Efficacy of prescribed opioids for acute pain after being discharged from the emergency department: A systematic review and meta-analysis.

BACKGROUND: Opioids are often prescribed for acute pain to patients discharged from the emergency department (ED), but there is a paucity of data on their short-term use. The purpose of this study was to synthesize the evidence regarding the efficacy of prescribed opioids compared to nonopioid analgesics for acute pain relief in ED-discharged patients. METHODS: MEDLINE, EMBASE, CINAHL, PsycINFO, CENTRAL, and gray literature databases were searched from inception to January 2023. Two independent reviewers selected randomized controlled trials investigating the efficacy of prescribed opioids for ED-discharged patients, extracted data, and assessed risk of bias. Authors were contacted for missing data and to identify additional studies. The primary outcome was the difference in pain intensity scores or pain relief. All meta-analyses used a random-effect model and a sensitivity analysis compared patients treated with codeine versus those treated with other opioids. RESULTS: From 5419 initially screened citations, 46 full texts were evaluated and six studies enrolling 1161 patients were included. Risk of bias was low for five studies. There was no statistically significant difference in pain intensity scores or pain relief between opioids versus nonopioid analgesics (standardized mean difference [SMD] 0.12; 95% confidence interval [CI] -0.10 to 0.34). Contrary to children, adult patients treated with opioid had better pain relief (SMD 0.28, 95% CI 0.13-0.42) compared to nonopioids. In another sensitivity analysis excluding studies using codeine, opioids were more effective than nonopioids (SMD 0.30, 95% CI 0.15-0.45). However, there were more adverse events associated with opioids (odds ratio 2.64, 95% CI 2.04-3.42). CONCLUSIONS: For ED-discharged patients with acute musculoskeletal pain, opioids do not seem to be more effective than nonopioid analgesics. However, this absence of efficacy seems to be driven by codeine, as opioids other than codeine are more effective than nonopioids (mostly NSAIDs). Further prospective studies on the efficacy of short-term opioid use after ED discharge (excluding codeine), measuring patient-centered outcomes, adverse events, and potential misuse, are needed.

Clinical outcomes following out-of-hospital cardiac arrest: The minute-by-minute impact of bystander cardiopulmonary resuscitation.

AIMS: The time-dependent prognostic role of bystander cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) patients has not been described with great precision, especially for neurologic outcomes. Our objective was to assess the association between bystander CPR, emergency medical service (EMS) response time, and OHCA patients' outcomes. METHODS: This cohort study used the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registries. Bystander-witnessed adult OHCA treated by EMS were included. The primary outcome was survival to hospital discharge and secondary outcome was survival with a good neurologic outcome (modified Rankin scale 0-2). Multivariable logistic regression models were used to assess the associations and interactions between bystander CPR, EMS response time and clinical outcomes. RESULTS: Out of 229,637 patients, 41,012 were included (18,867 [46.0%] without bystander CPR and 22,145 [54.0%] with bystander CPR). Bystander CPR was independently associated with higher survival (adjusted odds ratio [AOR] = 1.70 [95%CI 1.61-1.80]) and survival with a good neurologic outcome (AOR = 1.87 [95%CI 1.70-2.06]), while longer EMS response times were independently associated with lower survival to hospital discharge (each additional minute of EMS response time: AOR = 0.92 [95%CI 0.91-0.93], p < 0.001) and lower survival with a good neurologic outcome (AOR = 0.88 [95%CI 0.86-0.89], p < 0.001). There was no interaction between bystander CPR and EMS response time's association with survival (p = 0.12) and neurologic outcomes (p = 0.65). CONCLUSIONS: Although bystander CPR is associated with an immediate increase in odds of survival and of good neurologic outcome for OHCA patients, it does not influence the negative association between longer EMS response time and survival and good neurologic outcome.

Association of Initial Pulseless Electrical Activity Heart Rate and Clinical Outcomes following Adult Non-Traumatic Out-of-Hospital Cardiac Arrest.

