Plasma as endothelial rescue in septic shock: A randomized, phase 2a pilot trial.

BACKGROUND: Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer. We evaluated the efficacy and safety aspects of cell-free and pathogen inactivated pooled plasma (OctaplasLG®) as resuscitation in septic shock patients. STUDY DESIGN AND METHODS: This randomized, investigator-initiated phase IIa trial ran at a Danish single center intensive care unit, from 2017 to 2019. Patients were 18 years of age or older with septic shock and randomized to fluid optimization with OctaplasLG® or Ringer-acetate in the first 24 h. The primary endpoints were changes in biomarkers indicative of endothelial activation, damage, and microvascular perfusion from baseline to 24 h. Safety events and mortality were assessed during 90 days. RESULTS: Forty-four patients were randomized, 20 to OctaplasLG versus 24 to Ringer-acetate. The median age was 69, and 55% were men. Median Sequential Organ Failure Assessment score was 13. Baseline differences favoring the Ringer-acetate group were observed. The OctaplasLG® group was resuscitated with 740 mL plasma and the Ringer-acetate group with 841 mL crystalloids. There was no significant change in the microvascular perfusion or five biomarkers except VEGFR1 change, which was higher in patients receiving OctaplasLG® 0.12(SD 0.37) versus Ringer-acetate -0.24 (SD 0.39), with mean difference 0.36 (95% CI, 0.13-0.59, p = .003) in favor of Ringer-acetate. DISCUSSION: This study found that fluid resuscitation with OctaplasLG® in critically ill septic shock patients is feasible. Baseline confounding prevented assessment of the potential effect of OctaplasLG®.

Mild induced hypothermia and coagulation and platelet function in patients with septic shock: Secondary outcome of a randomized trial.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min [interquartile range, IQR 6.6-11.1] vs. 7.2 min [IQR 5.8-9.2]; p = .004) and marginally inhibited thrombus propagation (angle 68° [IQR 59-73] vs. 71° [IQR 63-75]; p = .014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm [IQR 66-76] with mild induced hypothermia vs. 72 mm (65-77) with routine thermal management, p = .9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p = .19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p < .001). The mild induced hypothermia group had lower platelet aggregation: ASPI 85U (IQR 50-113) versus 109U (IQR 74-148, p < .001), ADP 61U (IQR 40-83) versus 79 U (IQR 54-101, p < .001), TRAP 108 (IQR 83-154) versus 119 (IQR 94-146, p = .042) and COL 50U (IQR 34-66) versus 67U (IQR 46-92, p < .001). In patients with septic shock, mild induced hypothermia slightly impaired clot initiation, but did not change clot strength. Platelet aggregation was slightly impaired. The effect of mild induced hypothermia on viscoelastography and platelet aggregation was however not in a range that would have clinical implications. We did observe a substantial reduction in fibrinolysis.

Early Biomarker-Guided Prediction of Bloodstream Infection in Critically Ill Patients: C-Reactive Protein, Procalcitonin, and Leukocytes.

Background: Bloodstream infections (BSIs) often lead to critical illness and death. The primary aim of this study was to determine the diagnostic accuracy of the biomarkers C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count for the diagnosis of BSI in critically ill patients. Methods: This was a nested case-control study based on the Procalcitonin And Survival Study (PASS) trial (n = 1200). Patients who were admitted to the intensive care unit (ICU) <24 hours, and not expected to die within <24 hours, were recruited. For the current study, we included patients with a BSI within ±3 days of ICU admission and matched controls without a BSI in a 1:2 ratio. Diagnostic accuracy for BSI for the biomarkers on days 1, 2, and 3 of ICU admission was assessed. Sensitivity, specificity, and negative and positive predictive values were calculated for prespecified thresholds and for a data-driven cutoff. Results: In total, there were 525 patients (n = 175 cases, 350 controls). The fixed low threshold for all 3 biomarkers (CRP = 20 mg/L; leucocytes = 10 × 109/L; PCT = 0.4 ng/mL) resulted in negative predictive values on day 1: CRP = 0.91; 95% CI, 0.75-1.00; leukocyte = 0.75; 95% CI, 0.68-0.81; PCT = 0.91; 95% CI, 0.84-0.96). Combining the 3 biomarkers yielded similar results as PCT alone (P = .5). Conclusions: CRP and PCT could in most cases rule out BSI in critically ill patients. As almost no patients had low CRP and ∼20% had low PCT, a low PCT could be used, along with other information, to guide clinical decisions.

