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.

Effect of antiplatelet and anticoagulant medication use on injury severity and mortality in patients with traumatic brain injury treated in the intensive care unit.

BACKGROUND: Antiplatelet and anticoagulant medication are increasingly common and can increase the risks of morbidity and mortality in traumatic brain injury (TBI) patients. Our study aimed to quantify the association of antiplatelet or anticoagulant use in intensive care unit (ICU)-treated TBI patients with 1-year mortality and head CT findings. METHOD: We conducted a retrospective, multicenter observational study using the Finnish Intensive Care Consortium database. We included adult TBI patients admitted to four university hospital ICUs during 2003-2013. The patients were followed up until the end of 2016. The national drug reimbursement database provided information on prescribed medication for our study. We used multivariable logistic regression models to assess the association between TBI severity, prescribed antiplatelet and anticoagulant medication, and their association with 1-year mortality. RESULTS: Of 3031 patients, 128 (4%) had antiplatelet and 342 (11%) anticoagulant medication before their TBI. Clopidogrel (2%) and warfarin (9%) were the most common antiplatelets and anticoagulants. Three patients had direct oral anticoagulant (DOAC) medication. The median age was higher among antiplatelet/anticoagulant users than in non-users (70 years vs. 52 years, p < 0.001), and their head CT findings were more severe (median Helsinki CT score 3 vs. 2, p < 0.05). In multivariable analysis, antiplatelets (OR 1.62, 95% CI 1.02-2.58) and anticoagulants (OR 1.43, 95% CI 1.06-1.94) were independently associated with higher odds of 1-year mortality. In a sensitivity analysis including only patients over 70, antiplatelets (OR 2.28, 95% CI 1.16-4.22) and anticoagulants (1.50, 95% CI 0.97-2.32) were associated with an increased risk of 1-year mortality. CONCLUSIONS: Both antiplatelet and anticoagulant use before TBI were risk factors in our study for 1-year mortality. Antiplatelet and anticoagulation medication users had a higher radiological intracranial injury burden than non-users defined by the Helsinki CT score. Further investigation on the effect of DOACs on mortality should be done in ICU-treated TBI patients.

Trends in mortality after intensive care of patients with traumatic brain injury in Finland from 2003 to 2019: a Finnish Intensive Care Consortium study.

BACKGROUND: Several studies have suggested no change in the outcome of patients with traumatic brain injury (TBI) treated in intensive care units (ICUs). This is mainly due to the shift in TBI epidemiology toward older and sicker patients. In Finland, the share of the population aged 65 years and over has increased the most in Europe during the last decade. We aimed to assess changes in 12-month and hospital mortality of patients with TBI treated in the ICU in Finland. METHODS: We used a national benchmarking ICU database (Finnish Intensive Care Consortium) to study adult patients who had been treated for TBI in four tertiary ICUs in Finland during 2003-2019. We divided admission years into quartiles and used multivariable logistic regression analysis, adjusted for case-mix, to assess the association between admission year and mortality. RESULTS: A total of 4535 patients were included. Between 2003-2007 and 2016-2019, the patient median age increased from 54 to 62 years, the share of patients having significant comorbidity increased from 8 to 11%, and patients being dependent on help in activities of daily living increased from 7 to 15%. Unadjusted hospital and 12-month mortality decreased from 18 and 31% to 10% and 23%, respectively. After adjusting for case-mix, a reduction in odds of 12-month and hospital mortality was seen in patients with severe TBI, intracranial pressure monitored patients, and mechanically ventilated patients. Despite a reduction in hospital mortality, 12-month mortality remained unchanged in patients aged ≥ 70 years. CONCLUSION: A change in the demographics of ICU-treated patients with TBI care is evident. The outcome of younger patients with severe TBI appears to improve, whereas long-term mortality of elderly patients with less severe TBI has not improved. This has ramifications for further efforts to improve TBI care, especially among the elderly.

External validation of the NeuroImaging Radiological Interpretation System and Helsinki computed tomography score for mortality prediction in patients with traumatic brain injury treated in the intensive care unit: a Finnish intensive care consortium study.

