Doses Of Benzodiazepines Research Articles

Comparison of Clinical Manifestations of Patients Poisoned with Tricyclic Antidepressants Alone or with Benzodiazepine Intoxication According to the Dose of Benzodiazepines.

Tricyclic antidepressants poisoning (TCA) is associated with cardiovascular complications, electrocardiographic abnormalities, and central nervous system toxicity. This study aimed to compare the clinical manifestations of poisoned patients with tricyclic antidepressants alone or with benzodiazepine (BZD) intoxication according to the dose of BZDs. In this case-control study, 120 patients with TCA poisoning were divided into four groups: the first group of TCA poisoning alone, the second group of TCA and BZD poisoning of <7.75 mg, the third group of TCA and B poisoning of 7.75 to 80 mg, and the fourth group of more than 80 mg of TCA and BZD poisoning. Patients' demographic, clinical, and cardiac information was extracted from their records at admission and 6 h after admission. Cardiac complications 6 h after referral and total cardiac complications between TCA and TCA low-dose BZD groups were significantly reduced in the low-dose BZD poisoning group. Comparison of TCA and TCA groups with a moderate dose of BZD showed a significant reduction in time six and total cardiac complications. However, due to the significant difference in TCA values between the two groups, the results are not significant. Comparing the two groups of TCA and TCA with a high dose of BZD, both 6-hour cardiac complications and total cardiac complications in the high-dose BZD group, it was significantly reduced. However, the loss of consciousness was also considerably greater in the high-dose BZD group than in the TCA group. Concomitant BZDs with TCA can reduce cardiovascular complications from TCA poisoning. However, with high doses of BZDs, there is a greater loss of consciousness.

Sociodemographic differences in quality of treatment to Medicaid enrollees receiving buprenorphine

Background: Buprenorphine is a key medication to treat opioid use disorder, but little is known about how treatment quality varies across sociodemographic groups. Objective: We examined measures of treatment quality and explored variation by sociodemographic factors. Methods: We used Medicaid MAX data from 50 states from 2006 to 2014 to identify buprenorphine treatment episodes (N = 317,494). We used multivariable logistic regression to examine the quality of buprenorphine treatment along four dimensions: (1) sufficient duration, (2) effective dosage, and concurrent prescribing of (3) opioid analgesics and (4) benzodiazepines. We explored how quality varied by race/ethnicity, age, sex, and urbanicity. Results: In adjusted models, compared to non-Hispanic White individuals, non-Hispanic Black and Hispanic individuals had lower odds of receiving effective dosage (aORs = 0.79 and 0.89, respectively) and sufficient duration (aORs = 0.64 and 0.71, respectively), and lower odds of concurrent prescribing of opioid analgesics (aORs = 0.86 and 0.85, respectively) and benzodiazepines (aORs = 0.51 and 0.59, respectively). Older individuals had higher odds of sufficient duration (aORs from 1.21–1.33), but also had higher odds of concurrent opioid analgesics prescribing (aORs from 1.29–1.56) and benzodiazepines (aORs from 1.44–1.99). Females had higher odds of sufficient duration (aOR = 1.12), but lower odds of effective dosage (aOR = 0.77) and higher odds of concurrent prescribing of opioid analgesics (aOR = 1.25) and benzodiazepines (aOR = 1.16). Compared to individuals living in metropolitan areas, individuals living in non-metropolitan areas had higher odds of sufficient duration (aORs = 1.11 and 1.24) and effective dosage (aORs = 1.06 and 1.33), and lower odds of concurrent prescribing (aORs from 0.81–0.98). Conclusions: Black and Hispanic individuals were less likely to receive effective buprenorphine dosage and sufficient duration. Quality results were mixed for older and female individuals; although these individuals were more likely to receive treatment of sufficient duration, they were also more likely to be concurrently prescribed potentially contraindicated medications, and females were less likely to receive effective dosage. Findings raise concerns about adequacy of care for minority and other at-risk populations.

