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.

The effectiveness of a brief intervention for intensive care unit patients with hazardous alcohol use: a randomized controlled trial.

BACKGROUND: Screening for hazardous alcohol use and performing brief interventions (BIs) are recommended to reduce alcohol-related negative health consequences. We aimed to compare the effectiveness (defined as an at least 10% absolute difference) of BI with usual care in reducing alcohol intake in intensive care unit survivors with history of hazardous alcohol use. METHODS: We used Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score to assess history of alcohol use. PATIENTS: Emergency admitted adult ICU patients in three Finnish university hospitals, with an AUDIT-C score > 5 (women), or > 6 (men). We randomized consenting eligible patients to receive a BI or treatment as usual (TAU). INTERVENTION: BI was delivered by the time of ICU discharge or shortly thereafter in the hospital ward. CONTROLS: Control patients received TAU. OUTCOME: The primary outcome was self-reported alcohol consumption during the preceding week 6 and 12 months after randomization. Secondary outcomes were the change in AUDIT-C scores from baseline to 6 and 12 months, health-related quality of life, and mortality. The trial was terminated early due to slow recruitment during the pandemic. RESULTS: We randomized 234 patients to receive BI (N = 117) or TAU (N = 117). At 6 months, the median alcohol intake in the BI and TAU groups were 6.5 g (interquartile range [IQR] 0-141) and 0 g (0-72), respectively (p = 0.544). At 12 months, it was 24 g (0-146) and 0 g (0-96) in the BI and TAU groups, respectively (p = 0.157). Median change in AUDIT-C from baseline to 6 months was - 1 (- 4 to 0) and 2 (- 6 to 0), (p = 0.144) in the BI and TAU groups, and to 12 months - 3 (- 5 to - 1) and - 4 (- 7 to - 1), respectively (p = 0.187). In total, 4% (n = 5) of patients in the BI group and 11% (n = 13) of patients in the TAU group were abstinent at 6 months, and 10% (n = 12) and 15% (n = 17), respectively, at 12 months. No between-groups difference in mortality emerged. CONCLUSION: As underpowered, our study cannot reject or confirm the hypothesis that a single BI early after critical illness is effective in reducing the amount of alcohol consumed compared to TAU. However, a considerable number in both groups reduced their alcohol consumption. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03047577).

Hazardous alcohol consumption and perioperative complications in a cardiac surgery patient. A retrospective study.

BACKGROUND: We investigated the prevalence and effects of hazardous alcohol consumption on perioperative complications in cardiac surgery patients. Preoperative hazardous alcohol consumption has been associated with an increased risk of postoperative complications in noncardiac patient populations. METHODS: We retrospectively collected data from the Finnish Intensive Care Consortium database and electronic patient records on all cardiac surgery patients treated in the intensive care units (ICUs) of Helsinki University Hospital (n = 919) during 2017. Data on preoperative alcohol consumption were routinely collected using the alcohol use disorder identification test consumption (AUDIT-C) questionnaire. We analyzed perioperative data and outcomes for any associations with hazardous alcohol consumption. Outcome measures were length of stay in the ICU, re-admissions to ICU, bleeding and infectious complications, and incidence of postoperative arrhythmias. RESULTS: AUDIT-C scores were available for 758 (82.5%) patients, of whom 107 (14.1%) fulfilled the criteria for hazardous alcohol consumption (AUDIT-C score of 5/12 or higher for women and 6/12 or higher for men). Patients with hazardous alcohol consumption were younger, median age 59 (IQR 52.0-67.0) vs. 69.0 (IQR 63.0-74.0), p < .001, and more often men 93.5% vs. 71.9%, p < .001 than other patients and had an increased risk for ICU re-admissions [adjusted OR (aOR) 4.37 (95% CI, 1.60-11.95)] and severe postoperative infections aOR 3.26 (95% CI, 1.42-7.54). CONCLUSION: Cardiac surgery patients with a history of hazardous alcohol consumption are younger than other patients and are predominantly men. Hazardous alcohol consumption is associated with an increased risk of severe postoperative infections and ICU re-admissions.