ABO blood types and sepsis mortality.

BACKGROUND: We aimed to determine if the ABO blood types carry different risks of 30-day mortality, acute kidney injury (AKI), and endothelial damage in critically ill patients with sepsis. This was a retrospective cohort study of three independent cohorts of critically ill patients from the United States and Scandinavia consisting of adults with septic shock. We compared the 30-day mortality across the blood types within each cohort and pooled the results in a meta-analysis. We also estimated the incidence of AKI and degree of endothelial damage, as measured by blood concentrations of soluble thrombomodulin and syndecan-1. RESULTS: We included 12,342 patients with severe sepsis. In a pooled analysis blood type B carried a slightly lower risk of 30-day all-cause mortality compared to non-blood type B (adjusted HR 0.88; 95%-CI 0.79-0.98; p = 0.02). There was no difference in the risk of AKI. Soluble thrombomodulin and syndecan-1 concentrations were lower in patients with blood type B and O compared to blood type A, suggesting less endothelial damage. CONCLUSION: Septic patients with blood type B had less endothelial damage, and a small reduction in mortality. The exposure is, however, unmodifiable.

Clinical impact of frailty among patients with severe vital sign derangement: An observational study.

BACKGROUND: Frailty is associated with increased morbidity and mortality and frail patients may have reduced ability to tolerate severe vital sign derangement such as estimated by a high National Early Warning Score (NEWS). The clinical impact of frailty among patients that develop high NEWS during hospital admissions is sparsely studied. The aim of this study was to investigate the association between clinical frailty and admission to intensive care unit (ICU) among these patients. METHODS: We conducted a prospective observational study from November 2017 to January 2018. We included adult patients admitted to general wards that during hospitalization developed severe vital sign derangement defined as NEWS ≥7. Patients were without treatment restrictions at inclusion. Primary exposure was frailty as assessed by the Clinical Frailty Scale. Primary outcome was ICU admission within 90 days, which was analyzed using multivariate logistic regression. RESULTS: We included 109 patients with NEWS ≥7, of which 61 patients (56%) were frail. Ten of the 61 frail patients (16%) were admitted to ICU compared to 9 of the 48 non-frail patients (19%), adjusted odds ratio (aOR) 0.92 (95% CI 0.32-2.62). Frail patients were more likely to have new treatment restrictions (aOR 2.91; 95% CI 1.26-6.71). Their aOR for mortality was 1.95 (95% CI 0.84-4.55). CONCLUSION: Frail patients with severe vital sign derangement during acute hospital admissions were not more likely to be admitted to ICU nor was mortality higher. Treatment restrictions were more frequent among frail patients after vital sign derangements developed.

[Psychodynamic psychotherapy of patients with schizophrenia spectrum psychosis].

This Danish review is a description of the relevance and importance of psychodynamic psychotherapy in the understanding and treatment of patients with schizophrenia spectrum psychosis. Previous research is included, and the results of a recently published, large-scale, prospective comparative study showing good results of adding psychodynamic psychotherapy to treatment as usual are summarised. Concrete examples are given to demonstrate the specificity of the dynamics and the supportive characteristics of the effective interventions in the relationship between patient and therapist.

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

Self-Rated Health as a Predictor of Death after Two Years: The Importance of Physical and Mental Wellbeing Postintensive Care.

