Abnormal routine blood tests as predictors of mortality in acutely admitted patients.

BACKGROUND: This study aimed to improve early risk stratification in the emergency department by creating a simple blood test score based on routine biomarkers and assess its predictive ability for 30-day mortality of acutely admitted patients. METHODS: This was a secondary analysis of data from the TRIAGE II study. It included unselected acutely admitted medical and surgical patients, who had albumin, C-reactive protein, creatinine, haemoglobin, leukocytes, potassium, sodium and thrombocytes levels analysed upon admission. Patients were classified according to the number of biomarker results outside the reference range into four risk groups termed "very low", "low", "intermediate", and "high" with 0-1, 2-3, 4-5 and 6-8 abnormal biomarker results, respectively. Logistic regression was used to calculate odds ratios for 30-day mortality and receiver operating characteristic was used to test the discriminative value. The primary analysis was done in patients triaged with ADAPT (Adaptive Process Triage). Subsequently, we analysed two other cohorts of acutely admitted patients. RESULTS: The TRIAGE II cohort included 17,058 eligible patients, 30-day mortality was 5.2%. The primary analysis included 7782 patients. Logistic regression adjusted for age and sex showed an OR of 24.1 (95% CI 14.9-41.0) between the very low- and the high-risk group. The area under the curve (AUC) was 0.79 (95% CI 0.76-0.81) for the blood test score in predicting 30-day mortality. The subsequent analyses confirmed the results. CONCLUSIONS: A blood test score based on number of routine biomarkers with an abnormal result was a predictor of 30-day mortality in acutely admitted patients.

Prevalence of Infective Endocarditis in Enterococcus faecalis Bacteremia.

BACKGROUND: Enterococcus faecalis is the third most frequent cause of infective endocarditis (IE). Despite this, no systematic prospective echocardiography studies have examined the prevalence of IE in patients with E. faecalis bacteremia. OBJECTIVES: This study sought to determine the prevalence of IE in patients with E. faecalis bacteremia. The secondary objective was to identify predictors of IE. METHODS: From January 1, 2014, to December 31, 2016, a prospective multicenter study was conducted with echocardiography in consecutive patients with E. faecalis bacteremia. Predictors of IE were assessed using multivariate logistic regression with backward elimination. RESULTS: A total of 344 patients with E. faecalis bacteremia were included, all examined using echocardiography, including transesophageal echocardiography in 74% of the cases. The patients had a mean age of 74.2 years, and 73.5% were men. Definite endocarditis was diagnosed in 90 patients, resulting in a prevalence of 26.1 ± 4.6% (95% confidence interval [CI]). Risk factors for IE were prosthetic heart valve (odds ratio [OR]: 3.93; 95% CI: 1.76 to 8.77; p = 0.001), community acquisition (OR: 3.35; 95% CI: 1.74 to 6.46; p < 0.001), ≥3 positive blood culture bottles (OR: 3.69; 95% CI: 1.88 to 7.23; p < 0.001), unknown portal of entry (OR: 2.36; 95% CI: 1.26 to 4.40; p = 0.007), monomicrobial bacteremia (OR: 2.73; 95% CI: 1.23 to 6.05; p = 0.013), and immunosuppression (OR: 2.82; 95% CI: 1.20 to 6.58; p = 0.017). CONCLUSIONS: This study revealed a high prevalence of 26% definite IE in patients with E. faecalis bacteremia, suggesting that echocardiography should be considered in all patients with E. faecalis bacteremia.

Early Discharge from the Emergency Department Based on Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels: A TRIAGE III Substudy.

OBJECTIVE: Using biomarkers for early and accurate identification of patients at low risk of serious illness may improve the flow in the emergency department (ED) by classifying these patients as nonurgent or even suitable for discharge. A potential biomarker for this purpose is soluble urokinase plasminogen activator receptor (suPAR). We hypothesized that availability of suPAR might lead to a higher proportion of early discharges. DESIGN: A substudy of the interventional TRIAGE III trial, comparing patients with a valid suPAR measurement at admission to those without. The primary endpoint was the proportion of patients discharged alive from the ED within 24 hours. Secondary outcomes were length of hospital stay, readmissions, and mortality within 30 days. SETTING: EDs at two university hospitals in the Capital Region of Denmark. PARTICIPANTS: 16,801 acutely admitted patients were included. MEASUREMENTS AND MAIN RESULTS: The suPAR level was available in 7,905 patients (suPAR group), but not in 8,896 (control group). The proportion of patients who were discharged within 24 hours of admittance was significantly higher in the suPAR group compared to the control group (50.2% (3,966 patients) vs. 48.6% (4,317 patients), P = 0.04). Furthermore, the mean length of hospital stay in the suPAR group was significantly shorter compared to that in the control group (4.3 days (SD 7.4) vs. 4.6 days (SD 9.4), P = 0.04). In contrast, the readmission rate within 30 days was significantly higher in the suPAR group (10.6% (839 patients) vs. 8.8% (785 patients), P < 0.001). Among patients discharged within 24 hours, there was no significant difference in the readmission rate or mortality within 30 days. Readmission occurred in 8.5% (336 patients) vs. 7.7% (331 patients) (P = 0.18) and mortality in 1.3% (52 patients) vs. 1.8% (77 patients) (P = 0.08) for the suPAR group and control group, respectively. CONCLUSION: These post hoc analyses demonstrate that the availability of the prognostic biomarker suPAR was associated with a higher proportion of discharge within 24 hours and reduced length of stay, but more readmissions. In patients discharged within 24 hours, there was no difference in readmission or mortality. TRIAL REGISTRATION OF THE MAIN TRIAL: This trial is registered with NCT02643459.

