Onset of Prolonged High-Potency Benzodiazepine Use Among ICU Survivors: A Nationwide Cohort Study.

OBJECTIVES: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality. DESIGN: Retrospective cohort study. SETTING: Sweden, including all registered ICU admissions between 2010 and 2017. PATIENTS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion. INTERVENTIONS: Admission to intensive care. MEASUREMENTS AND MAIN RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers. CONCLUSIONS: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

Antidepressant drug use after intensive care: a nationwide cohort study.

Modern intensive care has improved survival rates, but emerging evidence suggests a high prevalence of post-intensive care unit (ICU) health problems, including post-traumatic stress disorder, depression and anxiety. These symptoms may have a detrimental effect on quality of life and increase mortality. The primary objective of this study is to examine the extent of initiation of antidepressant medication among ICU survivors and identify the factors associated with its usage. The secondary objective is to investigate whether the use of these medications is linked to an increased mortality. The nationwide study cohort included 125,130 ICU survivors admitted between 2010 and 2017. Within the first 3 months after ICU discharge, 7% of patients initiated antidepressant medication, by 1 year 15.5% had started medication. We found no tendency to a decrease during the 2-year follow-up period. Factors associated with antidepressant use included middle age, female sex, psychiatric and somatic comorbid conditions, substance dependence, higher illness severity, and longer ICU stay. Antidepressant users had a higher mortality rate, and deaths due to external causes and suicide were more frequent in this group. This study emphasizes the importance of detecting and addressing depression in ICU survivors to improve their quality of life and reduce mortality rates.

Onset of Prolonged High-Potency Benzodiazepine Use Among ICU Survivors: A Nationwide Cohort Study.

OBJECTIVES: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality. DESIGN: Retrospective cohort study. SETTING: Sweden, including all registered ICU admissions between 2010 and 2017. PATIENTS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion. INTERVENTIONS: Admission to intensive care. MEASUREMENTS AND MAIN RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers. Conclusions: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

Opioid use following cardio-thoracic intensive care: risk factors and outcomes: a cohort study.

Opioid misuse has become a serious public health problem. Patients admitted to cardio-thoracic critical care are usually exposed to opioids, but the incidence and effects of chronic opioid use are not known. The primary objective was to describe opioid use after admission to a cardio-thoracic intensive care unit. Secondary objectives were to identify factors associated with chronic opioid usage and analyze risk of death. This cohort study included all cardio-thoracic ICU care episodes in Sweden between 2010 and 2018. Among the 34,200 patients included in the final study cohort, 4050 developed persistent opioid use after ICU care. Younger age, preadmission opioid use, female sex, presence of comorbidities and earlier year of ICU admission were all found to be associated with persistent opioid use. The adjusted hazard ratio for mortality between 6 and 18 months after admission among individuals with persistent opioid use was 2.2 (95% CI 1.8-2.6; P < 0.001). For opioid-naïve patients before ICU admission, new onset of chronic opioid usage was significant during the follow-up period of 24 months. Despite the absence of conclusive evidence supporting extended opioid treatment, the average opioid consumption remains notably elevated twelve months subsequent to cardio-thoracic ICU care.

Benzodiazepine Dependence After Cardiothoracic Intensive Care: A Nationwide Cohort Study.

BACKGROUND: This study aimed to describe benzodiazepine use after cardiothoracic intensive care unit (ICU) care, including factors associated with new long-term high-potency benzodiazepine use after critical care, and to determine whether benzodiazepine use is associated with an increased risk of death. METHODS: A nationwide retrospective cohort study was conducted of all cardiothoracic ICU patients in Sweden between 2010 and 2018. All patients older than 18 years who survived the first 3 months after admission to a cardiothoracic ICU were eligible for inclusion. A total of 36,135 patients were screened, and 4163 were ineligible. RESULTS: In the final study cohort of 31,972 benzodiazepine-naive patients admitted to critical care, 578 patients had persistent high-potency benzodiazepine use. The proportion of new persistent benzodiazepine users was 5% in the first 3 months after ICU care, followed by a decline to a consistent level of 2% at 2 years of follow-up. Factors associated with persistent benzodiazepine use included higher age, female sex, psychiatric and somatic comorbidities, substance abuse, and preadmission opioid and low-potency benzodiazepine use. Adjusted hazard ratio for death 6 to 18 months after admission for new persistent benzodiazepine users was 2.2 (95% CI, 1.5-3.1; P < .001). CONCLUSIONS: High-potency benzodiazepine consumption is increased 2 years after admission to cardiothoracic ICU care despite lack of support for long-term use of benzodiazepines. Being older and female, prior opioid use, and comorbid conditions were among risk factors for persistent benzodiazepine use. Persistent benzodiazepine users had an increased risk of death.

