Association between oxidized nucleobases and mitochondrial DNA damage with long-term mortality in patients with sepsis.

BACKGROUND: Sepsis not only leads to short-term mortality during hospitalization, but is also associated with increased mortality during long-term follow-up after hospital discharge. Metabolic stress during sepsis may cause oxidative damage to both nuclear and mitochondrial DNA (mtDNA) and RNA, which could affect long-term health and life span. Therefore, the aim of this study was to assess the association of sepsis with oxidized nucleobases and (mt)DNA damage and long-term all-cause mortality in septic patients. METHODS: 91 patients with sepsis who visited the emergency department (ED) of the University Medical Center Groningen between August 2012 and June 2013 were included. Urine and plasma were collected during the ED visit. Septic patients were matched with 91 healthy controls. Death rate was obtained until June 2020.The degree of oxidation of DNA, RNA and free nucleobases were assessed in urine by mass-spectrometry. Lipid peroxidation was assessed in plasma using a TBAR assay. Additionally, plasma levels of mtDNA and damage to mtDNA were determined by qPCR. RESULTS: Sepsis patients denoted higher levels of oxidated DNA, RNA, free nucleobases and lipid peroxidation than controls (all p < 0.01). Further, sepsis patients displayed an increase in plasma mtDNA with an increase in mtDNA damage compared to matched controls (p < 0.01). Kaplan meier survival analyses revealed that high degrees of RNA- and nucleobase oxidation were associated with higher long-term all-cause mortality after sepsis (p < 0.01 and p = 0.01 respectively). Of these two, high RNA oxidation was associated with long-term all-cause mortality, independent of adjustment for age, medical history and sepsis severity (HR 1.29 [(1.17-1.41, 95% CI] p < 0.01). CONCLUSIONS: Sepsis is accompanied with oxidation of nuclear and mitochondrial DNA and RNA, where RNA oxidation is an independent predictor of long-term all-cause mortality. In addition, sepsis causes mtDNA damage and an increase in cell free mtDNA in plasma.

Pain score, desire for pain treatment and effect on pain satisfaction in the emergency department: a prospective, observational study.

BACKGROUND: Pain management in the Emergency Department has often been described as inadequate, despite proven benefits of pain treatment protocols. The aim of this study was to investigate the effectiveness of our current pain protocol on pain score and patient satisfaction whilst taking the patients' wishes for analgesia into account. METHODS: We conducted a 10-day prospective observational study in the Emergency Department. Demographics, pain characteristics, Numeric Rating Scale pain scores and the desire for analgesics were noted upon arrival at the Emergency Department. A second Numeric Rating Scale pain score and the level of patient satisfaction were noted 75-90 min after receiving analgesics. Student T-tests, Mann-Whitney U tests and Kruskall-Wallis tests were used to compare outcomes between patients desiring vs. not desiring analgesics or patients receiving vs. not receiving analgesics. Univariate and multivariate logistic regression models were used to investigate associations between potential predictors and outcomes. RESULTS: In this study 334 patients in pain were enrolled, of which 43.7% desired analgesics. Initial pain score was the only significant predictive factor for desiring analgesia, and differed between patients desiring (7.01) and not desiring analgesics (5.14). Patients receiving analgesics (52.1%) had a greater decrease in pain score than patients who did not receive analgesics (2.41 vs. 0.94). Within the group that did not receive analgesics there was no difference in satisfaction score between patients desiring and not desiring analgesics (7.48 vs. 7.54). Patients receiving analgesics expressed a higher satisfaction score than patients not receiving analgesics (8.10 vs. 7.53). CONCLUSIONS: This study pointed out that more than half of the patients in pain entering the Emergency Department did not desire analgesics. In patients receiving analgesics, our pain protocol has shown to adequately treat pain, leading to a higher satisfaction for emergency health-care at discharge. This study emphasizes the importance of questioning pain score and desire for analgesics to prevent incorrect conclusions of inadequate pain management, as described in previous studies.

Orthostatic blood pressure measurements are often overlooked during the initial evaluation of syncope in the emergency department.