Antipsychotic polypharmacy and clozapine prescribing patterns: evolution and correlates before and after a psychiatric hospitalisation

Background:Antipsychotic polypharmacy (APP) prescribing and clozapine underuse are considered inappropriate prescribing in schizophrenia. Psychiatric hospitalisations may be suitable occasions to re-evaluate patient pharmacotherapy and to switch to monotherapy.Objectives:To explore the evolution of APP and other psychotropic prescribing patterns during psychiatric hospitalisations, to detect characteristics associated with APP on admission and at discharge, and to examine clozapine prescribing patterns.Design:We performed a retrospective observational study based on electronic health records.Methods:Data on adult inpatients diagnosed with schizophrenia spectrum disorders were collected retrospectively from 6 Belgian hospitals in 2020-2021.Results:Of the 516 patients included, APP prescribing increased significantly from 47.9% on hospital admission to 59.1% at discharge. On admission and at discharge, APP was associated with prior clozapine use (ORadmission = 2.53, CI = 1.1–5.84, ORdischarge = 11.01, CI = 4.45–27.28), treatment with a first-generation antipsychotic (ORadmission = 26.79, CI = 13.08–54.86, ORdischarge = 25.2, CI = 12.2–52.04), increased antipsychotic exposure (ORadmission = 8.93, CI = 5.13–15.56, ORdischarge = 19.89, CI = 10–39.54), and a greater number of hypno-sedatives (ORadmission = 1.88, CI = 1.23–2.88, ORdischarge = 4.18, CI = 2.53–6.91). APP was negatively associated with involuntary admission (ORadmission = 0.31, CI = 0.14–0.7, ORdischarge = 0.3, CI = 0.13–0.68). When using an alternative definition of monotherapy (i.e. including patients with an add-on low-dose antipsychotic for sleep disorders), alcohol use disorder (ORadmission = 0.26, CI = 0.13–0.54) and higher age (ORdischarge = 0.53, CI = 0.29–0.95) were negatively associated with APP, and living in a residential facility (ORdischarge = 2.39 CI = 1.21–4.71) and a higher daily dosage of benzodiazepines during the stay (ORdischarge = 1.32 CI = 1.03–1.69) increased the odds of being discharged on APP. On admission, 9.3% of patients were being treated with clozapine. Although 28.1% of patients were eligible for clozapine treatment, only 11% of patients were discharged with a clozapine prescription. For 7 of the 10 patients with a new clozapine prescription, it was directly prescribed in combination with another antipsychotic, without a prior trial of clozapine monotherapy.Conclusion:Suboptimal prescriptions of antipsychotics in patients with schizophrenia persist after psychiatric hospitalisations and are associated with identifiable characteristics.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Persistent use of prescription opioids following lumbar spine surgery: Observational study with prospectively collected data from two Norwegian nationwide registries

Study design Prospective pharmacoepidemiological study. Objective To investigate the use of prescription opioids two years following degenerative lumbar spine surgery. Summary of background data There are limited data providing details to evaluate patterns of opioid use. The number of patients is often limited and data on opioid use following some of the most common surgical procedures are lacking. Methods Data from the Norwegian Registry for Spine Surgery and the Norwegian Prescription Database were linked on an individual level. The primary outcome measure was persistent opioid use the second year after surgery. Functional disability was measured with the Oswestry disability index (ODI). Study participants were operated between 2007 and 2017. Results Among 32886 study participants, 2754 (8.4%) met criteria for persistent opioid use the second year after surgery. Among persistent opioid users in the second year after surgery, 64% met the criteria for persistent opioid use the year preceding surgery. Persistent opioid use the year preceding surgery (OR 31.10, 95% CI 26.9-36.0, P = .001), use of high doses of benzodiazepines (OR 1.62, 95% CI 1.30-2.04, P = .001), and use of high doses of z-hypnotics (OR 1.90, 95% CI 1.58-2.22, P = .001) the year before surgery were associated with increased risk of persistent opioid use the second year after surgery. A higher ODI score at one year was observed in persistent opioid users compared to non-persistent users (41.5 vs 18.8 points) and there was a significant difference in ODI change (-13.7 points). Patients with persistent opioid use in the year preceding surgery were less likely to achieve a minimal clinically important ODI change at one year compared to non-persistent users (37.7% vs 52.6%, P = .001). Conclusion Patients with or at risk of developing persistent opioid should be identified and provided counseling and support to taper off opioid treatment.Level of Evidence: 2.