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 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.

Prevalence and impact of hazardous alcohol use in intensive care cohort: A multicenter, register-based study.

BACKGROUND: Reports of the prevalence and impact of hazardous alcohol use among intensive care unit (ICU) patients are contradictory. We aimed to study the prevalence of hazardous alcohol use among ICU patients and its association with ICU length of stay (LOS) and mortality. METHODS: Finnish ICUs have been using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) to evaluate and record patients' alcohol use into the Finnish Intensive Care Consortium's Database (FICC). We retrieved data from the FICC from a 3-month period. We excluded data from centers with an AUDIT-C recording rate of less than 70% of admissions. We defined hazardous alcohol use as a score of 5 or more for women and 6 or more for men from a maximum score of 12 points. RESULTS: Two thousand forty-five patients were treated in the 10 centers with an AUDIT-C recording rate of 70% or higher. AUDIT-C was available for 1576 (77%) patients and indicated hazardous alcohol use for 334 (21%) patients who were more often younger (median age 55 [interquartile range 42-65] vs 67 [57-74] [P < .001]) and male (78.1% vs 61.3% [P < .001]) compared to other patients. We found no difference in LOS or hospital mortality between hazardous and non-hazardous alcohol users. Among the non-abstinent, risk of death within a year increased with increasing AUDIT-C scores adjusted odds ratio 1.077 (95% confidence interval, 1.006-1.152) per point. CONCLUSION: The prevalence of hazardous alcohol use in Finnish ICUs was 21%. Patients with hazardous alcohol use were more often younger and male compared with non-hazardous alcohol users.

Prevalence of risk-drinking in critically ill patients, screened with carbohydrate-deficient transferrin and AUDIT-C score: A retrospective study.

Background Studies demonstrate that up to one-third of intensive care unit (ICU) admissions are directly or indirectly related to alcohol. Screening for alcohol use is not routine. This study examined the prevalence of elevated %CDT (carbohydrate-deficient transferrin) and above risk-level AUDIT-C (Alcohol Use Disorders Identification Test, Consumption) in patients admitted to ICU. Methods We conducted a retrospective analysis of clinical and laboratory data from a single ICU where %CDT and AUDIT-C were included in routine assessment. After excluding readmissions, 2532 adult patients from a 21-month period were included. Admission values of %CDT were available for 2049 patients, and AUDIT-C was available for 1617 patients. The association of %CDT and AUDIT-C with short- and long-term outcome was studied by using univariate and multivariate logistic regression analysis. Results %CDT was above the reference value in 23.7% (486/2048) of patients with available %CDT. Of patients with available AUDIT-C, 33% (544/1617) had a risk-level AUDIT-C score. Patients with a risk-level AUDIT-C score were significantly younger than those with a lower score (51 vs 64 years, P < .0001). Increased %CDT was associated with higher severity of illness. AUDIT-C was associated independently with increased risk of long-term mortality in multivariate analysis (P = .007). Conclusion One in three of ICU patients are risk-level alcohol users as measured with AUDIT-C score, and one in four are analysed with %CDT. The prevalence varies according to the method used and any method alone may be insufficient to detect risk-level consumption reliably. Editorial Comment Alcohol overconsumption is associated with need for ICU admission and with less favorable outcomes. Diagnosis of alcohol overconsumption though is problematic due to low sensitivity in screening. In a pilot study, a biomarker and a screening tool are compared. The finding is that multiple tools are needed to achieve an adequate sensitivity for detection.

Inhaled Xenon Attenuates Myocardial Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The Xe-Hypotheca Trial.