OBJECTIVE: Studies evaluating the prognostic value of the pulseless electrical activity (PEA) heart rate in out-of-hospital cardiac arrest (OHCA) patients have reported conflicting results. The objective of this study was to evaluate the association between the initial PEA heart rate and favorable clinical outcomes for OHCA patients. METHODS: The present post-hoc cohort study used the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry Version 3, which included OHCA patients in seven US and three Canadian sites from April 2011 to June 2015. The primary outcome was survival to hospital discharge and the secondary outcome was survival with a good functional outcome. For the primary analysis, the patients were separated into eight groups according to their first rhythms and PEA heart rates: (1) initial PEA heart rate of 1-20 beats per minute (bpm); (2) 21-40 bpm; (3) 41-60 bpm; (4) 61-80 bpm; (5) 81-100 bpm; (6) 101-120 bpm; (7) over 120 bpm; (8) initial shockable rhythm (reference category). Multivariable logistic regression models were used to assess the associations of interest. RESULTS: We identified 17,675 patients (PEA: 7,089 [40.1%]; initial shockable rhythm: 10,797 [59.9%]). Patients with initial PEA electrical frequencies ≤100 bpm were less likely to survive to hospital discharge than patients with initial shockable rhythms (1-20 bpm: adjusted odds ratio [AOR] = 0.15 [95%CI 0.11-0.21]; 21-40 bpm: AOR = 0.21 [0.18-0.25]; 41-60 bpm: AOR = 0.30 [0.25-0.36]; 61-80 bpm: AOR = 0.37 [0.28-0.49]; 81-100 bpm: AOR = 0.55 [0.41-0.65]). However, there were no statistical outcome differences between PEA patients with initial electrical frequencies of >100 bpm and patients with initial shockable rhythms (101-120 bpm: AOR = 0.65 [95%CI 0.42-1.01]; >120 bpm: AOR = 0.72 [95%CI 0.37-1.39]). Similar results were observed for survival with good functional outcomes (101-120 bpm: AOR = 0.60 [95%CI 0.31-1.15]; >120 bpm: AOR = 1.08 [95%CI 0.50-2.28]). CONCLUSIONS: We observed a good association between higher initial PEA electrical frequency and favorable clinical outcomes for OHCA patients. As there is no significant difference in outcomes between patients with initial PEA heart rates of more than 100 bpm and those with initial shockable rhythms, we can hypothesize that these patients could be considered in the same prognostic category.

Accuracy of the Initial Rhythm to Predict a Short No-Flow Time in Out-of-Hospital Cardiac Arrest.

OBJECTIVES: The no-flow time (NFT) can help establish prognosis in out-of-hospital cardiac arrest (OHCA) patients. It is often used as a selection criterion for extracorporeal resuscitation. In patients with an unwitnessed OHCA for whom the NFT is unknown, the initial rhythm has been proposed to identify those more likely to have had a short NFT. Our objective was to determine the predictive accuracy of an initial shockable rhythm for an NFT of 5 minutes or less (NFT ≤ 5). DESIGN: Retrospective analysis of prospectively collected data. SETTING: Prehospital OHCA in eight U.S. and three Canadian sites. PATIENTS: A total of 28,139 adult patients with a witnessed nontraumatic OHCA were included, of whom 11,228 (39.9%) experienced an emergency medical service-witnessed OHCA (NFT = 0), 695 (2.7%) had a bystander-witnessed OHCA, and an NFT less than or equal to 5, and 16,216 (57.6%) with a bystander-witnessed OHCA and an NFT greater than 5. INTERVENTIONS: Sensitivity, specificity, and likelihood ratios of an initial shockable rhythm to identify patients with an NFT less than or equal to 5 minutes. MEASUREMENTS AND MAIN RESULTS: The sensitivity of an initial shockable rhythm to identify patients with an NFT less than or equal to 5 was poor (25% [95% CI, 25-26]), but specificity was moderate (70% [95% CI, 69-71]). The positive and likelihood ratios were inverted (negative accuracy) (positive likelihood ratio, 0.76 [95% CI, 0.74-0.79]; negative likelihood ratio, 1.12 [95% CI, 1.10-1.12]). Including only patients with a bystander-witnessed OHCA improved the sensitivity to 48% (95% CI, 45-52), the positive likelihood ratio to 1.45 (95% CI, 1.33-1.58), and the negative likelihood ratio to 0.77 (95% CI, 0.72-0.83), while slightly lowering the specificity to 67% (95% CI, 66-67). CONCLUSIONS: Our analysis demonstrated that the presence of a shockable rhythm at the time of initial assessment was poorly sensitive and only moderately specific for OHCA patients with a short NFT. The initial rhythm, therefore, should not be used as a surrogate for NFT in clinical decision-making.

Safety assessment of a redirection program using an electronic application for low-acuity patients visiting an emergency department.