Unreported exclusion and sampling bias in interpretation of randomized controlled trials in patients with STEMI.

AIMS: To assess the impact of sampling bias due to reported as well as unreported exclusion of the target population in a multi-center randomized controlled trial (RCT) of ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We compared clinical characteristics and mortality between participants in the DANAMI-3 trial to contemporary non-participants with STEMI using unselected registries. A total of 179 DANAMI-3 participants (8%) and 617 contemporary non-participants (22%) had died (Log-Rank: P < 0.001) after a median follow-up of 1333 days (range: 1-2021 days). In an unadjusted Cox regression model all groups of non-participants had a higher hazard ratio to predict mortality compared to participants: eligible excluded (n = 144) (hazard ratio: 3.41 (95% CI: (2.69-4.32)), ineligible excluded (n = 472) (hazard ratio: 3.42 (95% CI: (2.44-4.80), eligible non-screened (n = 154) (hazard ratio: 3.37 (95% CI: (2.36-4.82)), ineligible non-screened (n = 154) (hazard ratio: 6.48 (95% CI: (4.77-8.80). CONCLUSION: Sampling bias had occurred due to both reported and unreported exclusion of eligible patients and the difference in mortality between participants and non-participants could not be explained only by the trial exclusion criteria. Thus, screening logs may not be suited to address the risks of sampling bias.

The Copenhagen Triage Algorithm is non-inferior to a traditional triage algorithm: A cluster-randomized study.

INTRODUCTION: Triage systems with limited room for clinical judgment are used by emergency departments (EDs) worldwide. The Copenhagen Triage Algorithm (CTA) is a simplified triage system with a clinical assessment. METHODS: The trial was a non-inferiority, two-center cluster-randomized crossover study where CTA was compared to a local adaptation of Adaptive Process Triage (ADAPT). CTA involves initial categorization based on vital signs with a final modification based on clinical assessment by an ED nurse. We used 30-day mortality with a non-inferiority margin at 0.5%. Predictive performance was compared using Receiver Operator Characteristics. RESULTS: We included 45,347 patient visits, 23,158 (51%) and 22,189 (49%) were triaged with CTA and ADAPT respectively with a 30-day mortality of 3.42% and 3.43% (P = 0.996) a difference of 0.01% (95% CI: -0.34 to 0.33), which met the non-inferiority criteria. Mortality at 48 hours was 0.62% vs. 0.71%, (P = 0.26) and 6.38% vs. 6.61%, (P = 0.32) at 90 days for CTA and ADAPT. CTA triaged at significantly lower urgency level (P<0.001) and was superior in predicting 30-day mortality, Area under the curve: 0.67 (95% CI 0.65-0.69) compared to 0.64 for ADAPT (95% CI 0.62-0.66) (P = 0.03). There were no significant differences in rate of admission to the intensive care unit, length of stay, waiting time nor rate of readmission within 30 or 90 days. CONCLUSION: A novel triage system based on vital signs and a clinical assessment by an ED nurse was non-inferior to a traditional triage algorithm by short term mortality, and superior in predicting 30-day mortality. TRIAL REGISTRATION: Clinicaltrials.gov NCT02698319.

Comparison between patients included in randomized controlled trials of ischemic heart disease and real-world data. A nationwide study.

