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

BackgroundThe 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.MethodsA retrospective analysis of data from the Time-differentiated Therapeutic Hypothermia (TTH48) trial (NCT01689077), which compared whether TTM at 33 degrees C for 48h 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.ResultsA 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 48h (p=0.22). Time to target temperature (34 degrees C) was significantly shorter for patients treated with endovascular devices (2.2 [1.1-4.0] vs. 4.2 [2.7-6.0] h, pPeer reviewe

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 degrees 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.Peer reviewe

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

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Highly variable pharmacokinetics of dexmedetomidine during intensive care: a case report

<p>Abstract</p> <p>Introduction</p> <p>Dexmedetomidine is a selective and potent alpha2-adrenoceptor agonist licensed for use in the sedation of patients initially ventilated in intensive care units at a maximum dose rate of 0.7 μg/kg/h administered for up to 24 hours. Higher dose rates and longer infusion periods are sometimes required to achieve sufficient sedation. There are some previous reports on the use of long-term moderate to high-dose infusions of dexmedetomidine in patients in intensive care units, but none of these accounts have cited dexmedetomidine plasma concentrations.</p> <p>Case presentation</p> <p>We describe the case of a 42-year-old Caucasian woman with severe hemorrhagic pancreatitis following laparoscopic cholecystectomy who received dexmedetomidine for 24 consecutive days at a maximum dose rate of 1.9 μg/kg/h. Samples for the measurement of dexmedetomidine concentrations in her plasma were drawn at intervals of eight hours. On average, the observed plasma concentrations were well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine. There was, however, marked variability in the concentration of dexmedetomidine in her plasma despite a stable infusion rate.</p> <p>Conclusion</p> <p>The pharmacokinetics of dexmedetomidine appears to be highly variable during intensive care.</p

Temporal Trends in Healthcare Costs and Outcome Following ICU Admission After Traumatic Brain Injury

Objective: To assess temporal trends in 1-year healthcare costs and outcome of intensive care for traumatic brain injury in Finland. Design: Retrospective observational cohort study. Setting: Multicenter study including four tertiary ICUs. Patients: Three thousand fifty-one adult patients (>= 18 yr) with significant traumatic brain injury treated in a tertiary ICU during 2003-2013. Intervention: None. Measurements and Main Results: Total 1-year healthcare costs included the index hospitalization costs, rehabilitation unit costs, and social security reimbursements. All costs are reported as 2013 U.S. dollars ($). Outcomes were 1-year mortality and permanent disability. Multivariate regression models, adjusting for case-mix, were used to assess temporal trends in costs and outcome in predefined Glasgow Coma Scale (3-8, 9-12, and 13-15) and age (18-40, 41-64, and >= 65 yr) subgroups. Overall 1-year survival was 76$39,809 (95% CI, $38,144-$41,473) per patient. Adjusted healthcare costs decreased only in the Glasgow Coma Scale 13-15 and 65 years and older subgroups, due to lower rehabilitation costs. Adjusted 1-year mortality did not change in any subgroup (p <0.05 for all subgroups). Adjusted risk of permanent disability decreased significantly in all subgroups (p <0.05). Conclusion: During the last decade, healthcare costs of ICU-admitted traumatic brain injury patients have remained largely the same in Finland. No change in mortality was noted, but the risk for permanent disability decreased significantly. Thus, our results suggest that cost-effectiveness of traumatic brain injury care has improved during the past decade in Finland.Peer reviewe

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 degrees 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. (C) 2020 Published by Elsevier Inc.Peer reviewe

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 mu g ml(-1); n = 40), sevoflurane (0.9% end-tidal; n = 39), S-ketamine (0.75 mu g 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.Peer reviewe