Delirium in a Tertiary Pediatric Cardiac Intensive Care Unit: Risk Factors and Outcomes.

Delirium is an increasingly recognized hospital complication associated with poorer outcomes in critically ill children. We aimed to evaluate risk factors for screening positive for delirium in children admitted to a pediatric cardiac intensive care unit (CICU) and to examine the association between duration of positive screening and in-hospital outcomes. Retrospective cohort study in a single-center quaternary pediatric hospital CICU evaluating children admitted from March 2014-October 2016 and screened for delirium using the Cornell Assessment of Pediatric Delirium. Statistical analysis used multivariable logistic and linear regression. Among 942 patients with screening data (98% of all admissions), 67% of patients screened positive for delirium. On univariate analysis, screening positive was associated with younger age, single ventricle anatomy, duration of mechanical ventilation, continuous renal replacement therapy, extracorporeal life support, and surgical complexity, as well as higher average total daily doses of benzodiazepines, opioids, and dexmedetomidine. On multivariable analysis, screening positive for delirium was independently associated with age <2 years, duration of mechanical ventilation, and greater than the median daily doses of benzodiazepine and opioid. In addition to these factors, duration of screening positive was also independently associated with higher STAT category (3-5) or medical admission, organ failure, acute kidney injury (AKI), and higher dexmedetomidine exposure. Duration of positive delirium screening was associated with both increased CICU and hospital length of stay (each additional day of positive screening was associated with a 3% longer CICU stay [95% CI = 1%-6%] and 2% longer hospital stay [95% CI = 0%-4%]). Screening positive for delirium is common in the pediatric CICU and is independently associated with prolonged intensive care unit (ICU) and hospital stay. Longer duration of mechanical ventilation and higher sedative doses are independent risk factors for screening positive for delirium. Efforts aimed at reducing these exposures may decrease the burden of delirium in this population.

The LiberAction Project: Implementation of a Pediatric Liberation Bundle to Screen Delirium, Reduce Benzodiazepine Sedation, and Provide Early Mobilization in a Human Resource-Limited Pediatric Intensive Care Unit.

Background: Delirium, bed immobilization, and heavy sedation are among the major contributors of pediatric post-intensive care syndrome. Recently, the Society of Critical Care Medicine has proposed the implementation of daily interventions to minimize the incidence of these morbidities and optimize children functional outcomes and quality of life. Unfortunately, these interventions require important clinical and economical efforts which prevent their use in many pediatric intensive care units (PICU).Aim: First, to evaluate the feasibility and safety of a PICU bundle implementation prioritizing delirium screening and treatment, early mobilization (<72 h from PICU admission) and benzodiazepine-limited sedation in a human resource-limited PICU. Second, to evaluate the incidence of delirium and describe the early mobilization practices and sedative drugs used during the pre- and post-implementation periods. Third, to describe the barriers and adverse events encountered during early mobilization.Methods: This observational study was structured in a pre- (15th November 2019–30th June 2020) and post-implementation period (1st July 2020–31st December 2020). All patients admitted in PICU for more than 72 h during the pre and post-implementation period were included in the study. Patients were excluded if early mobilization was contraindicated. During the pre-implementation period, a rehabilitation program including delirium screening and treatment, early mobilization and benzodiazepine-sparing sedation guidelines was developed and all PICU staff trained. During the post-implementation period, delirium screening with the Connell Assessment of Pediatric Delirium scale was implemented at bedside. Early mobilization was performed using a structured tiered protocol and a new sedation protocol, limiting the use of benzodiazepine, was adopted.Results: Two hundred and twenty-five children were enrolled in the study, 137 in the pre-implementation period and 88 in the post-implementation period. Adherence to delirium screening, benzodiazepine-limited sedation and early mobilization was 90.9, 81.1, and 70.4%, respectively. Incidence of delirium was 23% in the post-implementation period. The median cumulative dose of benzodiazepines corrected for the total number of sedation days (mg/kg/sedation days) was significantly lower in the post-implementation period compared with the pre-implementation period: [0.83 (IQR: 0.53–1.31) vs. 0.74 (IQR: 0.55–1.16), p = 0.0001]. The median cumulative doses of fentanyl, remifentanil, and morphine corrected for the total number of sedation days were lower in the post-implementation period, but these differences were not significant. The median number of mobilizations per patient and the duration of each mobilization significantly increased in the post-implementation period [3.00 (IQR: 2.0–4.0) vs. 7.00 (IQR: 3.0–12.0); p = 0.004 and 4 min (IQR: 3.50–4.50) vs. 5.50 min (IQR: 5.25–6.5); p < 0.0001, respectively]. Barriers to early mobilization were: disease severity and bed rest orders (55%), lack of physicians' order (20%), lack of human resources (20%), and lack of adequate devices for patient mobilization (5%). No adverse events related to early mobilization were reported in both periods. Duration of mechanical ventilation and PICU length of stay was significantly lower in the post-implementation period as well as the occurrence of iatrogenic withdrawal syndrome.Conclusion: This study showed that the implementation of a PICU liberation bundle prioritizing delirium screening and treatment, benzodiazepine-limited sedation and early mobilization was feasible and safe even in a human resource-limited PICU. Further pediatric studies are needed to evaluate the clinical impact of delirium, benzodiazepine-limited sedation and early mobilization protocols on patients' long-term functional outcomes and on hospital finances.