Long-term opioid use following bicycle trauma: a register-based cohort study.

PURPOSE: Chronic opioid use is a significant public health burden. Orthopaedic trauma is one of the main indications for opioid prescription. We aimed to assess the risk for long-term opioid use in a healthy patient cohort. METHODS: In this matched cohort study, bicycle trauma patients from a Swedish Level-I-Trauma Centre in 2006-2015 were matched with comparators on age, sex, and municipality. Information about dispensed opioids 6 months prior until 18 months following the trauma, data on injuries, comorbidity, and socioeconomic factors were received from national registers. Among bicycle trauma patients, the associations between two exposures (educational level and injury to the lower extremities) and the risk of long-term opioid use (> 3 months after the trauma) were assessed in multivariable logistic regression models. RESULTS: Of 907 bicycle trauma patients, 419 (46%) received opioid prescriptions, whereof 74 (8%) became long-term users. In the first quarter after trauma, the mean opioid use was significantly higher in the trauma patients than in the comparators (253.2 mg vs 35.1 mg, p < 0.001) and fell thereafter to the same level as in the comparators. Severe injury to the lower extremities was associated with an increased risk of long-term opioid use [OR 4.88 (95% CI 2.34-10.15)], whereas high educational level had a protecting effect [OR 0.42 (95% CI 0.20-0.88)]. CONCLUSION: The risk of long-term opioid use after a bicycle trauma was low. However, opioids should be prescribed with caution, especially in those with injury to lower extremities or low educational level.

Critical Influenza and COVID-19-A Comparative Nationwide Case-Control Study.

Refined knowledge of risk factors for critical influenza and COVID-19 may lead to improved understanding of pathophysiology and better pandemic preparedness. OBJECTIVES: To compare risk-factor profiles of patients admitted to intensive care with critical influenza and COVID-19. DESIGN SETTING AND PATIENTS: A nationwide retrospective matched case-control study, including all adults admitted to an ICU in Sweden with influenza or COVID-19 between 2014 and September 2020 and a matched control population (ratio 1:5, patients:controls). MEASUREMENTS AND MAIN RESULTS: Admission to an ICU. The study included 1,873 influenza and 2,567 COVID-19 ICU patients, and 9,365 and 12,835 controls, respectively, matched on sex, age, and geographical region. Influenza patients were older and less likely male, and carried a larger burden of comorbidity and a higher Simplified Acute Physiology Score III score, whereas short-term mortalities were similar when compared to COVID-19 patients. The risk-factor profiles at ICU admission were largely comparable including socioeconomic, psychiatric, and several somatic variables. Hypertension was a strong risk factor in critical COVID-19 patients compared with influenza. Nonglucocorticoid immunosuppressive therapy was associated with critical influenza but not COVID-19. Premorbid medication with statins and renin-angiotensin-aldosterone system inhibitors reduced the risk for both conditions, the opposite was a seen for glucocorticoid medication. Notably, medication with betablockers, oral anticoagulation, and platelet inhibitors reduced the risk of critical COVID-19 but not influenza. CONCLUSIONS: The risk-factor profiles for critical influenza and COVID-19 were largely comparable; however, some important differences were noted. Hypertension was a stronger risk factor for developing critical COVID-19, whereas the use of betablockers, oral anticoagulants, and platelet inhibitors all reduced the risk of ICU admission for COVID-19 but not influenza. Findings possibly reflected differences in pathophysiological mechanisms between these conditions.

Postinjury Sepsis-Associations With Risk Factors, Impact on Clinical Course, and Mortality: A Retrospective Observational Study.