INTRODUCTION: The objective of this study is, among half-year intensive care survivors, to determine whether self-assessment of health can predict two-year mortality. METHODS: The study is a prospective cohort study based on the Procalcitonin and Survival Study trial. Half-year survivors from this 1200-patient multicenter intensive care trial were sent the SF-36 questionnaire. We used both a simple one-item question and multiple questions summarized as a Physical Component Summary (PCS) and a Mental Component Summary (MCS) score. The responders were followed for vital status 730 days after inclusion. Answers were dichotomized into a low-risk and a high-risk group and hazard ratios (HR) with 95% confidence interval (CI) were calculated by Cox proportional hazard analyses. CONCLUSION: We found that self-rated health measured by a single question was a strong independent predictor of two-year all-cause mortality (HR: 1.8; 95% CI: 1.1-3.0). The multi-item component scores of the SF-36 also predicted two-year mortality (PCS: HR: 2.9; 95% CI 1.7-5.0) (MCS: HR: 1.9; 95% CI 1.1-3.4). These results suggest that self-rated health questions could help in identifying patients at excess risk. Randomized controlled trials are needed to test whether our findings represent causality.

Staff attitudes towards patients with schizophrenia.

INTRODUCTION: Stigmatizing attitudes have been reported in international studies among staff in psychiatry. The authors wanted to investigate if this was the case in Denmark. MATERIAL AND METHODS: A survey of attitudes among staff at two psychiatric units in Copenhagen was performed using the Mental Illness: Clinicians' Attitudes scales. The scales have 16 questions to which another four questions were added by the authors. RESULTS: A total of 548 staff members answered the questions (61 doctors and 487 other professionals). The majority of the respondents believed in the possibility of recovery for patients and only a minority associated a high degree of dangerousness with schizophrenia. The cause of the illness was mainly regarded as being biological, but all agreed to a bio-psycho-social aetiological approach. The majority of the respondents believed that the illness was chronic and agreed on the need for staff to also be aware of patients' somatic illness. The doctors did not question their role as "real doctors" or the scientific basis for psychiatry. The majority would not mind working with a colleague with schizophrenia, but about half would hesitate to disclose if they themselves were diagnosed with the illness. Being a woman working in community psychiatry with long experience and participation in a recovery educational programme was associated with less stigmatizing attitudes. CONCLUSION: The survey showed a relatively low level of stigmatizing attitudes. This runs counter to the results from international investigation. This trend could be interpreted both as a result of a shift towards a more recovery-oriented approach to treatment as well as a reflection of political correctness.

Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial.

BACKGROUND: Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. METHODS/DESIGN: The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P ≤0.001 is present at this point. DISCUSSION: The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated.

Supportive psychodynamic psychotherapy versus treatment as usual for first-episode psychosis: two-year outcome.

During recent decades, the field of treatment of schizophrenia has lacked empirical, systematic outcome studies that support psychodynamic psychotherapy as an evidence-based intervention for patients with schizophrenia. The Danish schizophrenia project (DNS) compared psychodynamic psychotherapy for psychosis with standard treatment in patients with a first-episode schizophrenia spectrum disorder. The study was designed as a prospective, comparative, longitudinal multi-site investigation of consecutively referred patients who were included during two years. The patients were treated with either manualized individual supportive psychodynamic psychotherapy (SPP) in addition to treatment as usual or with treatment as usual alone (TaU). Symptoms and functional outcomes were measured using the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale (GAF). The study included 269 consecutively admitted patients, age 18-35, of whom 79% remained in the study after two years. The intervention group improved significantly on measures of both PANSS and GAF scores, with large effect sizes at two years follow-up after inclusion. Further, improvement on GAF(function) (p = 0.000) and GAF(symptom) (p = 0.010) significantly favored SPP in combination with TaU over TaU alone. In spite of limitations, this study speaks in favor of including supportive psychodynamic psychotherapy in the treatment for patients with schizophrenic first-episode psychoses.

[Ethical consequences of the diagnosis of psychosis]. / Der er særlige etiske konsekvenser af psykosediagnosen.