Opioid and sedative requirements in extracorporeal membrane oxygenation patients on hydromorphone versus fentanyl.

The extracorporeal membrane oxygenation (ECMO) circuit causes pharmacokinetic alterations of medications which impact drug selection and dosing. Although hydromorphone has a favorable pharmacokinetic profile, it is unclear whether hydromorphone provides better patient-centered benefits compared to fentanyl. The objective of this study is to compare opioid and sedative requirements in ECMO patients started on a fentanyl- versus hydromorphone-based analgesia regimen. This was a non-interventional retrospective cohort study. It was conducted at a single center in the cardiovascular intensive care units and cardiac intensive care units. We included venovenous (VV) or venoarterial ECMO patients. Patients who were started on a fentanyl continuous infusion within 24h of cannulation were compared to patients started on a hydromorphone continuous infusion. A linear mixed effects model was performed to compare doses of opioid, sedative, and propofol between groups over time. We included 28 hydromorphone patients and 53 fentanyl patients, with 85% on VV ECMO. There were no differences between hydromorphone and fentanyl groups in opioid or sedative (including propofol and benzodiazepine) doses for any ECMO day (p value for interaction .63 and .83, respectively). Propofol doses alone, however, were significantly higher in the fentanyl group on ECMO days three, four, and five. There appear to be no major differences in opioid or sedative requirements whether ECMO patients are initiated on a hydromorphone- or fentanyl-based regimen.

Persistent Use of Prescription Opioids Following Lumbar Spine Surgery: Observational Study with Prospectively Collected Data From Two Norwegian Nationwide Registries.

Prospective pharmacoepidemiological study. To investigate the use of prescription opioids 2 years following degenerative lumbar spine surgery. There are limited data providing details to evaluate patterns of opioid use. The number of patients is often limited and data on opioid use following some of the most common surgical procedures are lacking. Data from the Norwegian Registry for Spine Surgery and the Norwegian Prescription Database were linked on an individual level. The primary outcome measure was persistent opioid use the second year after surgery. Functional disabilitywas measured with the Oswestry disability index (ODI). Study participants were operated between 2007 and 2017. Among 32,886 study participants, 2754 (8.4%) met criteria for persistent opioid use the second year after surgery. Among persistent opioid users in the second year after surgery, 64% met the criteria for persistent opioid use the year preceding surgery. Persistent opioid use the year preceding surgery (odds ratio [OR] 31.10, 95% confidence interval [CI] 26.9-36.0, P = 0.001), use of high doses of benzodiazepines (OR 1.62, 95% CI 1.30-2.04, P = 0.001), and use of high doses of z-hypnotics (OR 1.90, 95% CI 1.58-2.22, P = 0.001) the year before surgery were associated with increased risk of persistent opioid use the second year after surgery. A higher ODI score at 1 year was observed in persistent opioid users compared with non-persistent users (41.5 vs. 18.8 points) and there was a significant difference in ODI change (-13.7 points). Patients with persistent opioid use in the year preceding surgery were less likely to achieve a minimal clinically important ODI change at 1 year compared with non-persistent users (37.7% vs. 52.6%, P = 0.001). Patients with or at risk of developing persistent opioid should be identified and provided counseling and support to taper off opioid treatment.Level of Evidence: 2.