BACKGROUND: Emergency departments (EDs) are operating at or above capacity, which has negative consequences on patients in terms of quality of care and morbi-mortality. Redirection strategies for low-acuity ED patients to primary care practices are usually based on subjective eligibility criteria that sometimes necessitate formal medical assessment. Literature investigating the effect of those interventions is equivocal. The aim of the present study was to assess the safety of a redirection process using an electronic clinical support system used by the triage nurse without physician assessment. METHODS: A single cohort observational study was performed in the ED of a level 1 academic trauma center. All low-acuity patients redirected to nearby clinics through a clinical decision support system (February-August 2017) were included. This system uses different sets of medical prerequisites to identify patients eligible to redirection. Data on safety and patient experience were collected through phone questionnaires on day 2 and 10 after ED visit. The primary endpoint was the rate of redirected patients returning to any ED for an unexpected visit within 48 h. Secondary endpoints were the incidence of 7-day return visit and satisfaction rates. RESULTS: A total of 980 redirected low-acuity patients were included over the period: 18 patients (2.8%) returned unexpectedly to an ED within 48 h and 31 patients (4.8%) within 7 days. No hospital admission or death were reported within 7 days following the first ED visit. Among redirected patients, 81% were satisfied with care provided by the clinic staff. CONCLUSION: The implementation of a specific electronic-guided decision support redirection protocol appeared to provide safe deferral to nearby clinics for redirected low-acuity patients. EDs are pivotal elements of the healthcare system pathway and redirection process could represent an interesting tool to improve the care to low-acuity patients.

Evaluation of Interventions to Reduce Opioid Prescribing for Patients Discharged From the Emergency Department: A Systematic Review and Meta-analysis.

Importance: Limiting opioid overprescribing in the emergency department (ED) may be associated with decreases in diversion and misuse. Objective: To review and analyze interventions designed to reduce the rate of opioid prescriptions or the quantity prescribed for pain in adults discharged from the ED. Data Sources: MEDLINE, Embase, CINAHL, PsycINFO, and Cochrane Controlled Register of Trials databases and the gray literature were searched from inception to May 15, 2020, with an updated search performed March 6, 2021. Study Selection: Intervention studies aimed at reducing opioid prescribing at ED discharge were first screened using titles and abstracts. The full text of the remaining citations was then evaluated against inclusion and exclusion criteria by 2 independent reviewers. Data Extraction and Synthesis: Data were extracted independently by 2 reviewers who also assessed the risk of bias. Authors were contacted for missing data. The main meta-analysis was accompanied by intervention category subgroup analyses. All meta-analyses used random-effects models, and heterogeneity was quantified using I2 values. Main Outcomes and Measures: The primary outcome was the variation in opioid prescription rate and/or prescribed quantity associated with the interventions. Effect sizes were computed separately for interrupted time series (ITS) studies. Results: Sixty-three unique studies were included in the review, and 45 studies had sufficient data to be included in the meta-analysis. A statistically significant reduction in the opioid prescription rate was observed for both ITS (6-month step change, -22.61%; 95% CI, -30.70% to -14.52%) and other (odds ratio, 0.56; 95% CI, 0.45-0.70) study designs. No statistically significant reduction in prescribed opioid quantities was observed for ITS studies (6-month step change, -8.64%; 95% CI, -17.48% to 0.20%), but a small, statistically significant reduction was observed for other study designs (standardized mean difference, -0.30; 95% CI, -0.51 to -0.09). For ITS studies, education, policies, and guideline interventions (6-month step change, -33.31%; 95% CI, -39.67% to -26.94%) were better at reducing the opioid prescription rate compared with prescription drug monitoring programs and laws (6-month step change, -11.18%; 95% CI, -22.34% to -0.03%). Most intervention categories did not reduce prescribed opioid quantities. Insufficient data were available on patient-centered outcomes such as pain relief or patients' satisfaction. Conclusions and Relevance: This systematic review and meta-analysis found that most interventions reduced the opioid prescription rate but not the prescribed opioid quantity for ED-discharged patients. More studies on patient-centered outcomes and using novel approaches to reduce the opioid quantity per prescription are needed. Trial Registration: PROSPERO Identifier: CRD42020187251.

Electrical rhythm degeneration in adults with out-of-hospital cardiac arrest according to the no-flow and bystander low-flow time.

