Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure.

BACKGROUND: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy. METHODS: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment. RESULTS: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients. CONCLUSIONS: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT03057977 and NCT03057951.

Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids.

BACKGROUND: The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies. METHODS: This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety. RESULTS: Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26 mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms. CONCLUSION: TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.

A Comparison of Injectable Diazepam and Lorazepam in the Goal-Directed Management of Severe Alcohol Withdrawal.

BACKGROUND: Benzodiazepines are the gold standard for treatment of alcohol withdrawal, yet the selection of a preferred benzodiazepine is limited due to a lack of comparative studies. OBJECTIVES: The primary objective of this study was to compare the efficacy and safety of injectable lorazepam (LZP) and diazepam (DZP) in the treatment of severe alcohol withdrawal syndrome (AWS). METHODS: Retrospective cohort study of adult patients admitted to an intensive care unit with a primary diagnosis of AWS. Subjects who received at least 12 LZP equivalent units (LEU) of injectable DZP or LZP within 24 hours of initiation of the severe AWS protocol were included. The primary outcome was time with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores at goal over the first 24 hours of treatment. RESULTS: A total of 191 patients were included (DZP n = 89, LZP n = 102). Time with CIWA-Ar scores at goal during the first 24 hours was similar between groups (DZP 12 hours [interquartile range, IQR, = 9-15] vs LZP 14 hours [IQR = 10-17]), P = 0.06). At 24 hours, LEU requirement was similar (DZP 40 [IQR = 22-78] vs LZP 32 [IQR = 18-56], P = 0.05). Drug cost at 24 hours was higher in the DZP group ($204.6 [IQR = 112.53-398.97] vs $8 [IQR = 4.5-14], P < 0.01). CONCLUSION AND RELEVANCE: DZP or LZP are equally efficacious for the treatment of severe AWS. LZP may be preferred due to cost but both medications can be used interchangeably based on availability.

A Taxonomy of Hospital-Based Addiction Care Models: a Scoping Review and Key Informant Interviews.

BACKGROUND: There is pressing need to improve hospital-based addiction care. Various models for integrating substance use disorder care into hospital settings exist, but there is no framework for describing, selecting, or comparing models. We sought to fill that gap by constructing a taxonomy of hospital-based addiction care models based on scoping literature review and key informant interviews. METHODS: Methods included a scoping review of the literature on US hospital-based addiction care models and interventions for adults, published between January 2000 and July 2021. We conducted semi-structured interviews with 15 key informants experienced in leading, implementing, evaluating, andpracticing hospital-based addiction care to explore model characteristics, including their perceived strengths, limitations, and implementation considerations. We synthesized findings from the literature review and interviews to construct a taxonomy of model types. RESULTS: Searches identified 2,849 unique abstracts. Of these, we reviewed 280 full text articles, of which 76 were included in the final review. We added 8 references from reference lists and informant interviews, and 4 gray literature sources. We identified six distinct hospital-based addiction care models. Those classified as addiction consult models include (1) interprofessional addiction consult services, (2) psychiatry consult liaison services, and (3) individual consultant models. Those classified as practice-based models, wherein general hospital staff integrate addiction care into usual practice, include (4) hospital-based opioid treatment and (5) hospital-based alcohol treatment. The final type was (6) community-based in-reach, wherein community providers deliver care. Models vary in their target patient population, staffing, and core clinical and systems change activities. Limitations include that some models have overlapping characteristics and variable ways of delivering core components. DISCUSSION: A taxonomy provides hospital clinicians and administrators, researchers, and policy-makers with a framework to describe, compare, and select models for implementing hospital-based addiction care and measure outcomes.

[A case of severe rhabdomyolysis after γ-butyrolactone withdrawal].

γ-butyrolactone is a colorless transparent liquid used in the production of drugs such as cyclopropylamine and pyrrolidone, and is also used as an industrial solvent, diluent, curing agent, etc., and is listed as the third category of precursor chemicals control. There is less clinical exposure to γ-butyrolactone and insufficient studies on its withdrawal response. This article reports a case of severe life-threatening rhabdomyolysis in a patient with γ-butyrolactone withdrawal. After active treatment, the patient eventually recovered. The clinical characteristics and treatment methods of γ-butyrolactone withdrawal reaction were summarized, suggesting that severe withdrawal reaction may occur in γ-butyrolactone.

Iatrogenic Opioid Withdrawal Syndrome in Critically Ill Patients: a Retrospective Cohort Study.

