Neuroprotective Effects of Inhaled Xenon Gas on Brain Structural Gray Matter Changes After Out-of-Hospital Cardiac Arrest Evaluated by Morphometric Analysis: A Substudy of the Randomized Xe-Hypotheca Trial.

BACKGROUND: We have earlier reported that inhaled xenon combined with hypothermia attenuates brain white matter injury in comatose survivors of out-of-hospital cardiac arrest (OHCA). A predefined secondary objective was to assess the effect of inhaled xenon on the structural changes in gray matter in comatose survivors after OHCA. METHODS: Patients were randomly assigned to receive either inhaled xenon combined with target temperature management (33 °C) for 24 h (n = 55, xenon group) or target temperature management alone (n = 55, control group). A change of brain gray matter volume was assessed with a voxel-based morphometry evaluation of high-resolution structural brain magnetic resonance imaging (MRI) data with Statistical Parametric Mapping. Patients were scheduled to undergo the first MRI between 36 and 52 h and a second MRI 10 days after OHCA. RESULTS: Of the 110 randomly assigned patients in the Xe-Hypotheca trial, 66 patients completed both MRI scans. After all imaging-based exclusions, 21 patients in the control group and 24 patients in the xenon group had both scan 1 and scan 2 available for analyses with scans that fulfilled the quality criteria. Compared with the xenon group, the control group had a significant decrease in brain gray matter volume in several clusters in the second scan compared with the first. In a between-group analysis, significant reductions were found in the right amygdala/entorhinal cortex (p = 0.025), left amygdala (p = 0.043), left middle temporal gyrus (p = 0.042), left inferior temporal gyrus (p = 0.008), left parahippocampal gyrus (p = 0.042), left temporal pole (p = 0.042), and left cerebellar cortex (p = 0.005). In the remaining gray matter areas, there were no significant changes between the groups. CONCLUSIONS: In comatose survivors of OHCA, inhaled xenon combined with targeted temperature management preserved gray matter better than hypothermia alone. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00879892.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

One-year costs of intensive care in pediatric patients with traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a major cause of death and disability in the pediatric population. The authors assessed 1-year costs of intensive care in pediatric TBI patients. METHODS: In this retrospective multicenter cohort study of four academic ICUs in Finland, the authors used the Finnish Intensive Care Consortium database to identify children aged 0-17 years treated for TBI in ICUs between 2003 and 2013. The authors reviewed all patient health records and head CT scans for admission, treatment, and follow-up data. Patient outcomes included functional outcome (favorable outcome defined as a Glasgow Outcome Scale score of 4-5) and death within 6 months. Costs included those for the index hospitalization, rehabilitation, and social security up to 1 year after injury. To assess costs, the authors calculated the effective cost per favorable outcome (ECPFO). RESULTS: In total, 293 patients were included, of whom 61% had moderate to severe TBI (Glasgow Coma Scale [GCS] score 3-12) and 40% were ≥ 13 years of age. Of all patients, 82% had a favorable outcome and 9% died within 6 months of injury. The mean cost per patient was €48,719 ($54,557) (95% CI €41,326-€56,112). The index hospitalization accounted for 66%, rehabilitation costs for 27%, and social security costs for 7% of total healthcare costs. The ECPFO was €59,727 ($66,884) (95% CI €52,335-€67,120). A higher ECPFO was observed among patients with clinical and treatment-related variables indicative of parenchymal swelling and high intracranial pressure. Lower ECPFO was observed among patients with higher admission GCS scores and those who had epidural hematomas. CONCLUSIONS: Greater injury severity increases ECPFO and is associated with higher postdischarge costs in pediatric TBI patients. In this pediatric cohort, over two-thirds of all resources were spent on patients with favorable functional outcome, indicating appropriate resource allocation.

Psychotropic Medication After Intensive Care Unit-Treated Pediatric Traumatic Brain Injury.