Outcomes of Minnesota Detoxification Scale (MINDS) Assessment With High-Dose Front Loading Diazepam Treatment for Alcohol Withdrawal in Hospitalized Patients

BackgroundBenzodiazepines are the gold standard for alcohol withdrawal treatment but choice and dosing vary widely. In 2015, our institution implemented a Minnesota detoxification scale (MINDS) and single standardized high-dose diazepam based protocol for treatment of alcohol withdrawal to replace multiple Clinical Institute Withdrawal Assessment for Alcohol (CIWA) based protocols using lower dose benzodiazepines. We compared use of MINDS versus CIWA assessment protocols with high front loading diazepam treatment in care of patient experiencing alcohol withdrawal during hospitalization. MethodsRetrospective cohort study of hospitalized patients experiencing alcohol withdrawal to statistically analyze difference in outcomes between CIWA based lower benzodiazepine dose protocols used in 2013–2015 versus the MINDS based high-dose front-loading diazepam protocol used in 2015–2017. ResultsPatients treated with MINDS based high dose diazepam protocol were less likely to have physical restraints used (AOR = 0.8, CI: 0.70–0.92), had a shorter hospital length of stay, and fewer days on benzodiazepines (p < 0.001). Patients were more likely to be readmitted to the hospital within 30 days (AOR = 1.13, CI: 1.03–1.26) in MINDS based diazepam treatment group. Total diazepam equivalent dosing was similar in both groups. Mortality rates and ICU use rates were similar between the groups. ConclusionsHigher dose front loading long acting benzodiazepine can be safely used with beneficial outcomes in hospitalized alcohol withdrawal patients.

Optimized Benzodiazepine Treatment of Pediatric Status Epilepticus Through a Standardized Emergency Medical Services Resuscitation Tool

BackgroundOptimized benzodiazepine (BZD) dosing decreases morbidity and mortality in children with status epilepticus (SE), but previous studies have documented widespread underdosing. Prior interventions have focused on in-hospital SE treatment, although more than 75% of pediatric patients with SE are initially treated by emergency medical services (EMS). Our goal was to assess whether an EMS-focused, collaboratively developed dosing resuscitation aid (Medic One Pediatric [MOPed] cards) and training could improve BZD dosing and pediatric SE outcomes. MethodsWe conducted a retrospective review of patients aged 12 years and younger treated by EMS for SE and transferred to Seattle Children's Hospital during the 1 year before and immediately after MOPed card training. The primary outcome was the percentage of patients receiving underdosed BZD treatment. Secondary outcomes included time to second-line antiseizure medication (ASM), intubation, and intensive care unit (ICU) admission. ResultsThe 44 children before and 33 after MOPed implementation were similar with respect to age, gender, and pre-existing epilepsy diagnosis. The percentage of children receiving underdosed BZDs fell from 52% to 6% after MOPed implementation (P < 0.001). There was no significant decrease in requirement for intubation and ICU admission. The interval to treatment with a second-line ASM remained prolonged. ConclusionsEMS-focused training significantly increased the percentage of outpatient pediatric patients with SE who received recommended initial BZD treatment. This improvement in management of SE did not significantly alter the rate of intubation or ICU admission, suggesting the need for further optimization of out-of-hospital SE care, particularly access to and timely use of second-line ASMs.

Pharmacologic predictors of benzodiazepine response trajectory in anxiety disorders: a Bayesian hierarchical modeling meta-analysis.