The renewed 2018 syncope guidelines published by the European Society of Cardiology (ESC) reiterate that the initial evaluation of syncope should include history taking, physical examination, an electrocardiogram, and orthostatic blood pressure measurements (OBPM). However, the importance of evaluating for orthostatic hypotension (OH) often remains underappreciated in clinical practice. In this study, we examine the initial evaluation of syncope on an ED. We retrospectively reviewed 2 years of consecutive medical records of patients presenting with a syncope to the ED of a university hospital. We collected patient demographics and data on initial syncope evaluation for further analysis. In a cohort of 289 patients, OBPM and ECG were performed in 16 and 89% of the cases, respectively. An OBPM was performed in only 52% of the patients who received a working diagnosis of OH. In the other 48%, the OH diagnosis was likely made on the basis of history taking and exclusion of other syncope causes. OBPM are infrequently used during the initial evaluation of syncope irrespective of its consistent inclusion in ESC syncope guidelines. The discordance between clinical practice and the ESC syncope guidelines calls for increased awareness of the role of OBPM in the initial evaluation of syncope by either stricter guideline adherence or reappraisal of clinical practice.

Repeated vital sign measurements in the emergency department predict patient deterioration within 72 hours: a prospective observational study.

BACKGROUND: More than one in five patients presenting to the emergency department (ED) with (suspected) infection or sepsis deteriorate within 72 h from admission. Surprisingly little is known about vital signs in relation to deterioration, especially in the ED. The aim of our study was to determine whether repeated vital sign measurements in the ED can differentiate between patients who will deteriorate within 72 h and patients who will not deteriorate. METHODS: We performed a prospective observational study in patients presenting with (suspected) infection or sepsis to the ED of our tertiary care teaching hospital. Vital signs (heart rate, mean arterial pressure (MAP), respiratory rate and body temperature) were measured in 30-min intervals during the first 3 h in the ED. Primary outcome was patient deterioration within 72 h from admission, defined as the development of acute kidney injury, liver failure, respiratory failure, intensive care unit admission or in-hospital mortality. We performed a logistic regression analysis using a base model including age, gender and comorbidities. Thereafter, we performed separate logistic regression analyses for each vital sign using the value at admission, the change over time and its variability. For each analysis, the odds ratios (OR) and area under the receiver operator curve (AUC) were calculated. RESULTS: In total 106 (29.5%) of the 359 patients deteriorated within 72 h from admission. Within this timeframe, 18.3% of the patients with infection and 32.9% of the patients with sepsis at ED presentation deteriorated. Associated with deterioration were: age (OR: 1.02), history of diabetes (OR: 1.90), heart rate (OR: 1.01), MAP (OR: 0.96) and respiratory rate (OR: 1.05) at admission, changes over time of MAP (OR: 1.04) and respiratory rate (OR: 1.44) as well as the variability of the MAP (OR: 1.06). Repeated measurements of heart rate and body temperature were not associated with deterioration. CONCLUSIONS: Repeated vital sign measurements in the ED are better at identifying patients at risk for deterioration within 72 h from admission than single vital sign measurements at ED admission.

Titration of oxygen therapy in critically ill emergency department patients: a feasibility study.

BACKGROUND: Liberal use of oxygen in an emergency situation is common. Today, most health care professionals do not adjust the amount of oxygen given when a saturation of 100% or a PaO2 which exceeds the normal range is reached- which may result in hyperoxia. There is increasing evidence for the toxic effects of hyperoxia. Therefore, it seems justified to aim for normoxia when giving oxygen. This study evaluates whether it is feasible to aim for normoxia when giving oxygen therapy to patients at the emergency department (ED). METHODS: A prospective cohort study was performed at the ED of the University Medical Center Groningen (UMCG). A protocol was developed, aiming for normoxia. During a 14 week period all patients > 18 years arriving at the ED between 8 a.m. and 23 p.m. requiring oxygen therapy registered for cardiology, internal medicine, emergency medicine and pulmonology were included. Statistical analysis was performed using student independent t-test, Mann-Whitney U-test, Fisher's exact test or a Pearson's chi-squared test. RESULTS: During the study period the study protocol was followed and normoxia was obtained after 1 h at the ED in 86,4% of the patients. Patients with COPD were more at risk for not being titrated to normal oxygen levels. CONCLUSIONS: We showed that it is feasible to titrate oxygen therapy to normoxia at the ED. The study results will be used for further research assessing the potential beneficial effects of normoxia compared to hyper- or hypoxia in ED patients and for the development of guidelines.

Sepsis patients in the emergency department: stratification using the Clinical Impression Score, Predisposition, Infection, Response and Organ dysfunction score or quick Sequential Organ Failure Assessment score?

