longer delay to ROSC and lower admission MAP were predictors of severe or critical hypotension. Severe or critical hypotension was associated with poor outcome.

Haemodynamics and vasopressor support during prolonged targeted temperature management for 48 hours after out-of-hospital cardiac arrest: a post hoc substudy of a randomised clinical trial.

BACKGROUND: Comatose patients admitted after out-of-hospital cardiac arrest frequently experience haemodynamic instability and anoxic brain injury. Targeted temperature management is used for neuroprotection; however, targeted temperature management also affects patients' haemodynamic status. This study assessed the haemodynamic status of out-of-hospital cardiac arrest survivors during prolonged (48 hours) targeted temperature management at 33°C. METHODS: Analysis of haemodynamic and vasopressor data from 311 patients included in a randomised, clinical trial conducted in 10 European hospitals (the TTH48 trial). Patients were randomly allocated to targeted temperature management at 33°C for 24 (TTM24) or 48 (TTM48) hours. Vasopressor and haemodynamic data were reported hourly for 72 hours after admission. Vasopressor load was calculated as norepinephrine (µg/kg/min) plus dopamine(µg/kg/min/100) plus epinephrine (µg/kg/min). RESULTS: After 24 hours, mean arterial pressure (mean±SD) was 74±9 versus 75±9 mmHg (P=0.19), heart rate was 57±16 and 55±14 beats/min (P=0.18), vasopressor load was 0.06 (0.03-0.15) versus 0.08 (0.03-0.15) µg/kg/min (P=0.22) for the TTM24 and TTM48 groups, respectively. From 24 to 48 hours, there was no difference in mean arterial pressure (Pgroup=0.32) or lactate (Pgroup=0.20), while heart rate was significantly lower (average difference 5 (95% confidence interval 2-8) beats/min, Pgroup<0.0001) and vasopressor load was significantly higher in the TTM48 group (Pgroup=0.005). In a univariate Cox regression model, high vasopressor load was associated with mortality in univariate analysis (hazard ratio 1.59 (1.05-2.42) P=0.03), but not in multivariate analysis (hazard ratio 0.77 (0.46-1.29) P=0.33). CONCLUSIONS: In this study, prolonged targeted temperature management at 33°C for 48 hours was associated with higher vasopressor requirement but no sign of any detrimental haemodynamic effects.

The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: A post hoc analysis of the TTH48 trial.

BACKGROUND: Acute kidney injury (AKI) is common after cardiac arrest and targeted temperature management (TTM). The impact of different lengths of cooling on the development of AKI has not been well studied. In this study of patients included in a randomised controlled trial of TTM at 33 °C for 24 versus 48 h after cardiac arrest (TTH48 trial), we examined the influence of prolonged TTM on AKI and the incidence and factors associated with the development of AKI. We also examined the impact of AKI on survival. METHODS: This study was a sub-study of the TTH48 trial, which included patients cooled to 33 ±â€¯1 °C after out-of-hospital cardiac arrest for 24 versus 48 h. AKI was classified according to the KDIGO AKI criteria based on serum creatinine and urine output collected until ICU discharge for a maximum of seven days. Survival was followed for up to six months. The association of admission factors on AKI was analysed with multivariate analysis and the association of AKI on mortality was analysed with Cox regression using the time to AKI as a time-dependent covariate. RESULTS: Of the 349 patients included in the study, 159 (45.5%) developed AKI. There was no significant difference in the incidence, severity or time to AKI between the 24- and 48-h groups. Serum creatinine values had significantly different trajectories for the two groups with a sharp rise occurring during rewarming. Age, time to return of spontaneous circulation, serum creatinine at admission and body mass index were independent predictors of AKI. Patients with AKI had a higher mortality than patients without AKI (hospital mortality 36.5% vs 12.5%, p < 0.001), but only AKI stages 2 and 3 were independently associated with mortality. CONCLUSIONS: We did not find any association between prolonged TTM at 33 °C and the risk of AKI during the first seven days in the ICU. AKI is prevalent after cardiac arrest and TTM and occurs in almost half of all ICU admitted patients and more commonly in the elderly, with an increasing BMI and longer arrest duration. AKI after cardiac arrest is an independent predictor of time to death.

Cold fluids for induction of targeted temperature management: A sub-study of the TTH48 trial.