Despite frequent benzodiazepine use in anxiety disorders, the trajectory and magnitude of benzodiazepine response and the effects of benzodiazepine potency, lipophilicity, and dose on improvement are unknown. We performed a meta-analysis using weekly symptom severity data from randomized, parallel group, placebo-controlled trials of benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in anxiety was evaluated as a function of medication, disorder, time, potency, lipophilicity, and standardized dose and compared among benzodiazepines. Data from 65 trials (73 arms, 7 medications, 7110 patients) were included. In the logarithmic model of response, treatment effects emerged within 1 week of beginning treatment (standardized benzodiazepine-placebo difference = -0.235 ± 0.024, CrI: -0.283 to -0.186, P < .001) and placebo response plateaued at week 4. Doses <6 mg per day (lorazepam equivalents) produced faster and larger improvement than higher doses (P = .039 for low vs medium dose and P = .005 for high vs medium dose) and less lipophilic benzodiazepines (beta = 0.028 ± 0.013, P = .030) produced a greater response over time. Relative to the reference benzodiazepine (lorazepam), clonazepam (beta = -0.217 ± 0.95, P = .021) had a greater trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam). In adults with anxiety disorders, benzodiazepine-related improvement emerges early, and the trajectory and magnitude of improvement is related to dose and lipophilicity. Lower doses and less lipophilic benzodiazepines produce greater improvement.

Association between opioid-related deaths and persistent opioid prescribing in primary care in England: A nested case-control study.

This study aimed to evaluate the association between opioid-related deaths and persistent opioid utilisation in the United Kingdom (UK). This nested case-control study used the UK Clinical Practice Research Datalink, linking the Office for National Statistics death registration. Adult opioid users with recorded opioid-related death between 2000 and 2015 were included and matched to four opioid users (controls) based on a disease risk score. Persistent opioid utilisation (opioid prescriptions ≥3 quarters/year and oral morphine equivalent dose ≥4500 mg/year) and psychotropic prescriptions were identified annually during the three patient-years before the date of opioid-related death. Conditional logistic regression was used to assess the association between persistent opioid utilisation and opioid-related death, and the results were reported as adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Of the 902 149 opioid users, 230 opioid-related deaths (cases) and 920 controls were identified. Persistent opioid utilisation was significantly associated with an increased risk of opioid-related deaths (aOR 1.9, 95% CI 1.2, 2.9) when persistent opioid utilisation was defined by both annual dose and number of quarters. Concurrent prescription of opioids and tricyclic antidepressants (aOR 2.0, 95% CI 1.2, 3.5) or higher dose of benzodiazepine (aOR 6.5, 95% CI 4.0, 10.4) or gabapentinoids (aOR 6.2, 95% CI 2.9, 13.5) were associated with opioid-related death. Persistent opioid prescribing and concurrent prescribing of psychotropics were associated with a higher risk of opioid-related death and should be avoided in clinical practice. An evidence-based indicator to monitor the safety of prescribed opioids during opioid deprescribing is needed.

The Combined Effects of Alcohol and Benzodiazepines on Driving-Related Neurocognitive Skills: A Systematic Review

Research concerning the combined effects of alcohol and benzodiazepines on driving-related skills is largely inconsistent. Because as many as 88% of benzodiazepine users report the additional consumption of alcohol, this review aims to provide an updated and concise synthesis of the available high-quality research. We searched EBSCOhost, PubMed, Scopus, and Web of Science until April 1, 2020, for double-blind, placebo-controlled, repeated-measures intervention trials that examined the effects of alcohol (any dose provided as blood alcohol concentration [BAC]) in combination with oral benzodiazepines on neurocognitive tasks related to driving. We identified evidence of a substance and timing-dependent interaction for measures of reaction time, tracking, divided attention, and visual functioning. Administering alcohol in conjunction with or shortly after a benzodiazepine resulted in a stronger interactive effect than when administration occurred further apart. An additive and/or synergistic effect often occurred when a therapeutic dose of benzodiazepine was combined with alcohol at a BAC below .05%. Combined alcohol and benzodiazepine use was associated with significant impairments in driving-related neurocognitive skills. There is a clear need for more high-quality research in this area to better elucidate the mechanisms of alcohol and benzodiazepine interactions. Drivers may be unaware of impairments following the combination of these drugs at legal driving limits. Thus, drivers should be warned to take caution when consuming even small amounts of alcohol while under treatment with benzodiazepines.