BACKGROUND: The authors previously reported that inhaled xenon combined with hypothermia attenuates brain white matter injury in comatose survivors of out-of-hospital cardiac arrest (OHCA). OBJECTIVES: A pre-defined secondary objective was to assess the effect of inhaled xenon on myocardial ischemic damage in the same study population. METHODS: A total of 110 comatose patients who had experienced OHCA from a cardiac cause were randomized to receive either inhaled xenon (40% end-tidal concentration) combined with hypothermia (33°C) for 24 h (n = 55; xenon group) or hypothermia treatment alone (n = 55; control group). Troponin-T levels were measured at hospital admission, and at 24 h, 48 h, and 72 h post-cardiac arrest. All available cases were analyzed for troponin-T release. RESULTS: Troponin-T measurements were available from 54 xenon patients and 54 control patients. The baseline characteristics did not differ significantly between the groups. After adjustments for age, sex, study site, primary coronary percutaneous intervention (PCI), and norepinephrine dose, the mean ± SD post-arrival incremental change of the ln-transformed troponin-T at 72 h was 0.79 ± 1.54 in the xenon group and 1.56 ± 1.38 in the control group (adjusted mean difference -0.66; 95% confidence interval: -1.16 to -0.16; p = 0.01). The effect of xenon on the change in the troponin-T values did not differ in patients with or without PCI or in those with a diagnosis of ST-segment elevation myocardial infarction (group by PCI or ST-segment elevation myocardial infarction interaction effect; p = 0.86 and p = 0.71, respectively). CONCLUSIONS: Among comatose survivors of OHCA, in comparison with hypothermia alone, inhaled xenon combined with hypothermia suggested a less severe myocardial injury as demonstrated by the significantly reduced release of troponin-T.

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.

Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis--A randomised placebo-controlled pilot trial.

An overwhelming inflammatory process is the hallmark of severe sepsis and septic shock. Matrix metalloproteinases (MMPs)-8 and -9 are released from neutrophils and activated in sepsis to participate in inflammation in several ways. High levels of MMP-8 may associate with increased ICU mortality. The activity of MMP-8 and -9 is regulated by a natural inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Moreover, MMPs are chemically inhibited by tetracycline-group antibiotics, such as doxycycline. We therefore aimed to study plasma concentration and MMP inhibition after intravenous doxycycline in critically ill patients with severe sepsis and septic shock in a prospective, randomised, placebo-controlled double-blinded pilot trial. Twenty-four patients with severe sepsis or septic shock were randomised in 3 groups. Group 1 received 200, 100 and 100mg, group 2 100, 50 and 50mg of intravenous doxycycline and group 3 placebo on three consecutive days. We measured doxycycline concentrations from baseline up to day 5. MMPs and TIMP-1 concentrations were measured from baseline up to day 10 of study and we compared their changes over time from baseline to 72 h and from baseline to 120 h. Data from 23 patients were analysed. At 72 h all patients in group 1 showed doxycycline concentrations >1 mg/l, whereas none in group 2 did. No serious adverse effects of the drug were recorded. We observed no differences over time up to 72 or up to 120 h in the concentrations or activities of MMP-8, -9 or TIMP-1 in any of the groups. We found intravenous doxycycline 100, 50 and 50mg to be adequate to achieve a sub-antimicrobial concentration in patients with severe sepsis or septic shock but having no impact on MMP-8, -9 or TIMP-1 concentrations or activities.

Esophageal Ulcer as a Cause of Death: A Population-Based Study. Mortality of Esophageal Ulcer Disease.