OBJECTIVES: Overall outcomes for trauma patients have improved over time. However, mortality for postinjury sepsis has been reported to be unchanged. Estimate incidence of and risk factors for sepsis in ICU patients after major trauma and the association between sepsis, mortality, and clinical course. DESIGN SETTING AND PATIENTS: ICU in a large urban trauma center in Sweden with a well-developed trauma system. Retrospective cohort study of trauma patients admitted to the ICU for more than 24 hours were included. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was 30-day mortality. Secondary outcomes were 1-year mortality and impact on clinical course. In total, 722 patients with a median Injury Severity Score of 26 (interquartile range, 18-38) were included. Incidence of sepsis was 22%. Septic patients had a four-fold increase in length of stay and need for organ supportive therapy. The overall 30-day mortality rate was 9.3%. After exclusion of early trauma-related deaths in the first 48 hours, the 30-day mortality rate was 6.7%. There was an association between sepsis and this adjusted 30-day mortality (day 3 odds ratio, 2.1 [95% CI, 1.1-3.9]; day 4 odds ratio, 3.1 [95% CI, 1.5-6.1]; day 5 odds ratio, 3.0 [95% CI, 1.4-6.2]). Septic patients had a 1-year mortality of 17.7% (nonseptic 11.0%). Development of sepsis was independently associated with age, spine and chest injury, shock, red cell transfusion, and positive blood alcohol concentration at admission. The risk of sepsis increased, in a dose-dependent manner, with the number of transfusions. CONCLUSIONS: Postinjury sepsis was associated with a complicated clinical course and with mortality after exclusion of early, trauma-related deaths.

Temporal patterns of organ dysfunction after severe trauma.

BACKGROUND: Understanding temporal patterns of organ dysfunction (OD) may aid early recognition of complications after trauma and assist timing and modality of treatment strategies. Our aim was to analyse and characterise temporal patterns of OD in intensive care unit-admitted trauma patients. METHODS: We used group-based trajectory modelling to identify temporal trajectories of OD after trauma. Modelling was based on the joint development of all six subdomains comprising the sequential organ failure assessment score measured daily during the first two weeks post trauma. Further, the time for trajectories to stabilise and transition to final group assignments were evaluated. RESULTS: Six-hundred and sixty patients were included in the final model. Median age was 40 years, and median ISS was 26 (IQR 17-38). We identified five distinct trajectories of OD. Group 1, mild OD (n = 300), median ISS of 20 (IQR 14-27), had an early resolution of OD and a low mortality. Group 2, moderate OD (n = 135), and group 3, severe OD (n = 87), were fairly similar in admission characteristics and initial OD but differed in subsequent OD trajectories, the latter experiencing an extended course and higher mortality. In group 3, 56% of the patients developed sepsis as compared with 19% in group 2. Group 4, extreme OD (n = 40), received most blood transfusions, had the highest proportion of shock at admission and a median ISS of 41 (IQR 29-50). They experienced significant and sustained OD affecting all organ systems and a 28-day mortality of 30%. Group 5, traumatic brain injury with OD (n = 98), had the highest mortality of 35% and the shortest time to death for non-survivors, median 3.5 (IQR 2.4-4.8) days. Groups 1 and 5 reached their final group assignment early, > 80% of the patients within 48 h. In contrast, groups 2 and 3 had a prolonged time to final group assignment. CONCLUSIONS: We identified five distinct trajectories of OD after severe trauma during the first two weeks post-trauma. Our findings underline the heterogeneous course after trauma and describe some potentially important clinical insights that are suggested by the groupings and temporal trajectories.

Comparison of the sepsis-2 and sepsis-3 definitions in severely injured trauma patients.

PURPOSE: To evaluate the performance of the new SOFA-based sepsis definition in trauma patients. MATERIALS AND METHODS: A single-centre, retrospective, observational study. Primary outcome was 30-day mortality including a censoring analysis for early deaths. The primary outcome was evaluated with logistic regression, receiver operating characteristics (ROC) curves and Kaplan-Meier survival analyses. RESULTS: 722 severely injured patients were included between 2007 and 2016. 315 patients fulfilled the sepsis-2 criteria and 148 fulfilled the sepsis-3 criteria during the first ten days in the ICU. The odds ratios for 30-day mortality were 0.7 (CI 0.4-1.2) for sepsis-2 and 1.5 (CI 0.8-2.6) for sepsis-3. When censoring patients dying at day 1, sepsis-3 became associated with 30-day mortality whereas sepsis-2 did not. This finding was persistent and enhanced through continuing day-by-day censoring of early deaths. The same pattern was seen for the ROC curves analyses, censoring of early deaths resulted in significant discriminatory properties for sepsis-3 but not for sepsis-2. CONCLUSIONS: The sepsis-3 definition identifies much fewer patients and is more strongly associated with adverse outcomes than the sepsis-2 definition. The sepsis-3 definition seems to be useful in the post trauma setting.