BACKGROUND: Opioid withdrawal syndrome (OWS) may occur following the reduction or discontinuation of opioid analgesics. In critically ill pediatric patients, OWS is a common and clinically significant condition. However, OWS in adult patients has not been assessed in detail. Therefore, we aimed to investigate the incidence, risk factors, and clinical features of OWS in mechanically ventilated patients treated in an adult intensive care unit (ICU). METHODS: This study was a retrospective evaluation of data from patients treated in the medical ICU for > 3 days and who received only one type of opioid analgesic. OWS was assessed over a 24 hours period from discontinuation or reduction (by > 50%) of continuous opioid infusion. OWS was defined as the presence of ≥ 3 central nervous system or autonomic nervous system symptoms. RESULTS: In 126 patients treated with remifentanil (n = 58), fentanyl (n = 47), or morphine (n = 21), OWS was seen in 31.0%, 36.2%, and 9.5% of patients, respectively (P = 0.078). The most common symptom was a change in respiratory rate (remifentanil, 94.4%; fentanyl, 76.5%; morphine, 100%). Multivariate Cox-proportional hazards model showed that OWS was negatively associated with morphine treatment (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.037-0.743) and duration of opioid infusion (HR, 0.566; 95% CI, 0.451-0.712). CONCLUSION: OWS is not uncommon in mechanically ventilated adult patients who received continuous infusion of opioids for > 3 days. The use of morphine may be associated with a decreased risk of OWS.

The impact of a quality improvement project to standardize pain, agitation, and withdrawal assessments on the use of morphine and midazolam in the Pediatric Intensive Care Unit.

BACKGROUND: This study aims to assess the impact of a quality improvement initiative to increase assessments of pain, agitation, and iatrogenic withdrawal syndrome, on the use of sedative and analgesic medication in a pediatric intensive care unit. METHODS: This is a retrospective pre and post, observational, quality improvement study conducted in an 18-bed medical-surgical-cardiac, tertiary intensive care unit. We included patients consecutively admitted from October 1 to March 31 (pre-period 2015-2016, post-period 2016-2017) who were mechanically ventilated beyond 48 hours. A multidisciplinary team, including a family advisor, implemented the following interventions using rapid "Plan-Do-Study-Act cycles:" (a) standardized pain and sedation assessments, (b) standardized sedation goal setting, and (c) non-pharmacological strategies to manage pain and agitation. We did not implement any specific sedation protocol. We used audit and feedback to reinforce change. RESULTS: The post-intervention phase started once sedation scores were documented q12h for >60% of patients. The groups (n = 45 per group) were similar regarding demographics, severity of illness, and mechanical ventilation duration, but different in length of intensive care stay. The cumulative dose of midazolam equivalent was significantly lower in the post-intervention period (3.71 vs 2.65 mg/kg/mechanical ventilation day, P = 0.009, 95% CI: -1.12 (-1.89, -0.31)). Morphine equivalent usage went from 3.51 to 2.57 mg/kg/mechanical ventilation day (P = 0.066, 95% CI: -0.67 [-1.44, 0.05]). There were no significant pre-post-differences in the use of other sedative agents, rates of iatrogenic withdrawal syndrome or severe pain, nor medication cost. CONCLUSION: Implementation of a multifaceted QI project was successful at increasing standardized assessments of pain and agitation, and was associated with a significant reduction in midazolam use. We also observed a decrease in morphine use without increasing rates of severe pain. Incidence of iatrogenic withdrawal syndrome and cost were unchanged.

Extensive clinical experience: Hypothalamic-pituitary-adrenal axis recovery after adrenalectomy for corticotropin-independent cortisol excess.

OBJECTIVE: To identify predictors of hypothalamic-pituitary-adrenal (HPA) axis recovery interval and severity of glucocorticoid withdrawal symptoms (GWS) in patients undergoing adrenalectomy for corticotropin-independent cortisol excess. DESIGN: This is a retrospective study of patients with mild autonomous cortisol excess (MACE), moderate and severe Cushing syndrome (CS) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. RESULTS: Adrenalectomy was performed in 81 patients (79% women, median age 52 years [IQR 42-62]). HPA axis recovery occurred at a median of 4.3 months (IQR 1.6-11.4) after adrenalectomy (severe CS vs moderate CS vs MACE: median 11.4 vs 2.8 vs 2.1 months, P < 0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1-mg overnight dexamethasone suppression test >10 µg/dL or >276 nmol/L (9.7 vs 1.3 months if cortisol ≤10 µg/dL or ≤276 nmol/L, P < 0.01); body mass index (for every 3 kg/m2 decrease, glucocorticoid taper increased by 1 month, P < 0.05); age <45 (11.4 vs 2.3 months if ≥45 years, P < 0.05); duration of symptoms prior to diagnosis >1 year (11.4 vs 2.8 months if ≤1 year); moon facies (11.4 vs 2.2 months if no rounding of the face); and myopathy (13.1 vs 2.7 months if no myopathy, P < 0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P < 0.05) with a median of 1 and 0 events/patient, respectively. CONCLUSIONS: The HPA axis recovery interval was the longest for patients with severe CS. Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE. Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS. This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters.

Long-term abiraterone withdrawal syndrome.

WHAT IS KNOWN AND OBJECTIVE: Abiraterone acetate (AA) is an androgen receptor axis inhibitor, indicated together with prednisone, for metastatic castration-resistant prostate cancer. Withdrawal syndrome for classical antiandrogen treatments is well known, but not so known for AA. Abiraterone withdrawal syndrome (AWS) could be related to simultaneous prednisone discontinuation or to an androgenic effect of AA metabolites. CASE DESCRIPTION: A case is described of a patient with long-term AWS without prednisone discontinuation. The clinical and prostate-specific antigen (PSA) response allowed an 8-month delay in docetaxel treatment. WHAT IS NEW AND CONCLUSION: Prednisone did not play a role in AWS in this case. The long-term response allowed a delay in future treatment.