Psychosis is defined by the loss of reality testing. Apart from that, it is rather broadly and vaguely defined. Ethics is the art of defining what is right and what is wrong. Medical ethics apply a diversity of ethical principles to a complex clinical reality after discussion and consideration. In forensic psychiatry the diagnosis of psychosis has vast ethical implications. In the Danish law on psychiatry conditions for coercion and involuntary treatment are stated, and in the law on penalty the principle of treatment instead of penalty is stated. Thus, implications for diagnoses and treatment go far beyond other medical diagnoses.

[Stigmatizing of persons with a mental illness]. / Stigmatisering af mennesker med psykisk lidelse.

Persons with a mental illness and their relatives experience discrimination and expect to be discriminated. The public regards them as unpredictable and dangerous and do not wish to have any relation with them neither in private nor at work. This opinion is shared by people working in health care or social care. The myth of dangerousness is out of proportion and the media is to blame as they most often mention persons with mental illnesses as dangerous. Many countries make a great effort to reduce stigma and this is also under planning in Denmark.

Antipsychotic polypharmacy and risk of death from natural causes in patients with schizophrenia: a population-based nested case-control study.

OBJECTIVE: Concomitant prescription of more than 1 antipsychotic agent (antipsychotic polypharmacy) in the treatment of schizophrenia is prevalent, although monotherapy is generally recommended. Mortality from natural causes is markedly increased in schizophrenia, and the role of polypharmacy remains controversial. The objective was to investigate if antipsychotic polypharmacy is associated with the excess mortality from natural causes among patients with schizophrenia. METHOD: A population-based nested case-control study was conducted using patient data from January 1, 1996, to December 31, 2005, obtained from central Danish registers. From the study population of 27,633 patients with ICD-8- and ICD-10-diagnosed schizophrenia or other mainly nonaffective psychoses, aged 18-53 years, we identified 193 cases who died of natural causes within a 2-year period and 1,937 age- and sex-matched controls. Current drug use was defined as at least 1 prescription filled within 90 days before the date of death or the index date. The data were analyzed by conditional logistic regression. RESULTS: Risk of natural death did not increase with the number of concurrently used antipsychotic agents compared with antipsychotic monotherapy (no antipsychotics: adjusted odds ratio [OR] = 1.48 [95% CI, 0.89-2.46]; 2 antipsychotics: OR = 0.91 [95% CI, 0.61-1.36]; 3 or more antipsychotics: OR = 1.16 [95% CI, 0.68-2.00]). Current use of benzodiazepine derivatives with long elimination half-lives (more than 24 hours) was associated with increased risk of natural death in patients with schizophrenia treated with antipsychotics (OR = 1.78 [95% CI, 1.25-2.52]). CONCLUSIONS: Antipsychotic polypharmacy did not contribute to the excess mortality from natural causes in middle-aged patients with schizophrenia. The detected increased risk of death associated with benzodiazepines with long elimination half-lives calls for further clarification.

Gender differences in first episode psychosis.

BACKGROUND: In the description of 1 episode schizophrenia patients, female gender is associated with better social function and a higher degree of compliance, while males exhibit more negative symptoms and a higher degree of abuse. The question is raised whether gender specific differences exist which should be taken into consideration in order to provide optimal treatment for the patients. METHODS AND MATERIAL: Data from 269 persons (181 men and 88 women), included in the Danish national schizophrenia project (DNS), were registered at inclusion and year 2, and were analyzed according to gender, social functioning, psychopathology, drug consumption and abuse during the course of 2 years treatment. RESULTS: Women had longer duration of illness before treatment and exhibited more affective symptoms while men were more socially isolated and had more negative symptoms. Alcohol and drug abuse appeared significantly more among men. Women were comparatively more heavily medicated than men. Social function, PANSS negative, drug consumption, affective symptomatology and abuse improved significantly after 2 years follow-up. CONCLUSION: The gender differences demonstrated in the study suggest gender specific treatment interventions in order to provide optimal treatment for both male and female patients.