AIMS: For out-of-hospital cardiac arrest (OHCA) patients, the influence of the delay before the initiation of resuscitation, termed the no-flow time (NFT), and duration of bystander-only resuscitation low-flow time (BLFT) on the type of electrical rhythm observed has not been well described. The objective of this study is to determine the relationship between NFT, BLFT and the likelihood of a shockable rhythm over time. METHODS: Using a North American prospective registry (2005-2015; mostly urban settings), we selected adult (18 years and over) patients who experienced a witnessed OHCA from a suspected cardiac etiology. Patients with an emergency medical services witnessed OHCA were only included in sensitivity analyses. The association between the NFT, BLFT and the presence of a shockable rhythm was evaluated using a multivariable logistic regression adjusting for the registry version, age, sex, and public location. RESULTS: A total of 229,632 patients were logged in the registry, 50,957 of whom were included. Of these, 17,704 (34.7%) had an initial shockable rhythm. After the first minute, a significant decrease over time in the occurrence of shockable rhythm is observed but is slower when bystander cardiopulmonary resuscitation (CPR) is provided (each supplemental minute of BLFT: adjusted odds ratio = 0.95, 95 %CI = 0.94-0.95; each supplemental minute of NFT: adjusted odds ratio = 0.91, 95 %CI = 0.90-0.91]). CONCLUSIONS: In this large observational study, we were able to demonstrate that longer NFT were associated with lower odds of shockable presenting rhythms. Bystander CPR significantly mitigates the degradation of shockable rhythms over time, strengthening the need to improve bystander CPR rates around the world.

Can a Shockable Initial Rhythm Identify Out-of-Hospital Cardiac Arrest Patients with a Short No-flow Time?

AIMS: Initial shockable rhythms may be a marker of shorter duration between collapse and initiation of cardiopulmonary resuscitation, known as no-flow time (NFT), for patients suffering an out-of-hospital cardiac arrest (OHCA). Eligibility for extracorporeal resuscitation is conditional on a short NFT. Patients with an unwitnessed OHCA could be candidate for extracorporeal resuscitation despite uncertain NFT if an initial shockable rhythm is a reliable stand-in. Herein, we sought to describe the sensitivity and specificity of an initial shockable rhythm for predicting a NFT of five minutes or less. METHODS: Using a registry of OHCA in Montreal, Canada, adult patients who experienced a witnessed non-traumatic OHCA, but who did not receive bystander cardiopulmonary resuscitation, were included. The sensitivity and specificity of an initial shockable rhythm for predicting a NFT of five minute or less were calculated. The association between the NFT and the presence of a shockable rhythm was evaluated using a multivariable logistic regression. RESULTS: A total of 2450 patients were included, of whom 863 (35%) had an initial shockable rhythm and 1085 (44%) a NFT of five minutes or less. The sensitivity of an initial shockable rhythm to predict a NFT of five minutes or less was 36% (95% confidence interval [95%CI] 33-39), specificity was 66% (95%CI 63-68), the positive likelihood ratio was 1.05 (95%CI 0.94-1.17) and the negative likelihood ratio of 0.97 (95%CI 0.92-1.03). The probabilities of observing a shockable rhythm stayed stable up to 15 minutes, while the probabilities of observing a PEA lowered rapidly initially. Longer NFT were associated with lower odds of observing an initial shockable rhythm (adjusted odds ratio = 0.97 [95%CI 0.94-0.99], p = 0.012). CONCLUSIONS: An initial shockable rhythm is a poor predictor of a short NFT, despite there being an association between the NFT and the presence of a shockable rhythm.

Oxygen Therapy and Risk of Infection for Health Care Workers Caring for Patients With Viral Severe Acute Respiratory Infection: A Systematic Review and Meta-analysis.