BACKGROUND: Pre-intensive care unit (ICU) induction of targeted temperature management (TTM) with cold intravenous (i.v.) fluids does not appear to improve outcomes after in out-of-hospital cardiac arrest (OHCA). We hypothesized that this may be due to ineffective cooling and side effects. METHODS: A post hoc analysis of a sub-group of patients (n = 352) in the TTH48 trial (NCT01689077) who received or did not receive pre-ICU cooling using cold i.v. fluids. Data collection included patient characteristics, cardiac arrest factors, cooling methods, side effects and continuous core temperature measurements. The primary endpoint was the time to target temperature (TTT, <34 °C), and the secondary endpoints included the incidence of circulatory side effects, abnormal electrolyte levels and hypoxia within the first 24 h of ICU care. A difference of 1 h in the TTT was determined as clinically significant a priori. RESULTS: Of 352 patients included in the present analysis, 110 received pre-ICU cold fluids. The median time to the return of spontaneous circulation (ROSC) and TTT in the pre-ICU cold fluids group was longer than that of the group that did not receive pre-ICU cold fluids (318 vs. 281 min, p < 0.01). In a linear regression model including the treatment centre, body mass index (BMI), chronic heart failure, diabetes mellitus and time to ROSC, the use of pre-ICU cold i.v. fluids was not associated with a shorter time to the target temperature (standardized beta coefficient: 0.06, 95% CI for B -49 and 16, p  =  0.32). According to the receipt or not of pre-ICU cold i.v. fluids, there was no difference in the proportion of patients with hypoxia on ICU admission (1.8% vs. 3.3%, p =  0.43) or the proportion of patients with electrolyte abnormalities (hyponatremia: 1.8% vs. 2.9% p = 0.54; hypokalaemia: 1.8% vs. 4.5%, p =  0.20). Furthermore, there was no difference in hospital mortality between the groups. CONCLUSIONS: The initiation of TTM with cold i.v. fluids before ICU arrival did not decrease the TTT. We detected no significant between-group difference in mortality or the incidence of side effects according to the administration or not of pre-ICU cold i.v fluids.

Haemodynamics and vasopressor support during prolonged targeted temperature management for 48 hours after out-of-hospital cardiac arrest: a post hoc substudy of a randomised clinical trial.

BACKGROUND: Comatose patients admitted after out-of-hospital cardiac arrest frequently experience haemodynamic instability and anoxic brain injury. Targeted temperature management is used for neuroprotection; however, targeted temperature management also affects patients' haemodynamic status. This study assessed the haemodynamic status of out-of-hospital cardiac arrest survivors during prolonged (48 hours) targeted temperature management at 33°C. METHODS: Analysis of haemodynamic and vasopressor data from 311 patients included in a randomised, clinical trial conducted in 10 European hospitals (the TTH48 trial). Patients were randomly allocated to targeted temperature management at 33°C for 24 (TTM24) or 48 (TTM48) hours. Vasopressor and haemodynamic data were reported hourly for 72 hours after admission. Vasopressor load was calculated as norepinephrine (µg/kg/min) plus dopamine(µg/kg/min/100) plus epinephrine (µg/kg/min). RESULTS: After 24 hours, mean arterial pressure (mean±SD) was 74±9 versus 75±9 mmHg (P=0.19), heart rate was 57±16 and 55±14 beats/min (P=0.18), vasopressor load was 0.06 (0.03-0.15) versus 0.08 (0.03-0.15) µg/kg/min (P=0.22) for the TTM24 and TTM48 groups, respectively. From 24 to 48 hours, there was no difference in mean arterial pressure (Pgroup=0.32) or lactate (Pgroup=0.20), while heart rate was significantly lower (average difference 5 (95% confidence interval 2-8) beats/min, Pgroup<0.0001) and vasopressor load was significantly higher in the TTM48 group (Pgroup=0.005). In a univariate Cox regression model, high vasopressor load was associated with mortality in univariate analysis (hazard ratio 1.59 (1.05-2.42) P=0.03), but not in multivariate analysis (hazard ratio 0.77 (0.46-1.29) P=0.33). CONCLUSIONS: In this study, prolonged targeted temperature management at 33°C for 48 hours was associated with higher vasopressor requirement but no sign of any detrimental haemodynamic effects.

Hypothermic to ischemic ratio and mortality in post-cardiac arrest patients.