BACKGROUND: This study aimed at defining the mortality and the nature of fatal complications that arise out of esophageal ulcer for one clearly defined geographical area. METHODS: In this national, population-based study, the occurrence of fatal esophageal ulcer or ulcer requiring hospital treatment between January 1987 and December 2000 was assessed by the use of Finland's administrative databases. Medical records provided etiology of fatal ulcer and agonal symptoms. RESULTS: Due to an esophageal ulcer, 2,242 patients received treatment in Finnish hospitals, at an annual frequency of 3.2/100,000. Ulcer with hemorrhage (53.5%), perforation (38.4%), or aspiration pneumonia (2.3%) was the cause of death in 86 patients for an annual mortality of 0.12/100,000. Based on the number of ulcers treated, 3.8% cases ended fatally. Gastroesophageal reflux disease (GERD) seemed to be the etiologic factor for ulcer in 68 (79.0%) patients. The most common agonal symptoms were hematemesis (41.8%), abdominal pain (25.6%), melaena (22.1%), and dyspnea (17.4%). Twenty (23.3%) patients were found dead at home. CONCLUSION: The rarity of the disease, related disorders, and the diversity of symptoms make the complicated esophageal ulcer a diagnostic challenge. Effective monitored treatment for severe GERD may be an important step to prevent fatal outcome.

Serum matrix metalloproteinases in patients resuscitated from cardiac arrest. The association with therapeutic hypothermia.

AIM: To study the systemic levels of matrix metalloproteinases (MMP) -7, -8 and -9 and their inhibitor TIMP-1 in cardiac arrest patients and the association with mild therapeutic hypothermia treatment on the serum concentration of these enzymes. METHODS: MMP-7, -8 and -9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) were analysed in blood samples obtained from 51 patients resuscitated from cardiac arrest. The samples were taken at 24 and 48 h from restoration of spontaneous circulation (ROSC). The biomarker levels were compared between patients (N=51) and healthy controls (N=10) and between patients who did (N=30) and patients who did not (N=21) receive mild therapeutic hypothermia. RESULTS: MMP-7 (median 0.47 ng/ml), MMP-8 (median 31.16 ng/ml) and MMP-9 (median 253.00 ng/ml) levels were elevated and TIMP-1 levels suppressed (median 78.50 ng/ml) in cardiac arrest patients as compared with healthy controls at 24h from ROSC. Hypothermia treatment associated with attenuated elevation of MMP-9 (p=0.001) but not MMP-8 (p=0.02) or MMP-7 (p=0.69). Concentrations of MMPs -7, -8 and -9 correlated with the leukocyte count but not with C-reactive protein (CRP) or neurone-specific enolase (NSE) levels. CONCLUSION: We demonstrated that the systemic levels of MMP-7, -8 and -9 but not TIMP-1 are elevated in cardiac arrest patients in the 48 h post-resuscitation period relative to the healthy controls. Patients who received therapeutic hypothermia had lower MMP-9 levels compared to non-hypothermia treated patients, which generates hypothesis about attenuation of inflammatory response by hypothermia treatment.

Hypothermia-treated cardiac arrest patients with good neurological outcome differ early in quantitative variables of EEG suppression and epileptiform activity.

OBJECTIVE: To evaluate electroencephalogram-derived quantitative variables after out-of-hospital cardiac arrest. DESIGN: Prospective study. SETTING: University hospital intensive care unit. PATIENTS: Thirty comatose adult patients resuscitated from a witnessed out-of-hospital ventricular fibrillation cardiac arrest and treated with induced hypothermia (33 degrees C) for 24 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electroencephalography was registered from the arrival at the intensive care unit until the patient was extubated or transferred to the ward, or 5 days had elapsed from cardiac arrest. Burst-suppression ratio, response entropy, state entropy, and wavelet subband entropy were derived. Serum neuron-specific enolase and protein 100B were measured. The Pulsatility Index of Transcranial Doppler Ultrasonography was used to estimate cerebral blood flow velocity. The Glasgow-Pittsburgh Cerebral Performance Categories was used to assess the neurologic outcome during 6 mos after cardiac arrest. Twenty patients had Cerebral Performance Categories of 1 to 2, one patient had a Cerebral Performance Categories of 3, and nine patients had died (Cerebral Performance Categories of 5). Burst-suppression ratio, response entropy, and state entropy already differed between good (Cerebral Performance Categories 1-2) and poor (Cerebral Performance Categories 3-5) outcome groups (p = .011, p = .011, p = .008) during the first 24 hrs after cardiac arrest. Wavelet subband entropy was higher in the good outcome group between 24 and 48 hrs after cardiac arrest (p = .050). All patients with status epilepticus died, and their wavelet subband entropy values were lower (p = .022). Protein 100B was lower in the good outcome group on arrival at ICU (p = .010). After hypothermia treatment, neuron-specific enolase and protein 100B values were lower (p = .002 for both) in the good outcome group. The Pulsatility Index was also lower in the good outcome group (p = .004). CONCLUSIONS: Quantitative electroencephalographic variables may be used to differentiate patients with good neurologic outcomes from those with poor outcomes after out-of-hospital cardiac arrest. The predictive values need to be determined in a larger, separate group of patients.

HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis.

OBJECTIVE: To study the predictive value of high mobility group box-1 protein (HMGB1) and hospital mortality in adult patients with severe sepsis. STUDY DESIGN: Prospective observational cohort study in 24 ICUs in Finland. PATIENTS: Two hundred and forty-seven adult patients with severe sepsis. MEASUREMENTS AND MAIN RESULTS: Blood samples for HMGB1 analyses were drawn from 247 patients at baseline and from 210 patients 72 h later. The mean APACHE II and SAPS II scores were 24 (SD 9) and 44 (SD 17), respectively. The hospital mortality was 26%. The serum HMGB1 concentrations were measured first by semi-quantitative Western immunoblotting (WB) analysis. The median HMGB1 concentration on day 0 was 108% (IQR 98.5-119) and after 72 h 107% (IQR 98.8-120), which differed from healthy controls (97.5%, IQR 91.3-106.5; p=0.028 and 0.019, respectively). The samples were re-analysed by ELISA (in a subgroup of 170 patients) to confirm the results by WB. The median concentration in healthy controls was 0.65 ng/ml (IQR 0.51-1.0). This was lower than in patients with severe sepsis (3.6 ng/ml, IQR 1.9-6.5, p< 0.001). HMGB1 concentrations (WB and ELISA) did not differ between hospital survivors and non-survivors. In ROC analyses for HMGB1 levels (WB) on day 0 and 72 h with respect to hospital mortality, the areas under the curve were 0.51 and 0.56 (95% CI 0.40-0.61 and 0.47-0.65). CONCLUSIONS: Serum HMGB1 concentrations were elevated in patients with severe sepsis, but did not differ between survivors and non-survivors and did not predict hospital mortality.

Decrease of mortality of ruptured abdominal aortic aneurysm after centralization and in-hospital quality improvement of vascular service.

Our aim was to determine whether organizational changes could improve the outcome after ruptured abdominal aortic aneurysm (RAAA). Regional centralization and quality improvement in the in-hospital chain of treatment of RAAA included strengthening of the emergency preparedness and better availability of postoperative intensive care. During the reorganization, all patients with RAAA were admitted to Helsinki University Central Hospital (HUCH) from Helsinki and Uusimaa district. RAAA patients in the hospital district of Helsinki and Uusimaa between 1996 and 2004 were identified. The study period was divided into three periods: I, control; II, change; and III, present. Of the total of 626 patients with RAAA, 352 (56%) were admitted to the HUCH, of whom 315 (90%) underwent surgery. During the study period, population-based mortality decreased from 77% to 56% (P < 0.001) and 90-day mortality, from 54% to 28% (P = 0.002). Operative 30-day mortality was 19% during the third period and lower than previously (P = 0.001). Our results seem to argue in favor of centralization of emergency vascular services with adequate manpower and operative expertise in the first line and with availability of closed-unit postoperative critical care to achieve better results as these measures were associated with a positive impact on survival.

Collagenase 2/matrix metalloproteinase 8 in critically ill patients with secondary peritonitis.