BACKGROUND: Our aim was to assess the occurrence and risk factors for psychotropic medication use after pediatric traumatic brain injury treated in the intensive care unit. METHODS: We combined data from the Finnish Intensive Care Consortium database, data on reimbursed medications from the Social Insurance Institute, and individual electronic health care data. We analyzed data on children aged five to 17 years treated for traumatic brain injury in intensive care units of four university hospitals in Finland during 2003 to 2013 and being alive six months after injury with no history of psychotropic medication use before traumatic brain injury. RESULTS: We identified 248 patients of whom 46 (19%) were prescribed a new psychotropic medication after traumatic brain injury. In multivariable logistic regression, a higher age associated with a higher probability for use of any psychotropic medication. Subgroup analyses showed that higher age associated with an increased risk of antidepressant and antipsychotic use but with a decreased risk of stimulant use. Apart from age, we found no other clinical, radiological, or treatment-related factors that significantly associated with subsequent use of psychotropics. Psychotropic medication was most common (45%) in children aged 12 to 17 years and had moderate disability at six-month follow-up. CONCLUSIONS: One fifth of children treated in the intensive care unit for traumatic brain injury were prescribed a new psychotropic medication during a median follow-up of three years and five months. Psychotropic medication was most common among teenagers with moderate post-traumatic disability. The need and use of psychotropics postinjury seem multifactorial and not related to any traumatic brain injury type.

The Association Between Pressure Ulcer/Injury Development and Short-term Mortality in Critically Ill Patients: A Retrospective Cohort Study.

Pressure ulcers/injuries (PU/Is) affect the social, mental, and physical well-being of patients; increase treatment costs; prolong hospital stays; increase patient risk for infections; and may independently decrease life expectancy. PURPOSE: The aim of this retrospective study was to examine the association between PU/I development and mortality in a large cohort of consecutively admitted critically ill patients. METHODS: Data from adult patients ( >18 years of age) admitted to an intensive care unit (ICU) between 2010 and 2013 were extracted from the ICU electronic clinical information system. Patients were excluded if they had a PU/I present on admission, no recorded admission modified Jackson/Cubbin (mJ/C) or Sequential Organ Failure Assessment (SOFA) score, or their ICU outcome was undetermined. The mJ/C risk scale (score range 9-48) was used to assess the PU/I risk (the lower the score, the higher the PU/I risk), the SOFA score (score range 0-24; the higher the SOFA score, the sicker the patient, with a higher risk of death) was used to assess the severity of the condition and outcome. ICU outcome was defined as 1) moved from the ICU to a ward/recovering or 2) no response to ICU treatment/deceased. All data were transferred to statistical software for analysis. Logistic regression analysis was used to examine the outcome related to PU/I development, SOFA, and mJ/C scores. Descriptive contingency tables of different scenarios were used to further evaluate relationships among different risk factors related to mortality; the Wald χ2 test was used to assess the statistical significance of the contingency tables. RESULTS: Of the 6582 patients admitted, 6089 were included for analysis. Two hundred, one (201) had a PU/In on admission, 212 had missing mJ/C or SOFA scores, and ICU outcome was undetermined in 80 patients. Patient mean age was 61.1 ± 15.8 (range 18-94) years; 3891 (63.9%) were male, average length of stay (LOS) was 3.6 days, denoted by quartile (Q) (median 1.58 days; Q1: 0.9, Q3: 3.9 days), and 1589 (26.1%) stayed 3 days or more in the ICU. The incidence of PU/I was 6.9% (423 patients), and ICU mortality rate was 9.1% (n=553). The mean LOS of patients with PU/I was 13.35 ± 15.56 days (median 8.95, Q1: 4.88, Q3: 16.2) and 2.84 ± 3.87 days for patients with no PU/I (median: 1.20, Q1: 0.90, Q3: 3.17; P <.0001). Mean LOS was 3.42 ± 5.95 days (median: 1.30, Q1: 0.90, Q3: 3.70) among recovering and 5.00 ± 7.17 days among deceased patients (median 2.56, Q1: 1.26, Q3: 6.40; P <.0001). The proportion of patients with an admission mJ/C score of 29 or less ranged from 48.8% to 51.5%, and the mean SOFA score was 7.0 ± 3.2. PU/I development and SOFA or mJ/C scores were independent predictors of mortality. The probability of a negative outcome was higher in persons with PU/Is compared to persons with no PU/Is. Persons with lower SOFA scores (ie, less severely ill patients) and higher mJ/C scores for each factor separately (ie, at low risk of PU/I development) each factor separately had a lower mortality risk. CONCLUSION: PU/I development in critically ill patients treated at an ICU is an independent predictor of mortality, even though the PU/I incidence and hospital mortality were relatively low. The ICU admission SOFA and mJ/C score also were independent prognosticators of ICU mortality. Future research could focus on the role of different steps in the cascade of PU/I development, especially to the role of inflammation.