BACKGROUND: Admission computed tomography (CT) scoring systems can be used to objectively quantify the severity of traumatic brain injury (TBI) and aid in outcome prediction. We aimed to externally validate the NeuroImaging Radiological Interpretation System (NIRIS) and the Helsinki CT score. In addition, we compared the prognostic performance of the NIRIS and the Helsinki CT score to the Marshall CT classification and to a clinical model. METHODS: We conducted a retrospective multicenter observational study using the Finnish Intensive Care Consortium database. We included adult TBI patients admitted in four university hospital ICUs during 2003-2013. We analyzed the CT scans using the NIRIS and the Helsinki CT score and compared the results to 6-month mortality as the primary outcome. In addition, we created a clinical model (age, Glasgow Coma Scale score, Simplified Acute Physiology Score II, presence of severe comorbidity) and combined clinical and CT models to see the added predictive impact of radiological data to conventional clinical information. We measured model performance using area under curve (AUC), Nagelkerke's R2 statistics, and the integrated discrimination improvement (IDI). RESULTS: A total of 3031 patients were included in the analysis. The 6-month mortality was 710 patients (23.4%). Of the CT models, the Helsinki CT displayed best discrimination (AUC 0.73 vs. 0.70 for NIRIS) and explanatory variation (Nagelkerke's R2 0.20 vs. 0.15). The clinical model displayed an AUC of 0.86 (95% CI 0.84-0.87). All CT models increased the AUC of the clinical model by + 0.01 to 0.87 (95% CI 0.85-0.88) and the IDI by 0.01-0.03. CONCLUSION: In patients with TBI treated in the ICU, the Helsinki CT score outperformed the NIRIS for 6-month mortality prediction. In isolation, CT models offered only moderate accuracy for outcome prediction and clinical variables outweighing the CT-based predictors in terms of predictive performance.

Early thrombocytopenia is associated with an increased risk of mortality in patients with traumatic brain injury treated in the intensive care unit: a Finnish Intensive Care Consortium study.

BACKGROUND: Coagulopathy after traumatic brain injury (TBI) is associated with poor prognosis. PURPOSE: To assess the prevalence and association with outcomes of early thrombocytopenia in patients with TBI treated in the intensive care unit (ICU). METHODS: This is a retrospective multicenter study of adult TBI patients admitted to ICUs during 2003-2019. Thrombocytopenia was defined as a platelet count < 100 × 109/L during the first day. The association between thrombocytopenia and hospital and 12-month mortality was tested using multivariable logistic regression, adjusting for markers of injury severity. RESULTS: Of 4419 patients, 530 (12%) had early thrombocytopenia. In patients with thrombocytopenia, hospital and 12-month mortality were 26% and 48%, respectively; in patients with a platelet count > 100 × 109/L, they were 9% and 22%, respectively. After adjusting for injury severity, a higher platelet count was associated with decreased odds of hospital mortality (OR 0.998 per unit, 95% CI 0.996-0.999) and 12-month mortality (OR 0.998 per unit, 95% CI 0.997-0.999) in patients with moderate-to-severe TBI. Compared to patients with a normal platelet count, patients with thrombocytopenia not receiving platelet transfusion had an increased risk of 12-month mortality (OR 2.2, 95% CI 1.6-3.0), whereas patients with thrombocytopenia receiving platelet transfusion did not (OR 1.0, 95% CI 0.6-1.7). CONCLUSION: Early thrombocytopenia occurs in approximately one-tenth of patients with TBI treated in the ICU, and it is an independent risk factor for mortality in patients with moderate-to-severe TBI. Further research is necessary to determine whether this is modifiable by platelet transfusion.

Trends in Mortality after Intensive Care of Patients with Aneurysmal Subarachnoid Hemorrhage in Finland in 2003-2019: A Finnish Intensive Care Consortium study.

BACKGROUND: Previous studies suggest that case mortality of aneurysmal subarachnoid hemorrhage (aSAH) has decreased during the last decades, but most studies have been unable to assess case severities among individual patients. We aimed to assess changes in severity-adjusted aSAH mortality in patients admitted to intensive care units (ICUs). METHODS: We conducted a retrospective, register-based study by using the prospectively collected Finnish Intensive Care Consortium database. Four out of five ICUs providing neurosurgical and neurointensive care in Finland participated in the Finnish Intensive Care Consortium. We extracted data on adult patients admitted to Finnish ICUs with aSAH between 2003 and 2019. The primary outcome was 12-month mortality during three periods: 2003-2008, 2009-2014, and 2015-2019. Using a multivariable logistic regression model-with variables including age, sex, World Federation of Neurological Surgeons grade, preadmission dependency, significant comorbidities, and modified Simplified Acute Physiology Score II-we analyzed whether admission period was independently associated with mortality. RESULTS: A total of 1,847 patients were included in the study. For the periods 2003-2008 and 2015-2019, the mean number of patients with aSAH admitted per year increased from 81 to 123. At the same time, the patients' median age increased from 55 to 58 years (p = 0.001), and the proportion of patients with World Federation of Neurological Surgeons grades I-III increased from 42 to 58% (p < 0.001). The unadjusted 12-month mortality declined from 30% in 2003-2008 to 23% in 2015-2019 (p = 0.001), but there was no statistically significant change in severity-adjusted mortality. CONCLUSIONS: Between 2003 and 2019, patients with aSAH admitted to ICUs became older and the proportion of less severe cases increased. Unadjusted mortality decreased but age and case severity adjusted-mortality remained unchanged.