STUDY OBJECTIVE: To synthesize the evidence regarding the infection risk associated with different modalities of oxygen therapy used in treating patients with severe acute respiratory infection. Health care workers face significant risk of infection when treating patients with a viral severe acute respiratory infection. To ensure health care worker safety and limit nosocomial transmission of such infection, it is crucial to synthesize the evidence regarding the infection risk associated with different modalities of oxygen therapy used in treating patients with severe acute respiratory infection. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2000, to April 1, 2020, for studies describing the risk of infection associated with the modalities of oxygen therapy used for patients with severe acute respiratory infection. The study selection, data extraction, and quality assessment were performed by independent reviewers. The primary outcome measure was the infection of health care workers with a severe acute respiratory infection. Random-effect models were used to synthesize the extracted data. RESULTS: Of 22,123 citations, 50 studies were eligible for qualitative synthesis and 16 for meta-analysis. Globally, the quality of the included studies provided a very low certainty of evidence. Being exposed or performing an intubation (odds ratio 6.48; 95% confidence interval 2.90 to 14.44), bag-valve-mask ventilation (odds ratio 2.70; 95% confidence interval 1.31 to 5.36), and noninvasive ventilation (odds ratio 3.96; 95% confidence interval 2.12 to 7.40) were associated with an increased risk of infection. All modalities of oxygen therapy generate air dispersion. CONCLUSION: Most modalities of oxygen therapy are associated with an increased risk of infection and none have been demonstrated as safe. The lowest flow of oxygen should be used to maintain an adequate oxygen saturation for patients with severe acute respiratory infection, and manipulation of oxygen delivery equipment should be minimized.

Prognostic impact of the conversion to a shockable rhythm from a non-shockable rhythm for patients suffering from out-of-hospital cardiac arrest.

OBJECTIVE: For patients suffering from an out-of-hospital cardiac arrest (OHCA), having an initial shockable rhythm is a marker of good prognosis. It has been suggested as one of the main prognosticating factors for the selection of patients for extracorporeal resuscitation (E-CPR). However, the prognostic implication of converting from a non-shockable to a shockable rhythm, as compared to having an initial shockable rhythm, remains uncertain, especially among patients that can otherwise be considered eligible for E-CPR. The objective of this study was to evaluate the association between the initial rhythm and its subsequent conversion and survival following an OHCA, for the general population and for E-CPR candidates. METHODS: This study used a registry of OHCA in Montreal, Canada. Adult patients suffering from a non-traumatic OHCA for whom the initial rhythm was known were included. The association between the initial rhythm and its subsequent conversion or not and survival to discharge was assessed using a multivariable logistic regression. RESULTS: Of 6681 included patients, 1788 (27%) had an initial shockable rhythm, 1749 (26%) had pulseless electrical activity (PEA) and no subsequent shockable rhythm, 295 (4%) had PEA and a subsequent shockable rhythm, 2694 (40%) had asystole and no subsequent shockable rhythm, and 155 (2%) asystole and a subsequent shockable rhythm. As compared to patients having an initial shockable rhythm, patients in all other groups had significantly lower odds of survival to hospital discharge (p < 0.001 for all comparisons). Univariate analyses were performed for E-CPR candidates. Among these 556 (8%) patients, more patients with an initial shockable rhythm survived than patients in all other groups (p < 0.001 for all comparisons). CONCLUSIONS: The initial rhythm remains a much better prognostic marker than subsequent rhythms for all patients suffering from an OHCA, including in the subset of potential E-CPR candidates.

Association Between the Quantity of Subcutaneous Fat and the Inter-Device Agreement of 2 Tissue Oximeters.

OBJECTIVE: This study aimed to evaluate the association between the quantity of subcutaneous fat (assessed by skinfold thickness) and the inter-device agreement of 2 tissue oximeters. DESIGN: This is a prospective cohort study. SETTING: This study was conducted in a tertiary care academic urban hospital. PARTICIPANTS: Healthy volunteers were recruited. INTERVENTIONS: All patients recruited had their tissue saturations and skinfold thickness measured at 4 different sites (shoulder, forearm, knee, and calf) on both sides of the body using 2 tissue oximeters, the INVOS 5100C and the EQUANOX 7600. MEASUREMENTS AND MAIN RESULTS: Higher skinfold measures were associated with an increase in the difference between measures provided by both oximeters (slope = -0.59, Pearson correlation coefficient = -0.51, p < 0.001). This observed association persisted in a linear mixed model (-0.48 [95% confidence interval [CI] -0.61 to -0.36], p < 0.001). The sex of the volunteers also influenced the inter-oximeter agreement (women: -5.77 [95% CI -8.43 to -3.11], p < 0.001), as well as the forearm sites (left forearm: -7.16 [95% CI -9.85 to -4.47], p < 0.001; right forearm:-7.01 [95% CI -9.61 to -4.40], p < 0.001). CONCLUSION: The inter-device agreement of the 2 studied oximeters is correlated to the quantity of subcutaneous fat. Monitoring using tissue oximetry should be interpreted with great care when sensors are placed on sites with a significant quantity of subcutaneous fat. In addition to the monitoring of cerebral oximetry, following the variations of saturations at the same peripheral site seems to remain the most secure way to use that technology for the monitoring of critically ill patients.