1457P The end-of-life experiences for cancer patients with COVID-19 across the two peak pandemic waves

The COVID-19 (C-19) pandemic has seen much research scrutinising the impact of C-19 on cancer patients, focusing on understanding the impact of a cancer diagnosis and anti-cancer treatments on mortality. Yet there is paucity of work regarding the end-of-life care (EOLC) for cancer patients dying with C-19. Retrospective record review of all non-ventilated patients who died in a tertiary referral UK cancer centre with known or suspected C-19 across the 2 peak pandemic waves from 25/03/20 – 01/05/20 and 05/12/20 – 01/03/21. Demographics and risk factors for severe C-19 were described. EOLC assessment considered palliative care (PC) needs, medications prescribed and advance care plans including Treatment Escalation Plans (TEP) and Do Not Attempt Resuscitation (DNAR) orders. 34 patients were included. Most patients were female (18) and White British (19), mean age was 69 (45-82). 8 patients had recognised cardiovascular risk factors; 11 patients had no comorbidities additional to cancer. 26 patient had metastatic disease, 30 were receiving palliative treatment. Most patients were referred to PC for symptom control (20), 8 were referred for EOLC. All patients had DNAR orders and TEPs. The median number of PC reviews was 5 (range 1-24). Integrated Palliative Outcome Scale (IPOS) (a holistic assessment tool used in clinical care) scores on first assessment (n=24) recorded the main symptoms as weakness, lacking peace and anxiety. Family anxiety was the highest scoring aspect. Medical management at the end-of-life was, however, generally uncomplicated; total opioid (oral morphine equivalent) and benzodiazepine doses administered in last 24 hours before death were relatively low, median dose (range) 30mg (5-180 mg) and 10mg (0-30mg) respectively. With prompt recognition and access to standard EOLC, the symptom management of cancer patients dying from C-19 is relatively uncomplicated. As a transmissible disease, associated with social anxiety and restrictions, death from C-19 is, however, undeniably complicated. Timely acknowledgment of the vulnerability of patients with advanced cancer and C-19 is essential to facilitate early communication about patients’ priorities and wishes, and enhance family support.

Author Response: Prehospital Midazolam Use and Outcomes Among Patients With Out-of-Hospital Status Epilepticus.

We thank Dr. Kellinghaus and colleagues for sharing their experience of a large cohort of patients with status epilepticus in Europe. Their finding that patients in the SENSE registry are similarly not receiving the recommended initial benzodiazepine dose highlights the systemic nature of the problem: patients with status epilepticus are being undertreated.1

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

ObjectiveThis study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non‐BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE).MethodsThis retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non‐BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non‐BZD ASM.ResultsWe included 293 patients with a median (interquartile range) age of 3.8 (1.3–9.3) years. Thirty‐six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997–.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out‐of‐hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73–3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40–6.03, p < .0001) compared to patients with in‐hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01–2.06, p = .04). Forty‐seven percent of patients (n = 94) with out‐of‐hospital onset did not receive treatment before hospital arrival. Among patients with out‐of‐hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival.SignificanceFailure to escalate from BZDs to non‐BZD ASMs occurs mainly in out‐of‐hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non‐BZD ASMs after two BZD doses during handoffs between prehospital and in‐hospital settings.

The need for improved management of status epilepticus in children in Australia: Time from seizure onset to treatment is consistently delayed.

To determine if the management of paediatric status epilepticus (SE) follows accepted clinical practice guidelines. Retrospective, consecutive series of patients with SE who attended the emergency departments from two NSW sites over a 12-month period. SE was defined as a convulsive seizure, 5min or more in duration. Time to presentation to the ED, time to first- and second-line treatment, number of benzodiazepine (BZD) doses given prior to intubation and adherence to guidelines were evaluated. The outcomes included seizure duration, need for respiratory support, admission to intensive care, morbidity and mortality. The time from onset of seizure to ED presentation was a median (p25-p75) time of 22 (15-40) min. Forty-eight of 59 presentations received pre-hospital midazolam. The median (p25-p75) time to first-line treatment was 15 (8-25) min and to second-line treatment was 43.5 (35-59) min. There was no significant difference in the results in the two hospitals. The total number of BZD doses ranged from 1 to 7 (median 3). There was non-adherence to the clinical practice guidelines in 55 (93.2%) of 59 presentations. We found excessive benzodiazepine use and delay in both definitive treatment of status epilepticus and in escalation from first- to second-line anticonvulsant treatment. This raises the need for rapid escalation of treatment. We propose a 'status epilepticus code' for emergency departments.