OBJECTIVE: The aim of this study was to compare the stratification of sepsis patients in the emergency department (ED) for ICU admission and mortality using the Predisposition, Infection, Response and Organ dysfunction (PIRO) and quick Sequential Organ Failure Assessment (qSOFA) scores with clinical judgement assessed by the ED staff. PATIENTS AND METHODS: This was a prospective observational study in the ED of a tertiary care teaching hospital. Adult nontrauma patients with suspected infection and at least two Systemic Inflammatory Response Syndrome criteria were included. The primary outcome was direct ED to ICU admission. The secondary outcomes were in-hospital, 28-day and 6-month mortality, indirect ICU admission and length of stay. Clinical judgement was recorded using the Clinical Impression Scores (CIS), appraised by a nurse and the attending physician. The PIRO and qSOFA scores were calculated from medical records. RESULTS: We included 193 patients: 103 presented with sepsis, 81 with severe sepsis and nine with septic shock. Fifteen patients required direct ICU admission. The CIS scores of nurse [area under the curve (AUC)=0.896] and the attending physician (AUC=0.861), in conjunction with PIRO (AUC=0.876) and qSOFA scores (AUC=0.849), predicted direct ICU admission. The CIS scores did not predict any of the mortality endpoints. The PIRO score predicted in-hospital (AUC=0.764), 28-day (AUC=0.784) and 6-month mortality (AUC=0.695). The qSOFA score also predicted in-hospital (AUC=0.823), 28-day (AUC=0.848) and 6-month mortality (AUC=0.620). CONCLUSION: Clinical judgement is a fast and reliable method to stratify between ICU and general ward admission in ED patients with sepsis. The PIRO and qSOFA scores do not add value to this stratification, but perform better on the prediction of mortality. In sepsis patients, therefore, the principle of 'treat first what kills first' can be supplemented with 'judge first and calculate later'.

Protocol of the sepsivit study: a prospective observational study to determine whether continuous heart rate variability measurement during the first 48 hours of hospitalisation provides an early warning for deterioration in patients presenting with infection or sepsis to the emergency department of a Dutch academic teaching hospital.

INTRODUCTION: One in five patients with sepsis deteriorates within 48 hours after hospital admission. Regrettably, a clear tool for the early detection of deterioration is still lacking. The SepsiVit study aims to determine whether continuous heart rate variability (HRV) measurement can provide an early warning for deterioration in patients presenting with suspected infection or sepsis to the emergency department (ED). METHODS AND ANALYSIS: The protocol of a prospective observational study in the ED. We will include 171 adult medical patients presenting with suspected infection or sepsis and at least two systemic inflammatory response syndrome criteria. Patients with known pregnancy, cardiac transplantation or not admitted to our hospital are excluded.High sample frequency ECG signals (500 Hz), respiratory rate, blood pressure and peripheral oxygen saturation will be recorded continuously during the first 48 hours of hospitalisation using a bedside patient monitor (Philips IntelliVue MP70). Primary endpoint is patient deterioration, defined as the development of organ dysfunction, unplanned intensive care unit admission or in-hospital mortality. The ECG data will be used for offline HRV analysis. We will compare the HRV between two groups (deterioration/no deterioration) and analyse whether HRV provides an early warning for deterioration. Furthermore, we will create a multivariate predictive model for deterioration based on heart rate, respiratory rate and HRV. As planned secondary analyses, we (1) perform a subgroup analysis for patients with pneumosepsis and urosepsis and (2) determine whether HRV using lower sample frequencies (1 Hz or less) suffices to predict deterioration. ETHICS AND DISSEMINATION: The Institutional Review Board of the University Medical Center Groningen granted a waiver for the study (METc 2015/164). Results will be disseminated through international peer-reviewed publications and conference presentations. A lay summary of the results will be provided to the study participants. TRIAL REGISTRATION NUMBER: NTR6168; Pre-results.

Ultrasound and NICOM in the assessment of fluid responsiveness in patients with mild sepsis in the emergency department: a pilot study.

OBJECTIVE: We investigated whether combining the caval index, assessment of the global contractility of the heart and measurement of stroke volume with Noninvasive Cardiac Output Monitoring (NICOM) can aid in fluid management in the emergency department (ED) in patients with sepsis. SETTING: A prospective observational single-centre pilot study in a tertiary care centre. PRIMARY AND SECONDARY OUTCOMES: Ultrasound was used to assess the caval index, heart contractility and presence of B-lines in the lungs. Cardiac output and stroke volume were monitored with NICOM. Primary outcome was increase in stroke volume after a fluid bolus of 500 mL, while secondary outcome included signs of fluid overload. RESULTS: We included 37 patients with sepsis who received fluid resuscitation of at least 500 mL saline. The population was divided into patients with a high (>36.5%, n=24) and a low caval index (<36.5%, n=13). We observed a significant increase (p=0.022) in stroke volume after 1000 mL fluid in the high caval index group in contrast to the low caval index group but not after 500 mL of fluid. We did not find a significant association between global contractility of the left ventricle and the response on fluid therapy (p=0.086). No patient showed signs of fluid overload. CONCLUSIONS: Our small pilot study suggests that at least 1000 mL saline is needed to induce a significant response in stroke volume in patients with sepsis and a high caval index. This amount seems to be safe, not leading to the development of fluid overload. Therefore, combining ultrasound and NICOM is feasible and may be valuable tools in the treatment of patients with sepsis in the ED. A larger trial is needed to confirm these results.