Psychotropic medication use among patients with a traumatic brain injury treated in the intensive care unit: a multi-centre observational study.

BACKGROUND: Psychiatric sequelae after traumatic brain injury (TBI) are common and may impede recovery. We aimed to assess the occurrence and risk factors of post-injury psychotropic medication use in intensive care unit (ICU)-treated patients with TBI and its association with late mortality. METHODS: We conducted a retrospective multi-centre observational study using the Finnish Intensive Care Consortium database. We included adult TBI patients admitted in four university hospital ICUs during 2003-2013 that were alive at 1 year after injury. Patients were followed-up until end of 2016. We obtained data regarding psychotropic medication use through the national drug reimbursement database. We used multivariable logistic regression models to assess the association between TBI severity, treatment-related variables and the odds of psychotropic medication use and its association with late all-cause mortality (more than 1 year after TBI). RESULTS: Of 3061 patients, 2305 (75%) were alive at 1 year. Of these, 400 (17%) became new psychotropic medication users. The most common medication types were antidepressants (61%), antipsychotics (35%) and anxiolytics (26%). A higher Glasgow Coma Scale (GCS) score was associated with lower odds (OR 0.93, 95% CI 0.90-0.96) and a diffuse injury with midline shift was associated with higher odds (OR 3.4, 95% CI 1.3-9.0) of new psychotropic medication use. After adjusting for injury severity, new psychotropic medication use was associated with increased odds of late mortality (OR 1.19, 95% CI 1.19-2.17, median follow-up time 6.4 years). CONCLUSIONS: Psychotropic medication use is common in TBI survivors. Higher TBI severity is associated with increased odds of psychotropic medication use. New use of psychotropic medications after TBI was associated with increased odds of late mortality. Our results highlight the need for early identification of potential psychiatric sequelae and psychiatric evaluation in TBI survivors.

Posttraumatic epilepsy in intensive care unit-treated pediatric traumatic brain injury patients.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a well-described complication of traumatic brain injury (TBI). The majority of the available data regarding PTE stem from the adult population. Our aim was to identify the clinical and radiological risk factors associated with PTE in a pediatric TBI population treated in an intensive care unit (ICU). METHODS: We used the Finnish Intensive Care Consortium database to identify pediatric (<18 years) TBI patients treated in four academic university hospital ICUs in Finland between 2003 and 2013. Our primary outcome was the development of PTE, defined as the need for oral antiepileptic medication in patients alive at 6 months. We assessed the risk factors associated with PTE using multivariable logistic regression modeling. RESULTS: Of the 290 patients included in the study, 59 (20%) developed PTE. Median age was 15 years (interquartile range [IQR] 13-17), and 80% had an admission Glasgow Coma Scale (GCS) score ≤12. Major risk factors for developing PTE were age (adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 1.00-1.16), obliterated suprasellar cisterns (OR 6.53, 95% CI 1.95-21.81), and an admission GCS score of 9-12 in comparison to a GCS score of 13-15 (OR 2.88, 95% CI 1.24-6.69). SIGNIFICANCE: We showed that PTE is a common long-term complication after ICU-treated pediatric TBI. Higher age, moderate injury severity, obliterated suprasellar cisterns, seizures during ICU stay, and surgical treatment are associated with an increased risk of PTE. Further studies are needed to identify strategies to decrease the risk of PTE.

Association of extracerebral organ failure with 1-year survival and healthcare-associated costs after cardiac arrest: an observational database study.