BACKGROUND: The objective was to compare patients with ischemic heart disease (IHD) undergoing percutaneous coronary intervention (PCI) who were included in randomized controlled trials (RCTs) (trial participants) with patients who were not included (nonparticipants) on a trial-by-trial basis and according to indication for PCI. METHODS: In this cohort study, we compared patients with IHD who were randomized in RCTs in relation to undergoing PCI in Denmark between 2011 and 2015 were considered as RCT-participants in this study. The RCT-participants were compared with contemporary nonparticipants with IHD undergoing PCI in the same period, and they were identified using unselected national registry data. The primary end point was all-cause mortality. RESULTS: A total of 10,317 (30%) patients were included in 10 relevant RCTs (trial participants), and a total of 23,644 (70%) contemporary patients did not participate (nonparticipants). In all the included RCTs, nonparticipants had higher hazard ratios for mortality compared to trial participants (P < .001). Among all patients treated with PCI, the pooled estimates showed a significantly higher mortality rate for nonparticipants compared to trial participants (hazard ratio: 2.03, 95% CI: 1.88-2.19) (P < .001). When patients were stratified according to indication for PCI, the pooled estimates showed a significantly lower mortality rate for trial participants compared to nonparticipants in all strata (P for all < .001). CONCLUSIONS: Trial participants in recently performed RCTs including patients undergoing PCI were not representative of the general population of patients with IHD treated with PCI according to clinical characteristics and mortality. The difference in mortality was found irrespective of the indication for PCI. Thus, results from RCTs including patients undergoing PCI should be extrapolated with caution to the general patient population.

Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality: a cluster-randomized clinical trial (TRIAGE III).

BACKGROUND: Risk stratification of patients in the emergency department can be strengthened using prognostic biomarkers, but the impact on patient prognosis is unknown. The aim of the TRIAGE III trial was to investigate whether the introduction of the prognostic and nonspecific biomarker: soluble urokinase plasminogen activator receptor (suPAR) for risk stratification in the emergency department reduces mortality in acutely admitted patients. METHODS: The TRIAGE III trial was a cluster-randomized interventional trial conducted at emergency departments in the Capitol Region of Denmark. Eligible hospitals were required to have an emergency department with an intake of acute medical and surgical patients and no previous access to suPAR measurement. Three emergency departments were randomized; one withdrew shortly after the trial began. The inclusion period was from January through June of 2016 consisting of twelve cluster-periods of 3-weeks alternating between intervention and control and a subsequent follow-up of ten months. Patients were allocated to the intervention if they arrived in interventional periods, where suPAR measurement was routinely analysed at arrival. In the control periods suPAR measurement was not performed. The main outcome was all-cause mortality 10 months after arrival of the last patient in the inclusion period. Secondary outcomes included 30-day mortality. RESULTS: The trial enrolled a consecutive cohort of 16,801 acutely admitted patients; all were included in the analyses. The intervention group consisted of 6 cluster periods with 8900 patients and the control group consisted of 6 cluster periods with 7901 patients. After a median follow-up of 362 days, death occurred in 1241 patients (13.9%) in the intervention group and in 1126 patients (14.3%) in the control group. The weighted Cox model found a hazard ratio of 0.97 (95% confidence interval, 0.89 to 1.07; p = 0.57). Analysis of all subgroups and of 30-day all-cause mortality showed similar results. CONCLUSIONS: The TRIAGE III trial found no effect of introducing the nonspecific and prognostic biomarker suPAR in emergency departments on short- or long-term all-cause mortality among acutely admitted patients. Further research is required to evaluate how prognostic biomarkers can be implemented in routine clinical practice. TRIAL REGISTRATION: clinicaltrials.gov, NCT02643459 . Registered 31 December 2015.

Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia.

INTRODUCTION: In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). MATERIAL AND METHODS: This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. RESULTS: Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. DISCUSSION: Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.

[Acute dyspnoea triggered by spontaneous pneumothorax in a pregnant woman with pulmonary agenesis].

A 29-year-old pregnant woman was admitted to hospital with chest pain and dyspnoea. A thoracal computed tomography (CT) was performed to rule out pulmonary embolism, and it revealed a left-sided pneumothorax, which was treated with tube thoracostomy. Three days after discharge she was readmitted with spontaneous pressure pneumothorax. Her clinical condition did not improve, and a pulmonary scintigraphy and a new thoracal CT showed unilateral right pulmonary agenesis. Pulmonary agenesis is very rare in adulthood, and in this case it was complicated with spontaneous pneumothorax.

Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice.