[Quality development in a community mental health centre. Method for registration. Cross-sectional study at a community mental health centre in the Inner Noerrobro area]. / Kvalitetsudvikling i et distriktspsykiatrisk center, en metode til løbende monitorering. Tvaersnitsundersøgelse ved Distriktspsykiatrisk Center Indre Nørrebro.

INTRODUCTION: The present investigation demonstrates a method for registration, the results of which are used to identify patient populations with special needs and to better organise treatment in order to serve their needs. MATERIALS AND METHOD: A retrospective prevalence study based on patient files, including 273 patients who on 7th September 2001 were in treatment at a community mental health centre in the Inner Noerrebro area of Copenhagen. Patient data included sociodemography, psychopathology, diagnosis and social function. RESULTS: Severe psychiatric illness was demonstrated with a mean CGI (Clinical Global Impression) 5.3 and a low social function with a mean GAF (Global Assessment of Function) 40.2. 78% had a diagnosis of schizophrenia or paranoid psychosis (DF 20-29). 49% had a severe disturbance (from an index based on diagnosis, social function and use of health service). 23% had an additional substance misuse. Immigrants accounted for 23% of the patient population, but only 14% in the background population. There were no significant differences between immigrants and Danes in terms of diagnosis and severity of illness. Significantly fewer immigrants had substance misuse. Significantly more immigrants were never admitted to hospital. Significantly more immigrants had children living at home. CONCLUSION: The method used is simple and the results can be used for a better organisation of services, with focus on specific needs on a group level. In collaboration with the Centre for Transcultural Psychiatry a subspecialised service for patients with an immigrant background was established.

Treatment of patients with first-episode psychosis: two-year outcome data from the Danish National Schizophrenia Project.

First episode psychosis interventions have been in focus in the last two decades in an attempt to improve the course and outcome of schizophrenic disorders. The Danish National Schizophrenia Project began in 1997 its intake of patients, aged 16-35, with a first psychotic episode of a schizophrenic spectrum disorder, diagnosed by ICD-10 (F20-29). The study was carried out as a prospective, longitudinal, multicentre investigation, encompassing 16 centres, spread all over the country. The sample consists of 562 patients consecutively diagnosed during two years. Patients were treated with "supportive psychodynamic psychotherapy as a supplement to treatment as usual", "integrated, assertive, psychosocial and educational treatment programme", or "treatment as usual". Data on symptoms and social function and sociodemographic data were obtained at inclusion, and at year 1 and 2. The three sub-cohorts did not differ at baseline. After one year, the total sample of patients improved significantly concerning symptoms and social function. The significance of the improvement remained after two years. After one year, patients in the two intervention groups improved more concerning symptoms and social function than patients in the treatment-as-usual group. Improvement in the intervention groups continued into the second year. Patients receiving integrated assertive treatment faired better than those being treated with the less intensive method of supportive psychodynamic psychotherapy, and the latter group improved more than the treatment-as-usual group.

Current issues in Scandinavian acute psychiatric wards.

The aim of the paper is to provide an overview of some of the most important issues faced by acute inpatient facilities in three Scandinavian countries, including reflections and critical remarks for discussion in this field. Information was drawn from scientific articles and official reports published in recent years, as well as the authors' own knowledge of acute facilities in their home countries. Acute inpatient facilities, including General Hospital Psychiatric Units (GHPUs), in all Scandinavian countries have several issues and problems in common, which include the organisation and capacity of acute services, the assessment of dangerousness and suicidality, the use of coercion and efforts to reduce coercion, the need to define and improve the quality of acute services, and the necessity to improve collaboration and continuity between acute services and other services. Although the emphasis some of these issues receive can vary across the three countries, Scandinavian mental health professionals (and policy makers) have begun to systematically share their experiences in developing a growing spirit of collaboration. Despite the role of welfare state and the deployment of substantial resources in Scandinavian countries, mental health practitioners are struggling to implement best practices in acute wards, to develop differentiated forms of acute services, and to reach the right balance and coordination between acute services and other services.