A Systematic Review and Pooled Prevalence of Delirium in Critically Ill Children.

Pediatric delirium is a neuropsychiatric disorder with disrupted cerebral functioning due to underlying disease and/or critical care treatment. Pediatric delirium can be classified as hypoactive, hyperactive, and mixed. This systematic review was conducted to estimate the pooled prevalence of pediatric delirium using validated assessment tools in children (Cornell Assessment of Pediatric Delirium, Pediatric Confusion Assessment Method for the ICU, PreSchool Confusion Assessment Method for the ICU, Pediatric Confusion Assessment Method for the ICU Severity Scale, and Sophia Observation Withdrawal Symptoms Pediatric Delirium scale), identify modifiable and nonmodifiable risk factors, and explore the association of pediatric delirium with clinical outcomes. A systematic search of PubMed, EMBASE, and CINAHL databases was undertaken for full articles pertaining to pediatric delirium prevalence. No language or date barriers were set. Studies were included where the following eligibility criteria were met: study design aimed to estimate pediatric delirium prevalence arising from treatment in the intensive care setting, using a validated tool. Only randomized controlled trials, cross-sectional studies, or cohort studies allowing an estimate of the prevalence of pediatric delirium were included. Data were extracted by the primary researcher (D.S.) and accuracy checked by coauthors. A narrative synthesis and pooled prevalence meta-analysis were undertaken. Pediatric delirium, as determined by the Cornell Assessment of Pediatric Delirium score, is estimated to occur in 34% of critical care admissions. Eight of 11 studies reporting on subtype identified hypoactive delirium as most prevalent (46-81%) with each of the three remaining reporting either hyperactive (44%), mixed (57%), or equal percentages of hypoactive and mixed delirium (43%) as most prevalent. The development of pediatric delirium is associated with cumulative doses of benzodiazepines, opioids, the number of sedative classes used, deep sedation, and cardiothoracic surgery. Increased time mechanically ventilated, length of stay, mortality, healthcare costs, and associations with decreased quality of life after discharge were also found. Multi-institutional and longitudinal studies are required to better determine the natural history, true prevalence, long-term outcomes, management strategies, and financial implications of pediatric delirium.

Prescriptions of analgesics during chronic cancer disease trajectories: A complete national cohort study.

Pain management principles vary considerably between chronic noncancer, acute and cancer pain. Cancer patients responding to oncological treatment may live with low tumor burden for years. Opioid treatment should reflect that the ratio between benefits and risks in these patients is different from patients with a rapidly progressive disease. Our study investigated the prescription patterns of analgesics in patients who died 6 to 9 years after cancer diagnosis. A pharmaco-epidemiological study based on the Norwegian Prescription Database and Cancer Registry of Norway. The 1-year periodic prevalence of receiving different analgesics and of persistent opioid use were analyzed. Persistent opioid use was defined as >365 Defined Daily Doses or >9000 mg Oral Morphine Equivalents during 365 days with prescriptions in all quarters of the 365 days period. Data were reported for the first 7 years for patients who lived 8-9 years after cancer diagnosis (N= 1502), while for patients who lived 6-7 years (N= 3817) data was reported for the first 5 years after diagnosis. Compared to age- and gender adjusted general population, the 1-year periodic prevalence of opioid prescription was doubled the first year after diagnosis and remained raised with approximately 50%. The prevalence of persistent opioid use was threefold of the general population. Approximately 55% of patients with persistent opioid use 4 years after a cancer diagnosis were co-medicated with high doses of benzodiazepines and/or benzodiazepine-related hypnotics. The findings of increased opioid use raise concerns regarding whether the benefits outweigh risks and side effects in this population.