Subjective sleep quality and its etiology in the emergency department.

OBJECTIVE: Patient sleep quality has a significant impact on recovery. However, most hospital units do not provide an optimal environment for sleep and there are currently no data available on how well patients sleep during their emergency department stay. The main objective of this study was to assess the subjective quality of nighttime sleep and factors that affect sleep in the emergency department (ED). METHODS: A prospective sample of patients aged 18 years and older who presented to the ED from July 2015 to October 2015 was investigated. All participants were on stretcher and slept at least one night in the ED. Participants were asked to complete a sleep questionnaire adapted to the ED environment on sleep quality and its potentially modifying factors. RESULTS: A total of 235 patients participated in the study (mean age: 64±20 years, 51% women). Compared to the week at home prior to admission, subjective sleep quality was lower in the ED (p<0.001): almost half the participants took more than 30 minutes to fall asleep, and they reported waking up 3.5 times per night on average. Lower subjective sleep quality in the ED was associated with higher stress, noise, and pain, as well as with stretcher comfort and lower home sleep quality the week prior to admission. CONCLUSIONS: Subjective sleep quality in the emergency department is not optimal, and is influenced by stress, noise, pain, and stretcher comfort, all potentially modifiable factors.

The prognostic significance of repeated prehospital shocks for out-of-hospital cardiac arrest survival.

OBJECTIVES: Patients suffering from an out-of-hospital cardiac arrest (OHCA) associated with an initial shockable rhythm have a better prognosis than their counterparts. The implications of recurrent or refractory malignant arrhythmia in such context remain unclear. The objective of this study is to evaluate the association between the number of prehospital shocks delivered and survival to hospital discharge among patients in OHCA. METHODS: This cohort study included adult patients with an initial shockable rhythm over a 5-year period from a registry of OHCA in Montreal, Canada. The relationship between the number of prehospital shocks delivered and survival to discharge was described using dynamic probabilities. The association between the number of prehospital shocks delivered and survival to discharge was assessed using multivariable logistic regression. RESULTS: A total of 1,788 patients (78% male with a mean age of 64 years) were included in this analysis, of whom 536 (30%) received treatments from an advanced care paramedic. A third of the cohort (583 patients, 33%) survived to hospital discharge. The probability of survival was highest with the first shock (33% [95% confidence interval 30%-35%]), but decreased to 8% (95% confidence interval 4%-13%) following nine shocks. A higher number of prehospital shocks was independently associated with lower odds of survival (adjusted odds ratio=0.88 [95% confidence interval 0.85-0.92], p < 0.001). CONCLUSION: Survival remains possible even after a high number of shocks for patients suffering from an OHCA with an initial shockable rhythm. However, requiring more shocks is independently associated with worse survival.

The simple query "Do you want more pain medication?" is not a reliable way to assess acute pain relief in patients in the emergency department.

OBJECTIVE: The management of acute pain constitutes an essential skill of emergency department (ED) physicians. However, the accurate assessment of pain intensity and relief represents a clinically challenging undertaking. Some studies have proposed to define effective pain relief as the patient's refusal for additional analgesic administration. The aim of this study was to verify whether such a refusal is effectively indicative of pain relief. METHODS: This prospective cohort study included ED patients who received single or multiple doses of pain medication for an acute pain problem. Patients were evaluated for pain relief using one Likert scale and two dichotomous questions: Is your pain relieved? and Do you want more analgesics? Non-relieved patients were further analysed using a checklist as to the reasons behind their refusal for supplemental pain medication. RESULTS: We have recruited 378 adult patients with a mean age of 50.3 years (±19.1); 60% were women and had an initial mean pain level of 7.3 (±2.0) out of 10. We observed that 68 out of 244 patients who were adequately relieved from pain asked for more analgesics (28%), whereas 51 out of 134 patients who were not relieved from pain refused supplemental drugs (38%). Reasons for refusal included wanting to avoid side effects, feeling sufficiently relieved, and disliking the medication's effects. CONCLUSION: Over a third of ED patients in acute pain were not relieved but refused supplemental pain medication. Patients have reported legitimate reasons to decline further analgesics, and this refusal cannot be used as an indication of pain relief.

Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir.