The Power of Flash Mob Research: Conducting a Nationwide Observational Clinical Study on Capillary Refill Time in a Single Day.

BACKGROUND: Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients; various methods are available to assess CRT. Conventional clinical research often demands large numbers of patients, making it costly, labor-intensive, and time-consuming. We studied the interobserver agreement on CRT in a nationwide study by using a novel method of research called flash mob research (FMR). METHODS: Physicians in the Netherlands were recruited by using word-of-mouth referrals, conventional media, and social media to participate in a nationwide, single-day, "nine-to-five," multicenter, cross-sectional, observational study to evaluate CRT. Patients aged ≥ 18 years presenting to the ED or who were hospitalized were eligible for inclusion. CRT was measured independently (by two investigators) at the patient's sternum and distal phalanx after application of pressure for 5 s (5s) and 15 s (15s). RESULTS: On October 29, 2014, a total of 458 investigators in 38 Dutch hospitals enrolled 1,734 patients. The mean CRT measured at the distal phalanx were 2.3 s (5s, SD 1.1) and 2.4 s (15s, SD 1.3). The mean CRT measured at the sternum was 2.6 s (5s, SD 1.1) and 2.7 s (15s, SD 1.1). Interobserver agreement was higher for the distal phalanx (κ value, 0.40) than for the sternum (κ value, 0.30). CONCLUSIONS: Interobserver agreement on CRT is, at best, moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared with sternal CRT measurements. FMR proved a valuable instrument to investigate a relatively simple clinical question in an inexpensive, quick, and reliable manner.

The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients: Results from a Prospective Pilot Study.

BACKGROUND: Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with severe sepsis. OBJECTIVE: 1) To explore the reliability of Skin Autofluorescence (AF) as an index of tissue AGEs in ICU patients, 2) to compare its levels to healthy controls, 3) to describe the time course of AGEs and influencing factors during ICU admission, and 4) to explore their association with disease severity, outcome, and markers of oxidative stress and inflammation. METHODS: Skin AF, serum N"-(carboxyethyl)lysine (CEL), N"-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU patients with multiple organ failure and compared to age-matched healthy controls. Correlations with (changes in) clinical parameters of disease severity, LDL dienes, and CRP were studied and survival analysis for in-hospital mortality was performed. RESULTS: Forty-five ICU patients (age: 59±15 years; 60% male), and 37 healthy controls (59±14; 68%) were included. Skin AF measurements in ICU patients were reproducible (CV right-left arm: 13%, day-to-day: 10%), with confounding effects of skin reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients vs healthy controls (2.7±0.7 vs 1.8±0.3 au; p<0.001). Serum CEL (23±10 vs, 16±3 nmol/gr protein; p<0.001), LDL dienes (19 (15-23) vs. 9 (8-11) µmol/mmol cholesterol; <0.001), and sRAGE (1547 (998-2496) vs. 1042 (824-1388) pg/ml; p = 0.003) were significantly higher in ICU patients compared to healthy controls, while CML was not different (27 (20-39) vs 29 (25-33) nmol/gr protein). While CRP and LDL dienes decreased significantly, Skin AF and serum AGEs and sRAGE did not change significantly during the first 7 days of ICU admission. CML and CEL were strongly correlated with SOFA scores and CML above the median at baseline was associated with increased risk for mortality (Hazard ratio 3.3 (1.3-8.3); p = 0.01). All other markers did not correlate with disease severity and did not predict mortality. CONCLUSIONS: This study demonstrates that markers for the AGE-RAGE axis are elevated in critically ill patients compared to healthy controls but remain stable for at least 7 days despite clearly fading inflammation and oxidative stress. Circulating AGEs may be associated with disease severity and outcome. Further research should be conducted to elucidate the role of the AGE-RAGE axis in the exaggerated inflammatory response leading to multiple organ failure and death, and whether or not this may be a target for treatment.

Trends in vital signs and routine biomarkers in patients with sepsis during resuscitation in the emergency department: a prospective observational pilot study.