BACKGROUND: Organ dysfunction is common after cardiac arrest and associated with worse short-term outcome, but its impact on long-term outcome and treatment costs is unknown. METHODS: We used nationwide registry data from the intensive care units (ICU) of the five Finnish university hospitals to evaluate the association of 24-h extracerebral Sequential Organ Failure Assessment (24h-EC-SOFA) score with 1-year survival and healthcare-associated costs after cardiac arrest. We included adult cardiac arrest patients treated in the participating ICUs between January 1, 2003, and December 31, 2013. We acquired the confirmed date of death from the Finnish Population Register Centre database and gross 1-year healthcare-associated costs from the hospital billing records and the database of the Finnish Social Insurance Institution. RESULTS: A total of 5814 patients were included in the study, and 2401 were alive 1 year after cardiac arrest. Median (interquartile range (IQR)) 24h-EC-SOFA score was 6 (5-8) in 1-year survivors and 7 (5-10) in non-survivors. In multivariate regression analysis, adjusting for age and prior independency in self-care, the 24h-EC-SOFA score had an odds ratio (OR) of 1.16 (95% confidence interval (CI) 1.14-1.18) per point for 1-year mortality. Median (IQR) healthcare-associated costs in the year after cardiac arrest were €47,000 (€28,000-75,000) in 1-year survivors and €12,000 (€6600-25,000) in non-survivors. In a multivariate linear regression model adjusting for age and prior independency in self-care, an increase of one point in the 24h-EC-SOFA score was associated with an increase of €170 (95% CI €150-190) in the cost per day alive in the year after cardiac arrest. In the same model, an increase of one point in the 24h-EC-SOFA score was associated with an increase of €4400 (95% CI €3300-5500) in the total healthcare-associated costs in 1-year survivors. CONCLUSIONS: Extracerebral organ dysfunction is associated with long-term outcome and gross healthcare-associated costs of ICU-treated cardiac arrest patients. It should be considered when assessing interventions to improve outcomes and optimize the use of resources in these patients.

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% (n = 2,304), and of 1-year survivors, 37% (n = 850) were permanently disabled. Mean unadjusted 1-year healthcare cost was $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.

Predictors of hospital and one-year mortality in intensive care patients with refractory status epilepticus: a population-based study.

BACKGROUND: The aim was to determine predictors of hospital and 1-year mortality in patients with intensive care unit (ICU)-treated refractory status epilepticus (RSE) in a population-based study. METHODS: This was a retrospective study of the Finnish Intensive Care Consortium (FICC) database of adult patients (16 years of age or older) with ICU-treated RSE in Finland during a 3-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating RSE in the ICU. All five university hospitals and 11 out of 15 central hospitals participated in the present study. The total adult referral population in the study hospitals was 3.92 million, representing 91% of the adult population of Finland. Patients whose condition had a post-anoxic aetiological basis were excluded. RESULTS: We identified 395 patients with ICU-treated RSE, corresponding to an annual incidence of 3.4/100,000 (95% confidence interval (CI) 3.04-3.71). Hospital mortality was 7.4% (95% CI 0-16.9%), and 1-year mortality was 25.4% (95% CI 21.2-29.8%). Mortality at hospital discharge was associated with severity of organ dysfunction. Mortality at 1 year was associated with older age (adjusted odds ratio (aOR) 1.033, 95% CI 1.104-1.051, p = 0.001), sequential organ failure assessment (SOFA) score (aOR 1.156, CI 1.051-1.271, p = 0.003), super-refractory status epilepticus (SRSE) (aOR 2.215, 95% CI 1.20-3.84, p = 0.010) and dependence in activities of daily living (ADL) (aOR 2.553, 95% CI 1.537-4.243, p < 0.0001). CONCLUSIONS: Despite low hospital mortality, 25% of ICU-treated RSE patients die within a year. Super-refractoriness, dependence in ADL functions, severity of organ dysfunction at ICU admission and older age predict long-term mortality. TRIAL REGISTRATION: Retrospective registry study; no interventions on human participants.

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892.

Incidence and mortality of super-refractory status epilepticus in adults.