BACKGROUND: We studied the associations between ischemia and hypothermia duration, that is, the hypothermic to ischemic ratio (H/I ratio), with mortality in patients included in a trial on two durations of targeted temperature management (TTM) at 33°C. METHODS: The TTH48 (NCT01689077) trial compared 24 and 48 hours of TTM in patients after cardiac arrest. We calculated the hypothermia time from return of spontaneous circulation (ROSC) until the patient reached 37°C after TTM and the ischemic time from CA to ROSC. We compared continuous variables with the Mann-Whitney U test. Using COX regression, we studied the independent association of the logarithmically transformed H/I ratio and time to death as well as interaction between time to ROSC, hypothermia duration, and intervention group. We visualized the predictive ability of variables with receiver operating characteristic curve analysis. RESULTS: Of the 338 patients, 237 (70%) survived for 6 months. The H/I ratio was 155 (IQR 111-238) in survivors and 114 (IQR 80-169) in non-survivors (P < .001). In a Cox regression model including factors associated with outcome in univariate analysis, the logarithmically transformed H/I ratio was a significant predictor of outcome (hazard ratio 0.52 (0.37-0.72, P = .001)). After removing an outlier, we found no interaction between time to ROSC and intervention group (P = .55) or hypothermia duration in quartiles (P = .07) with mortality. There was no significant difference in the area under the curve (AUC) between time to ROSC and H/I ratio (ΔAUC 0.03 95% CI -0.006-0.07, P = .10). CONCLUSIONS: We did not find any consistent evidence of a modification of the effect of TTM based on ischemia duration.

Neuroprotective Properties of Xenon.

Xenon is a rare noble gas that was introduced into clinical practice more than 70 years ago. Xenon's clinical properties are predicated by its ability to fit into preformed cavities of macromolecules thereby altering their biological functions. One such action targets the NMDA-subtype of the glutamate receptors thereby inhibiting its excitatory action. As the glutamate receptors are pivotal for both anesthesia and acute neurological injury, its clinical use has included both general anesthesia as well as neuroprotection. In this manuscript, the efficacy and safety of xenon in clinical trials that address both the anesthetic and neuroprotective applications are discussed. Because of the clinical safety of this chemically inert monatomic gas, the lack of an alternative for neuroprotection, and encouraging phase 2 trial data, a multinational pivotal randomized clinical trial (XePOHCAS) has been launched to assess the utility of xenon for patients that have been successfully resuscitated following an out of hospital cardiac arrest but still remain comatose, indicating ongoing neurological ischemic-perfusion injury. If successful, the trial will herald a new era of treatments for previously intractable conditions such as traumatic brain injury, ischemic and hemorrhagic strokes, and anesthetic-induced developmental neurotoxicity.

Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest: an analysis of the TTH48 trial.

BACKGROUND: The aim of this study was to explore the performance and outcomes for intravascular (IC) versus surface cooling devices (SFC) for targeted temperature management (TTM) after out-of-hospital cardiac arrest. METHODS: A retrospective analysis of data from the Time-differentiated Therapeutic Hypothermia (TTH48) trial (NCT01689077), which compared whether TTM at 33 °C for 48 h results in better neurologic outcomes compared with standard 24-h duration. Devices were assessed for the speed of cooling and rewarming rates. Precision was assessed by measuring temperature variability (TV), i.e., the standard deviation (SD) of all temperature measurements in the cooling phase. Main outcomes were overall mortality and poor neurological outcome, including death, severe disability, or vegetative status. RESULTS: A total of 352 patients had available data and were included in the analysis; of those, 218 (62%) were managed with IC. A total of 114/218 (53%) patients with IC and 61/134 (43%) with SFC were cooled for 48 h (p = 0.22). Time to target temperature (≤ 34 °C) was significantly shorter for patients treated with endovascular devices (2.2 [1.1-4.0] vs. 4.2 [2.7-6.0] h, p < 0.001), but temperature was also lower on admission (35.0 [34.2-35.6] vs. 35.3 [34.5-35.8]°C; p = 0.02) and cooling rate was similar (0.4 [0.2-0.8] vs. 0.4 [0.2-0.6]°C/h; p = 0.14) when compared to SFC. Temperature variability was significantly lower in the endovascular device group when compared with SFC methods (0.6 [0.4-0.9] vs. 0.7 [0.5-1.0]°C; p = 0.007), as was rewarming rate (0.31 [0.22-0.44] vs. 0.37 [0.29-0.49]°C/hour; p = 0.02). There was no statistically significant difference in mortality (endovascular 65/218, 29% vs. others 43/134, 32%; p = 0.72) or poor neurological outcome (endovascular 69/218, 32% vs. others 51/134, 38%; p = 0.24) between type of devices. CONCLUSIONS: Endovascular cooling devices were more precise than SFC methods in patients cooled at 33 °C after out-of-hospital cardiac arrest. Main outcomes were similar with regard to the cooling methods.