OBJECTIVES: Sepsis lacks a reliable and readily available measure of disease activity. Thereby, it remains unclear how to monitor response to treatment. Research on numerous (new) biomarkers associated with sepsis provided disappointing results and little is known about changes in vital signs during sepsis resuscitation. We hypothesised that trends in vital signs together with routine biomarker levels during resuscitation might provide information about the response to treatment at a very early stage of sepsis in the emergency department (ED). We therefore explore trends in vital signs and routine biomarker levels during sepsis resuscitation in the ED. DESIGN: Prospective observational pilot study. SETTING: ED of a tertiary care teaching hospital. PARTICIPANTS: 99 Adult non-trauma patients with suspected infection and 2 or more systemic inflammatory response syndrome criteria admitted to the ED. PRIMARY AND SECONDARY OUTCOME MEASURES: Vital signs and biomarker levels at admittance (T0) and after 3 h in the ED (T1). RESULTS: In total, data of 99 patients were analysed. Of these patients, 63 presented with sepsis, 30 with severe sepsis and 6 with septic shock. All vital signs decreased, except for peripheral oxygen saturation which increased. Almost all routine biomarker levels decreased during resuscitation, except for C reactive protein, bands, potassium, troponin T and direct bilirubin which remained stable. Sodium, chloride and N-terminal prohormone of brain natriuretic peptide increased slightly. CONCLUSIONS: Vital signs and biomarker levels showed descending trends during resuscitation, except for parameters directly affected by treatment modalities. Despite these trends, most patients improved clinically. Trends in vital signs and routine biomarkers might be helpful in predicting clinical course and response to treatment in patients with sepsis during early resuscitation.

Transferring the critically ill patient: are we there yet?

During the past few decades the numbers of ICUs and beds has increased significantly, but so too has the demand for intensive care. Currently large, and increasing, numbers of critically ill patients require transfer between critical care units. Inter-unit transfer poses significant risks to critically ill patients, particularly those requiring multiple organ support. While the safety and quality of inter-unit and hospital transfers appear to have improved over the years, the effectiveness of specific measures to improve safety have not been confirmed by randomized controlled trials. It is generally accepted that critically ill patients should be transferred by specialized retrieval teams, but the composition, training and assessment of these teams is still a matter of debate. Since it is likely that the numbers and complexity of these transfers will increase in the near future, further studies are warranted.

Ventricular Tachycardia After Naloxone Administration: a Drug Related Complication? Case Report and Literature Review.

OBJECTIVE: To present a case of ventricular tachycardia following naloxone administration and to review current literature concerning ventricular tachycardia associated with naloxone. METHODS: We present a case and review the literature concerning ventricular tachycardia (VT) as a complication of naloxone administration. RESULTS: In our patient, a 44-year old male intoxicated multi-drug user, VT presented on the electrocardiogram shortly after naloxone (twice 0.4 mg intra-osseous) administration for suspected methadone overdose. After initial medical treatment he was treated with electro cardioversion because of hemodynamic instability. Our patient was subsequently stabilized and admitted to our intensive care unit (ICU). Eight comparable cases concerning VT after administration of naloxone were found in the literature, both in multi-drug uses as in patients receiving opiates for elective surgery. CONCLUSION: We suggest VT as a possible, but rarely reported serious complication of naloxone administration (Naranjo scale possible to probable). Patients who are multi-drug users or receive opiates in high doses may be prone to VT/VF due to acute (iatrogenic) opiate withdrawal or reduction of sympathetic suppression and therefore overstimulation. Also, antagonism of the protective mechanism of opioids against sympathetic excess (due to substance abuse, cardiac disease or hypoxia, as seen in all cases) may induce VT/VF. We suggest the use of small dosages (0.1 mg vs 0.4 mg), cardiac monitoring, and to have defibrillation devices stand-by.

Oxygen therapy for sepsis patients in the emergency department: a little less?

Liberal oxygen therapy has been a cornerstone in the treatment of critically ill patients. Recently, awareness of hyperoxia toxicity has emerged. We investigated the partial pressure of oxygen in arterial blood (PaO2) in sepsis patients admitted to the emergency department treated with a reduced inspired oxygen fraction of 0.4 instead of 0.6-0.8. A prospective pilot study was carried out over a 3-month period. Patients admitted with two or more SIRS criteria and a suspicion of infection were included. They received 10 l O2/min through a VentiMask 40%. Of 83 patients, 77 had a PaO2 greater than 9.5 kPa with 10 l O2/min, of whom 51 had hyperoxia. Six patients showed hypoxia with 10 l O2/min. Of the hyperoxic patients, 8% died in hospital versus 6% with normoxia. Less than 8% of patients had hypoxia with 10 l O2/min; 66% were hyperoxic. Titration of oxygen therapy to normoxia in the emergency department should be evaluated.