OBJECTIVES: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24h or more after the onset of anesthetic therapy. We defined the incidence and outcome of SRSE in adults in Finland. METHODS: We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify adult patients with SRSE treated in ICUs in Finland during a three-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating refractory SE (RSE) with general anesthesia in the intensive care unit (ICU). We included consecutive adult (16 years or older) patients with RSE and identified those who had SRSE. Patients with postanoxic etiologies were excluded. RESULTS: All five university hospitals and 10/15 of the central hospitals participated. The adult referral population of the study hospitals is 3.9 million, representing 91% of the total adult population of Finland. We identified 395 patients with ICU-treated RSE, 87 (22%) of whom were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% confidence interval [CI]: 0.6-0.9). The one-year mortality rates were 36% (95% CI: 26-46%) for patients with SRSE and 22% (95% CI: 17-27%) for patients with RSE. Mortality was highest (63%) in patients with SRSE aged over 75 years. CONCLUSIONS: Approximately 20% of patients with RSE treated in Finnish ICUs progressed to having SRSE. The incidence of SRSE, 0.7/100,000, is about 5-10% of the incidence of SE. The mortality of patients with SRSE, 36%, was comparable to earlier studies and twofold higher than the mortality of patients with RSE. This article is part of a Special Issue entitled "Status Epilepticus".

Sleep apnoea is associated with major cardiac events in peripheral arterial disease.

Obstructive sleep apnoea (OSA) is associated with atherosclerosis and cardiovascular events. Peripheral arterial disease (PAD) represents severe atherosclerosis with a high mortality after vascular surgery. The role of OSA in the prognosis of these patients is not yet established. 84 patients (aged 67 ± 9 years) scheduled for sub-inguinal surgical revascularisation were enrolled for preoperative polysomnography. The threshold for significant OSA was an apnoea/hypopnoea index ≥ 20 events·h(-1). Major adverse cardiovascular and cerebrovascular events (MACCE), including cardiac death, myocardial infarction, coronary revascularisation, angina pectoris requiring hospitalisation and stroke, were used as a combined end-point. During follow-up (median 52 months), 17 out of 39 patients with and six out of 45 patients without significant OSA suffered MACCE. In the multivariate Cox regression, the primary predictors of MACCE were significant OSA (hazard ratio (HR) 5.1 (95% CI 1.9-13.9); p=0.001) and pre-existing coronary artery disease (HR 4.4 (95% CI 1.8-10.6); p=0.001). Other significant predictors were a ≥ 4 year history of PAD (HR 3.8 (95% CI 1.3-11.5); p=0.02) and decreasing high-density lipoprotein/total cholesterol ratio (HR 0.95 per percentage (95% CI 0.90-1.00); p=0.048). OSA is associated with poor long-term outcome in patients with PAD following revascularisation. OSA might have an important role in the pathogenesis of cardiovascular morbidity and mortality in these patients.

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.

Feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out-of-hospital cardiac arrest.

OBJECTIVES: Preclinical studies reveal the neuroprotective properties of xenon, especially when combined with hypothermia. The purpose of this study was to investigate the feasibility and cardiac safety of inhaled xenon treatment combined with therapeutic hypothermia in out-of-hospital cardiac arrest patients. DESIGN: An open controlled and randomized single-centre clinical drug trial (clinicaltrials.gov NCT00879892). SETTING: A multipurpose ICU in university hospital. PATIENTS: Thirty-six adult out-of-hospital cardiac arrest patients (18-80 years old) with ventricular fibrillation or pulseless ventricular tachycardia as initial cardiac rhythm. INTERVENTIONS: Patients were randomly assigned to receive either mild therapeutic hypothermia treatment with target temperature of 33°C (mild therapeutic hypothermia group, n=18) alone or in combination with xenon by inhalation, to achieve a target concentration of at least 40% (Xenon+mild therapeutic hypothermia group, n=18) for 24 hours. Thirty-three patients were evaluable (mild therapeutic hypothermia group, n=17; Xenon+mild therapeutic hypothermia group, n=16). MEASUREMENTS AND MAIN RESULTS: Patients were treated and monitored according to the Utstein protocol. The release of troponin-T was determined at arrival to hospital and at 24, 48, and 72 hours after out-of-hospital cardiac arrest. The median end-tidal xenon concentration was 47% and duration of the xenon inhalation was 25.5 hours. The frequency of serious adverse events, including inhospital mortality, status epilepticus, and acute kidney injury, was similar in both groups and there were no unexpected serious adverse reactions to xenon during hospital stay. In addition, xenon did not induce significant conduction, repolarization, or rhythm abnormalities. Median dose of norepinephrine during hypothermia was lower in xenon-treated patients (mild therapeutic hypothermia group=5.30 mg vs Xenon+mild therapeutic hypothermia group=2.95 mg, p=0.06). Heart rate was significantly lower in Xenon+mild therapeutic hypothermia patients during hypothermia (p=0.04). Postarrival incremental change in troponin-T at 72 hours was significantly less in the Xenon+mild therapeutic hypothermia group (p=0.04). CONCLUSIONS: Xenon treatment in combination with hypothermia is feasible and has favorable cardiac features in survivors of out-of-hospital cardiac arrest.