Thioredoxin a novel biomarker of post-injury sepsis.

BACKGROUND: Thioredoxin (TRX), an endogenous anti-oxidant protein induced in inflammatory conditions, has been shown to increase in plasma and to be associated with outcome in septic patients. This biomarker has never been studied in a trauma setting. We hypothesized that TRX would be increased after trauma and associated with post-injury sepsis. METHODS: Single-centre prospective observational study conducted at the intensive care unit (ICU) at the Karolinska University Hospital, Stockholm, Sweden, a level-1 trauma centre. Eighty-three severely injured trauma patients, 18 years or older, with an ICU stay of three days or more were included. Plasma samples were obtained on day 1 and 3 after informed consent. Clinical, physiological and outcome data were retrieved from the trauma and ICU research registries. Plasma samples were also obtained from 15 healthy subjects. In addition, a standardized porcine trauma model was conducted where a femur fracture followed by a controlled hemorrhage period were inflicted in four pigs. RESULTS: In pigs, however not significant, there was a continuing increase in plasma-TRX after femur fracture and sequential hemorrhage despite near normalisation of cardiac index and lactate levels. In patients, median injury severity score was 29 and 48 patients developed sepsis during their ICU stay. A three-fold increase in initial TRX was seen in trauma patients when compared to healthy volunteers. Thioredoxin was significantly higher in patients in shock on admission, those subject to massive transfusion and in the most severely injured patients. No difference was seen between survivors and non-survivors. Plasma-TRX on day 1 was significantly increased in patients who later developed post-injury sepsis. In a logistic regression analysis including TRX, C-reactive protein, injury severity, massive transfusion, and admission blood pressure, TRX was the only variable independently associated with post-injury sepsis. CONCLUSIONS: This study demonstrates that TRX is released into plasma in response to severe trauma and independently associated with post-injury sepsis. The use of TRX as a biomarker in trauma patients needs further evaluation in larger studies. LEVEL OF EVIDENCE: Retrospective cohort study, level III.

Quality of anaesthesia for Caesarean sections: a cross-sectional study of a university hospital in a low-income country.

OBJECTIVE: To evaluate the quality of anaesthesia for Caesarean sections at Muhimbili National Hospital, Dar es Salaam, Tanzania. METHOD: We developed an instrument consisting of 40 quality indicators using an expert group process based on the existing literature. Using the instrument, we observed 50 Caesarean sections. Twenty-eight of the indicators were structural indicators, such as essential drugs, oxygen supply and anaesthetic equipment. Twelve were process indicators such as evaluation of airway, blood pressure assessment or insertion of an intravenous line. RESULTS: The median patient age was 28.5 years. A total of 75% (range 61-82%) of the structural indicators were present in the operating theatres, and 55% (range 33-83%) of the process indicators were performed. The neonates' median Apgar score was 9 (range 3-10). Seven babies required ventilation, four babies were stillborn, and all others were alive at follow-up 2 days after partus. All mothers were alive 2 days post-surgery. CONCLUSION: The low process score suggests that quality improvement initiatives should focus on the processes of anaesthesia for Caesarean sections rather than new drugs and equipment.

A comparative analysis of the bifunctional Cox proteins of two heteroimmune P2-like phages with different host integration sites.