Secondary peritonitis is an important indication for surgical intensive care admissions, and it is associated with high morbidity and mortality. Collagenase 2/matrix metalloproteinase (MMP) 8 is a tissue matrix-degrading enzyme that is released from leukocytes upon inflammatory stimuli and may thus contribute to peritonitis-associated organ damage. We studied the levels and activity of MMP-8 in the peritoneal fluid of 15 critically ill patients with secondary peritonitis. The MMP-8 levels were measured from the patients' peritoneal fluid, serum, and urine, and from the serum and urine of 10 healthy controls by immunofluorometric assay. Median MMP-8 level in peritoneal fluid supernatant was 1,317 microg/L (interquartile range [IQR]) (1,254-1,359 microg/L) being significantly higher than in the sera of the patients (P=0.008). Molecular forms and isoform distribution of MMP-8, MMP-1, and MMP-13 in peritoneal fluid, assessed by Western immunoblotting, revealed that the neutrophil-type MMP-8 was the major collagenase species in peritoneal fluid, and it was partially in an activated form. Catalytically competent, active MMP-8 produced the characteristic cleavage products from intact human type I collagen. The serum levels of MMP-8 were higher in the patients, 49 microg/L (IQR, 23-214 microg/L), than in the controls, 11 microg/L (IQR, 8-24 microg/L) (P<0.01). The MMP-8 levels in the urine were higher in the patients, 0.27 microg/L (IQR, 0.04-1.89 microg/L), than in the controls, 0.03 microg/L (IQR, 0.0-0.05 microg/L) (P=0.013). Our data demonstrate for the first time that MMP-8 levels are remarkably elevated and in an active and catalytically competent form in the peritoneal fluid samples of patients with secondary peritonitis.

Intra-abdominal pressure in severe acute pancreatitis.

BACKGROUND: Hospital mortality in patients with severe acute pancreatitis (SAP) remains high. Some of these patients develop increased intra-abdominal pressure (IAP) which may contribute to organ dysfunction. The aims of this study were to evaluate the frequency of increased IAP in patients with SAP and to assess the development of organ dysfunction and factors associated with high IAP. METHODS: During 2001-2003 a total of 59 patients with severe acute pancreatitis were treated in the intensive care unit (ICU) of Helsinki University Hospital. IAP was measured by the intravesical route in 37 patients with SAP. Data from these patients were retrospectively reviewed. RESULTS: Maximal IAP, APACHE II score, maximal SOFA score, maximal creatinine, age and maximal lactate were significantly higher in nonsurvivors. There was a significant correlation of the maximal IAP with the maximal SOFA, APACHE II, maximal creatinine, maximal lactate, base deficit and ICU length of stay. Patients were divided into quartiles according to the maximal IAP. Maximal IAP was 7-14, 15-18, 19-24 and 25-33 mmHg and the hospital mortality rate 10%, 12.5%, 22.2% and 50% in groups 1-4, respectively. A statistically significant difference was seen in the maximal SOFA, ICU length of stay, maximal creatinine and lactate values. The mean ICU-free days in groups 1-4 were 45.7, 38.8, 32.0 and 27.5 days, respectively. The difference between groups 1 and 4 was statistically significant. CONCLUSION: In patients with SAP, increased IAP is associated with development of early organ failure reflected in increased mortality and fewer ICU-free days. Frequent measurement of IAP during intensive care is important in optimizing abdominal perfusion pressure and recognizing patients potentially benefitting from decompressive laparotomy.

Comparison of 2 acute renal failure severity scores to general scoring systems in the critically ill.