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.

Single-subject analysis of N400 event-related potential component with five different methods.

There are several different approaches to analyze event-related potentials (ERPs) at single-subject level, and the aim of the current study is to provide information for choosing a method based on its ability to detect ERP effects and factors influencing the results. We used data from 79 healthy participants with EEG referenced to mastoid average and investigated the detection rate of auditory N400 effect in single-subject analysis using five methods: visual inspection of participant-wise averaged ERPs, analysis of variance (ANOVA) for amplitude averages in a time window, cluster-based non-parametric testing, a novel Bayesian approach and Studentized continuous wavelet transform (t-CWT). Visual inspection by three independent raters yielded N400 effect detection in 85% of the participants in at least one paradigm (active responding or passive listening), whereas ANOVA identified the effect in 68%, the cluster-method in 59%, the Bayesian method in 89%, and different versions of t-CWT in 22-59% of the participants. Thus, the Bayesian method was the most liberal and also showed the greatest concordance between the experimental paradigms (active/passive). ANOVA detected significant effect only in cases with converging evidence from other methods. The t-CWT and cluster-based method were the most conservative methods. As we show in the current study, different analysis methods provide results that do not completely overlap. The method of choice for determining the presence of an ERP component at single-subject level thus remains unresolved. Relying on a single statistical method may not be sufficient for drawing conclusions on single-subject ERPs.

Validation of prognostic models in intensive care unit-treated pediatric traumatic brain injury patients.

OBJECTIVE: There are few specific prognostic models specifically developed for the pediatric traumatic brain injury (TBI) population. In the present study, the authors tested the predictive performance of existing prognostic tools, originally developed for the adult TBI population, in pediatric TBI patients requiring stays in the ICU. METHODS: The authors used the Finnish Intensive Care Consortium database to identify pediatric patients (< 18 years of age) treated in 4 academic ICUs in Finland between 2003 and 2013. They tested the predictive performance of 4 classification systems-the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) TBI model, the Helsinki CT score, the Rotterdam CT score, and the Marshall CT classification-by assessing the area under the receiver operating characteristic curve (AUC) and the explanatory variation (pseudo-R2 statistic). The primary outcome was 6-month functional outcome (favorable outcome defined as a Glasgow Outcome Scale score of 4-5). RESULTS: Overall, 341 patients (median age 14 years) were included; of these, 291 patients had primary head CT scans available. The IMPACT core-based model showed an AUC of 0.85 (95% CI 0.78-0.91) and a pseudo-R2 value of 0.40. Of the CT scoring systems, the Helsinki CT score displayed the highest performance (AUC 0.84, 95% CI 0.78-0.90; pseudo-R2 0.39) followed by the Rotterdam CT score (AUC 0.80, 95% CI 0.73-0.86; pseudo-R2 0.34). CONCLUSIONS: Prognostic tools originally developed for the adult TBI population seemed to perform well in pediatric TBI. Of the tested CT scoring systems, the Helsinki CT score yielded the highest predictive value.

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.