AIM: No consensus exists on classification of hypoglycemia awareness. We compared three methods for assessment of hypoglycemia awareness in a clinical setting. METHODS: A questionnaire including the three methods was filled in by 372 outpatients with Type 1 diabetes [43% women, age 51 ± 14 years (mean ± S.D.)], duration of diabetes 24 ± 13 years, and hemoglobin A1c 8.2 ± 1.0%). Method A (Diabetes Care, 17, 697-703) and B (Diabetes Care, 18, 517-522) classify into two degrees of awareness, while Method C (Diabetes/Metabolism Research and Reviews, 19, 232-240) includes three classes. RESULTS: Normal awareness was reported in 75%, 51%, and 41% (A, B, C); 25% and 28% had impaired awareness (A, B); and 13% were unaware (C); 46% belonged to the intermediate class of impaired awareness (C), while 21% were not classifiable (B). Higher rates of severe hypoglycemic events were reported by patients with impaired awareness (A, B) and unawareness (C) compared to aware patients. Patients with impaired awareness (C) had more severe hypoglycemia than aware patients and less severe hypoglycemia than unaware patients. A lower rate of severe hypoglycemia was reported by aware patients classified by Method C than A. Fractions of patients with normal awareness without an event of severe hypoglycemia were 0.81, 0.86, and 0.91 (A, B, C). CONCLUSION: All three methods for assessment of hypoglycemia awareness are feasible in clinical practice since the degree of awareness is associated with risk of severe hypoglycemia. The trisected method (C) identifies an intermediate group with impaired awareness and with a risk of severe hypoglycemia that is significantly different from those of aware and unaware patients.

Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity.

INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity. MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded. RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness. CONCLUSION: High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity.

In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group (P = .004) and from 76 to 109 pg/L in the low-RAS group (P = .01), with no difference between RAS groups (P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.

Erythropoietin during hypoglycaemia in type 1 diabetes: relation to basal renin-angiotensin system activity and cognitive function.

AIMS: Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function. METHODS: We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1 diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion. RESULTS: Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia. CONCLUSIONS: Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia.

Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity.

AIMS: Hypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the 'dead-in-bed syndrome' in patients with type 1 diabetes. Evidence suggests that the renin-angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS activity affects cardiac repolarization during hypoglycaemia, thereby potentially carrying prognostic information on risk of the 'dead-in-bed syndrome'. METHODS AND RESULTS: Nine subjects with high RAS activity and nine subjects with low RAS activity were subjected to single-blinded placebo-controlled hypoglycaemia (nadir plasma glucose 2.4 mmol/L). QTc/QTcF and QT dynamics were registered by Holter monitoring. QTc prolonged during [8 (+/-2.3) ms, P < 0.01] and after [11 (+/-3) ms, P < 0.001] hypoglycaemia. Dynamic QT parameters reacted ambiguously. Low RAS activity was associated with a slightly more pronounced QT prolongation [6 (+/-3) ms, P = 0.04]. Adrenaline tended to increase more in the low-RAS group (P = 0.08) and was correlated to QTc (r = 0.67, P < 0.01) and QTcF (r = 0.58, P < 0.05) during hypoglycaemia. CONCLUSION: Low basal RAS activity may be associated with a slightly more pronounced QT prolongation during hypoglycaemia, when compared with high RAS activity. The impact, however, is modest and the clinical consequence is unclear.

Cardiac repolarization during hypoglycaemia and hypoxaemia in healthy males: impact of renin-angiotensin system activity.

AIMS: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. METHODS AND RESULTS: Ten subjects with high RAS activity and 10 subjects with low RAS activity were studied on three different occasions: (i) hypoglycaemia (nadir P-glucose 2.7 +/- 0.5 mmol/L), (ii) hypoxaemia (nadir pO(2) 5.8 +/- 0.5 kPa), and (iii) normoglycaemic normoxia (control day). QT parameters were registered by Holter monitoring. Hypoglycaemia and hypoxaemia induced QTc prolongation (P < 0.001, both stimuli). The QT/RR slope and the VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0.04; hypoxia: P = 0.03. RAS activity had no impact on QTc [P = 0.48 (hypoglycaemia) and P = 0.40 (hypoxaemia)] or any of the other outcome variables. CONCLUSION: Basal RAS activity has significant impact on QT dynamics, but not the corrected QT interval, during recovery from hypoglycaemia and hypoxaemia. The impact, however, is modest and more subtle than initially expected. The clinical relevance is unclear.

[Pure red cell aplasia developed during treatment with erythropoietin. Complete remission during immunosuppressive therapy]. / Pure red cell-aplasi udviklet under erytropoietinbehandling. Komplet remission under immunosupprimerende terapi.

In a patient with chronic renal failure due to diabetes mellitus pure red-cell aplasia developed during treatment with erythropoietin (epoetin alfa). The treatment with erythropoietin was stopped and immunosuppressive therapy resulted in normalisation of the bone marrow function and increase of the Hb level to normal values. Pure red cell aplasia which develops during treatment with erythropoietin has recently been reported in a few other patients with anaemia due to chronic renal failure. Hitherto our patient is the first case reported in Denmark.