BACKGROUND: Several proposed definitions for acute renal failure (ARF) exist, but little is known of their significance in clinical practice. We evaluated the ability to predict hospital mortality in 2 ARF-specific severity-of-illness scoring methods, the Risk, Injury, Failure, Loss, End-Stage Renal Disease (RIFLE) score and the score presented by Bellomo et al in 2001. METHODS: The study included 668 consecutive patients with 694 treatment episodes treated in 2 intensive care units (ICUs) in a university hospital within 11 months. ARF prevalence was classified according to the RIFLE and Bellomo scores. As references, we evaluated 2 general severity-of-illness scoring systems, the admission Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. RESULTS: Admission SOFA scores and maximum RIFLE scores for the first 3 days in the ICU were independent predictors of hospital mortality by means of forward conditional logistic regression. In receiver operating characteristic analysis, SOFA and APACHE II scores performed better than ARF-specific scores, and discriminative powers for hospital mortality were only moderate for the RIFLE and Bellomo scores: areas under the curve were 0.653 (95% confidence interval, 0.588 to 0.719) and 0.587 (95% confidence interval, 0.514 to 0.660), respectively. CONCLUSION: Neither of the ARF-specific scoring methods presented good discriminative power regarding hospital mortality. However, maximum RIFLE score for the first 3 days in the ICU was found to be an independent predictor of hospital mortality, along with admission SOFA score.

N-acetylcysteine for the prevention of kidney injury in abdominal aortic surgery: a randomized, double-blind, placebo-controlled trial.

In this prospective, randomized, placebo-controlled, double-blind trial we studied the effects of IV N-acetylcysteine for prevention of renal injury in patients undergoing abdominal aortic surgery. Seventy patients without previously documented renal dysfunction were randomly allocated to receive either N-acetylcysteine (150 mg/kg mixed in 250 mL of 5% dextrose infused in 20 min, followed by an infusion of 150 mg/kg in 250 mL of 5% dextrose over 24 h) or placebo. The infusion was started after the induction of anesthesia. The primary outcome measure was renal injury as measured by the increases in urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine ratio (indicator of renal tubular injury) and urinary albumin/creatinine ratio (indicator of glomerular injury). Renal function was assessed by measuring plasma creatinine and serum cystatin C concentrations. The urinary NAG/creatinine ratio increased significantly from baseline to before crossclamp and remained increased on day 5 in both groups. The urinary albumin/creatinine ratio increased significantly from baseline to 6 h after declamping in the N-acetylcysteine group. However, the changes in the NAG/creatinine ratio and the albumin/creatinine ratio were not significantly different between the two groups. Plasma creatinine and serum cystatin C values remained unchanged during the study period in both groups. In conclusion, N-acetylcysteine did not offer any significant protection from renal injury during elective aortic operation in patients with normal preoperative renal function, and some degree of tubular injury seems to occur before aortic crossclamp.

The effect of N-acetylcysteine on blood coagulation and platelet function in patients undergoing open repair of abdominal aortic aneurysm.

N-acetylcysteine (NAC) may offer renal and hepatic protection during surgery, but in experimental studies it has been shown to impair coagulation. Since very little is known about the effects of NAC on blood coagulation in surgical patients, we studied its effects during abdominal aortic reconstruction. NAC (a bolus of 150 mg/kg followed by a continuous 24-h infusion of 150 mg/kg) or the same volume of placebo was given intravenously, in a randomized double-blinded fashion, to 20 patients undergoing abdominal aortic aneurysm repair. The haematocrit, platelet count, prothrombin time, thromboelastometry, and platelet aggregation were studied during and after surgery. Total blood loss was also measured. The median (25th-75th percentiles) decrease of the prothrombin time value was 33.0% (30-37%) after NAC treatment and 6.5% (4-8%) after placebo (P<0.001). Postoperative prothrombin time values remained lower in the patients receiving NAC. In thromboelastometry tracings the coagulation time was more prolonged after the bolus of NAC (P=0.02). Platelet aggregation induced with adenosine diphosphate decreased after NAC but not after placebo. Low prothrombin time values before and after bolus infusions were associated with increased blood loss (P=0.008 and P=0.015, respectively). NAC has anticoagulant and platelet-inhibiting properties in patients undergoing major vascular surgery. This abnormal haemostatic activity should be considered when NAC is administered to patients with increased bleeding risk.