Incidence and risk factors of posttraumatic hydrocephalus and its association with outcome following intensive care unit treatment for traumatic brain injury: a multicenter observational study.

OBJECTIVE: Posttraumatic hydrocephalus (PTH) is a recognized long-term complication of traumatic brain injury (TBI). The authors assessed the incidence and risk factors of PTH and its association with outcome in patients with TBI who were treated in the intensive care unit (ICU). METHODS: The authors used the Finnish Intensive Care Consortium (FICC) database to retrospectively identify all adult patients with TBI treated in 4 Finnish tertiary ICUs during 2003-2013. All patients were followed up from hospital discharge to a diagnosis of PTH, death, or the end of 2016. PTH was defined as a need for a postdischarge ventriculoperitoneal or ventriculoatrial shunt. The authors collected data on shunt-insertion procedures, mortality, and disability status from nationwide registries cross-linked to the FICC database. The authors calculated the occurrence and incidence rates of PTH and used multivariable logistic regression modeling to determine risk factors for PTH and its association with outcome. RESULTS: Sixty-one of 2882 patients (2.1%) developed PTH during a median follow-up time of 4.6 years, with a median of 102 days (interquartile range 54-220 days) between hospital discharge and PTH. Risk factors for PTH were increasing age (OR 1.02 per year, 95% CI 1.01-1.04); a midline shift of > 5 mm (OR 1.88, 95% CI 1.01-3.48); traumatic subarachnoid hemorrhage (OR 3.59, 95% CI 1.79-7.21); external ventricular drainage (OR 3.54, 95% CI 1.68-7.46); and decompressive craniectomy (OR 3.68, 95% CI 1.37-9.88). PTH was independently associated with permanent disability after case-mix adjustment (OR 3.62, 95% CI 2.11-6.22). CONCLUSIONS: PTH is an uncommon long-term complication of TBI, with several risk factors that are identifiable early during neurointensive care. The development of PTH is independently associated with poor functional outcome. Whether earlier detection and treatment of PTH leads to improved outcomes remains unknown, highlighting the importance of adequate follow-up and prompt detection and treatment of the condition.

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.

One-year healthcare costs of patients with spontaneous intracerebral hemorrhage treated in the intensive care unit.

Background: Spontaneous intracerebral hemorrhage (ICH) entails significant mortality and morbidity. Severely ill ICH patients are treated in intensive care units (ICUs), but data on 1-year healthcare costs and patient care cost-effectiveness are lacking. Methods: Retrospective multi-center study of 959 adult patients treated for spontaneous ICH from 2003 to 2013. The primary outcomes were 12-month mortality or permanent disability, defined as being granted a permanent disability allowance or pension by the Social Insurance Institution by 2016. Total healthcare costs were hospital, rehabilitation, and social security costs within 12 months. A multivariable linear regression of log transformed cost data, adjusting for case mix, was used to assess independent factors associated with costs. Results: Twelve-month mortality was 45% and 51% of the survivors were disabled at the end of follow-up. The mean 12-month total cost was €49,754, of which rehabilitation, tertiary hospital and social security costs accounted for 45%, 39%, and 16%, respectively. The highest effective cost per independent survivor (ECPIS) was noted among patients aged >70 years with brainstem ICHs, low Glasgow Coma Scale (GCS) scores, larger hematoma volumes, intraventricular hemorrhages, and ICH scores of 3. In multivariable analysis, age, GCS score, and severity of illness were associated independently with 1-year healthcare costs. Conclusions: Costs associated with ICHs vary between patient groups, and the ECPIS appears highest among patients older than 70 years and those with brainstem ICHs and higher ICH scores. One-third of financial resources were used for patients with favorable outcomes. Further detailed cost-analysis studies for patients with an ICH are required.

Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients.

INTRODUCTION: Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine. METHODS: Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 µg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests. RESULTS: The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion. CONCLUSIONS: The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 µg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00747721.