BACKGROUND & AIM: The resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies. METHODS: HCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan-Meier analysis. RESULTS: Faldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (<1%) at baseline. Virologic response to faldaprevir/deleobuvir/ribavirin was not compromised by common baseline NS3 polymorphisms (e.g. Q80K in 17.5% of GT-1a) or by NS5B A421V, present in 20% of GT-1a. In GT-1b, alanine at NS5B codon 499 (present in 15% of baseline sequences) was associated with reduced response. Treatment-emergent RAVs consolidated previous findings: NS3 R155 and D168 were key faldaprevir RAVs; NS5B A421 and P495 were key deleobuvir RAVs. Among on-treatment virologic breakthroughs, RAVs emerged in both NS3 and NS5B (>90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months). CONCLUSION: Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen.

Risk of Delayed Intracranial Hemorrhage in Anticoagulated Patients with Mild Traumatic Brain Injury: Systematic Review and Meta-Analysis.

BACKGROUND: Delayed intracranial hemorrhage is a potential complication of head trauma in anticoagulated patients. OBJECTIVE: Our aim was to use a systematic review and meta-analysis to determine the risk of delayed intracranial hemorrhage 24 h after head trauma in patients who have a normal initial brain computed tomography (CT) scan but took vitamin K antagonist before injury. METHODS: EMBASE, Medline, and Cochrane Library were searched using controlled vocabulary and keywords. Retrospective and prospective observational studies were included. Outcomes included positive CT scan 24 h post-trauma, need for surgical intervention, or death. Pooled risk was estimated with logit proportion in a random effect model with 95% confidence intervals (CIs). RESULTS: Seven publications were identified encompassing 1,594 patients that were rescanned after a normal first head scan. For these patients, the pooled estimate of the incidence of intracranial hemorrhage on the second CT scan 24 h later was 0.60% (95% CI 0-1.2%) and the resulting risk of neurosurgical intervention or death was 0.13% (95% CI 0.02-0.45%). CONCLUSIONS: The present study is the first published meta-analysis estimating the risk of delayed intracranial hemorrhage 24 h after head trauma in patients anticoagulated with vitamin K antagonist and normal initial CT scan. In most situations, a repeat CT scan in the emergency department 24 h later is not necessary if the first CT scan is normal. Special care may be required for patients with serious mechanism of injury, patients showing signs of neurologic deterioration, and patients presenting with excessive anticoagulation or receiving antiplatelet co-medication.

Evaluating acute pain intensity relief: challenges when using an 11-point numerical rating scale.

Percentage of pain intensity difference (PercentPID) is a recognized way of evaluating pain relief with an 11-point numerical rating scale (NRS) but is not without flaws. A new metric, the slope of relative pain intensity difference (SlopePID), which consists in dividing PercentPID by the time between 2 pain measurements, is proposed. This study aims to validate SlopePID with 3 measures of subjective pain relief: a 5-category relief scale (not, a little, moderate, very, complete), a 2-category relief question ("I'm relieved," "I'm not relieved"), and a single-item question, "Wanting other medication to treat pain?" (Yes/No). This prospective cohort study included 361 patients in the emergency department who had an initial acute pain NRS > 3 and a pain intensity assessment within 90 minutes after analgesic administration. Mean age was 50.2 years (SD = 19.3) and 59% were women. Area under the curves of receiver operating characteristic curves analyses revealed similar discriminative power for PercentPID (0.83; 95% confidence interval [CI], 0.79-0.88) and SlopePID (0.82; 95% CI, 0.77-0.86). Considering the "very" category from the 5-category relief scale as a substantial relief, the average cutoff for substantial relief was a decrease of 64% (95% CI, 59-69) for PercentPID and of 49% per hour (95% CI, 44-54) for SlopePID. However, when a cutoff criterion of 50% was used as a measure of pain relief for an individual patient, PercentPID underestimated pain-relieved patients by 12.1% (P < 0.05) compared with the SlopePID measurement, when pain intensity at baseline was an odd number compared with an even number (32.9% vs 45.0%, respectively). SlopePID should be used instead of PercentPID as a metric to evaluate acute pain relief on a 0 to 10 NRS.

Discovery of BI 207524, an indole diamide NS5B thumb pocket 1 inhibitor with improved potency for the potential treatment of chronic hepatitis C virus infection.

The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.

Baseline hepatitis C virus (HCV) NS3 polymorphisms and their impact on treatment response in clinical studies of the HCV NS3 protease inhibitor faldaprevir.

A challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%; P = 0.47) or treatment naive (62% compared to 66%; P = 0.72).