The Cox protein of the coliphage P2 is multifunctional; it acts as a transcriptional repressor of the Pc promoter, as a transcriptional activator of the P(LL) promoter of satellite phage P4, and as a directionality factor for site-specific recombination. The Cox proteins constitute a unique group of directionality factors since they couple the developmental switch with the integration or excision of the phage genome. In this work, the DNA binding characteristics of the Cox protein of WPhi, a P2-related phage, are compared with those of P2 Cox. P2 Cox has been shown to recognize a 9 bp sequence, repeated at least 6 times in different targets. In contrast to P2 Cox, WPhi Cox binds with a strong affinity to the early control region that contains an imperfect direct repeat of 12 nucleotides. The removal of one of the repeats has drastic effects on the capacity of WPhi to bind to the Pe-Pc region. Again in contrast to P2 Cox, WPhi Cox has a lower affinity to attP compared to the Pe-Pc region, and a repeat of 9 bp can be found that has 5 bp in common with the repeat in the Pe-Pc region. WPhi Cox, however, is essential for excisive recombination in vitro. WPhi Cox, like P2 Cox, binds cooperatively with integrase to attP. Both Cox proteins induce a strong bend in their DNA targets upon binding.

Early inequalities in excellent health and performance among young adult women and men in Sweden.

BACKGROUND: Although health inequality between young adult women and men has been strikingly evident in symptoms of ill health, we found no studies examining these inequalities with a focus on positive health and performance. OBJECTIVE: The aim of the present study was to examine possible inequalities between young adult women and men in a combined assessment of positive health and health-related performance. METHODS: Women and men aged 18 to 25 years studying medicine or computer science at 6 colleges/universities in 5 cities in Sweden were recruited for this study. All respondents answered a Web-based questionnaire regarding health, health-related performance, information and communication technology exposure, mood, and individual factors. A combined assessment of excellent health and health-related performance (EHHP) was defined and tested. Prevalence ratios (PRs) with 95% CIs of EHHP were calculated separately for female and male respondents. To assess potential determinants of EHHP, differences in the relationships between EHHP and the explanatory factors were compared for both sexes. RESULTS: In a study group of young adult students consisting of 1046 women and 1312 men, women were less likely than men to have EHHP (PR 0.90 [95% CI, 0.83-0.98]). This inequality was even stronger within each course of study (medicine or computer science). Health-related factors showed similar patterns of relationship to EHHP for women and men; however, the strength of these relationships differed between the sexes. Logical relationships were observed between EHHP and almost all of the symptoms as well as between EHHP, the mood index, and health-related behavior. CONCLUSIONS: The well-known inequality in symptoms of ill health between young adult women and men was prevalent even in a combined assessment of positive health and health-related performance. That this inequality was prevalent in a relatively homogeneous sample of young adults indicates the importance of gender-based psychological and psychosocial factors beyond the more well-known structural gender-differentiating factors of vertical and horizontal segregation and disproportional responsibilities for domestic work. It may therefore be essential to emphasize these gender-based psychological and psychosocial factors when designing future studies and health promotion programs.

Assessment of long-term work attendance within human service organisations.

Terms and theories of work attendance vary according to their use and focus. This paper analyzes long-term work attendance in relation to social, psychosocial, and health-related factors. Register-based and questionnaire-based data covering 3,804 human service organisation workers over a three-year period were analyzed at individual and work-unit level. The results showed positive relationships between work attendance and male gender, high income, work commitment, job satisfaction, and having positive feelings towards work. High work attendance combined with work commitment, stress, or pain did not show any negative long-term effects upon short-term or long-term sick leave. Instead, work attendance seemed to be more associated with stable patterns of behaviour. Register-based measures of work attendance (at most 4-7 days of sick leave per worker per year) may be a useful tool in managing psychosocial work environment and related behaviour, but their inability to encompass information regarding individual health and disease must be borne in mind.

Dimerization of bacteriophage P2 integrase is not required for binding to its DNA target but for its biological activity.

Coliphage P2 integrates into the host chromosome upon lysogenization via site-specific recombination mediated by the phage integrase (Int). P2 integrase belongs to the tyrosine family of recombinases. In this work, it is shown that P2 integrase forms dimers but not oligomers in the absence of its DNA target. Furthermore, the C-terminal end of the protein and amino acid (aa) E197 have been found to be involved in dimerization. Amino acid E197 is located in a conserved region of the tyrosine recombinases that has not previously been implicated in dimerization. The dimerization deficient mutants were unaffected in binding to its phage attachment site (attP) substrate, but had a reduced ability to complement an int-defective prophage.