[Pain therapy for premature babies and neonates]. / Schmerztherapie bei Früh- und Neugeborenen.

Pain is a central topic on neonatal intensive care units (NICU). Acute as well as prolonged (continuous and chronic) pain frequently occurs. Due to a lack of validated physiological measurement instruments for pain (e. g. saliva cortisol, skin conductance and heart rate variability) pain in neonatology can only be assessed by external observation through the bedside team with pain scores using a regular, standardized procedure. During this very vulnerable period pain and medications (analgesics/sedatives) can negatively influence the brain development of premature babies and neonates. Therefore, limitation of the number of pain stimuli and the medicinal guideline "as much as necessary but as little as possible" are eminently important. When dealing with prolonged (continuous and chronic) pain, further challenges are a reduction of analgesics and sedatives as well as avoidance of withdrawal symptoms.

The use of methadone to facilitate opioid weaning in pediatric critical care patients: a systematic review of the literature and meta-analysis.

BACKGROUND: Continuous opioid infusion therapy is commonly utilized in the pediatric intensive care setting to treat pain and facilitate tolerance of invasive therapies. Transitioning to methadone is one common strategy for weaning from continuous opioid infusions, but in practice this transition can be challenging, and many children still experience iatrogenic withdrawal. AIM: We reviewed the literature to evaluate the best available evidence to guide methadone therapy in this setting, and to summarize associated adverse events. METHODS: We included all studies of methadone used to facilitate weaning from continuous opioid infusions in pediatric critical care patients, including medical, cardiac, and surgical patients, excluding case reports and studies treating neonatal abstinence syndrome, or acute or chronic pain. Medline, Embase, and CINAHL databases from inception to May 2015 were queried; references of included works and conference proceedings were also reviewed. Two authors independently extracted data from each study. Meta-analysis with fixed- and random-effects models was used to pool results of studies when applicable. RESULTS: Twelve studies involving 459 patients met criteria for inclusion. A wide variety of methadone dosing and taper strategies were reported. Mean inpatient methadone taper times varied widely, from 4.3 to 26.2 days. Excessive sedation was the most frequently reported adverse event, occurring in up to 16% of patients. Withdrawal occurred in 27% of patients among studies reporting this outcome. In three of three studies in which a new methadone protocol was introduced, a decreased proportion of patients experienced withdrawal (standardized mean difference, SMD = -0.60, 95% CI = -0.998 to -0.195, P = 0.004). CONCLUSION: We did not identify sufficient evidence to recommend any particular methadone weaning strategy, or to recommend methadone over other medications or prescribed infusion weaning, for successful weaning of continuous opioid infusions in the pediatric intensive care setting.

Development and implementation of an alcohol withdrawal protocol using a 5-item scale, the Brief Alcohol Withdrawal Scale (BAWS).

BACKGROUND: The standard of care for management of alcohol withdrawal is symptom-triggered treatment using the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). Many items of this 10-question scale rely on subjective assessments of withdrawal symptoms, making it time-consuming and cumbersome to use. Therefore, there is interest in shorter and more objective methods to assess alcohol withdrawal symptoms. METHODS: A 6-item withdrawal scale developed at another institution was piloted. Based on comparison with the CIWA-Ar, this was adapted into a 5-item scale named the Brief Alcohol Withdrawal Scale (BAWS). The BAWS was compared with the CIWA-Ar and a withdrawal protocol utilizing the BAWS was developed. The new protocol was implemented on an inpatient unit dedicated to treating substance withdrawal. Data was collected on the first 3 months of implementation and compared with the 3 months prior to that. RESULTS: A BAWS score of 3 or more predicted CIWA-Ar score ≥8 with a sensitivity of 85.3% and specificity of 65.8%. The demographics of the patients in the 2 time periods were similar: the mean age was 45.9; 70.6% were male; 30.9% received concurrent treatment for opioid withdrawal; and 14.2% were receiving methadone maintenance. During the BAWS phase, patients received significantly less diazepam (mean dose 81.4 vs. 60.3 mg, P < .001). There was no significant difference in length of stay. No patients experienced a seizure, delirium, or required transfer to a higher level of care during any of the 664 admissions in either phase. CONCLUSIONS: This simple protocol utilizing a 5-item withdrawal scale performed well in this setting. Its use in other settings, particularly with patients with concurrent medical illnesses or more severe withdrawal, needs to be explored further.

Best Practices for Intrathecal Baclofen Therapy: Troubleshooting.

INTRODUCTION: Troubleshooting helps optimize intrathecal baclofen (ITB) therapy in cases of underdose, overdose, and infection. METHODS: An expert panel of 21 multidisciplinary physicians currently managing >3200 ITB patients was convened, and using standard methodologies for guideline development, created an organized approach to troubleshooting ITB. They conducted a structured literature search that identified 263 peer-reviewed papers, and used results from an online survey of 42 physicians currently managing at least 25 ITB patients each. RESULTS: The panel developed two algorithms. The first was for loss-of-efficacy and applies to patients with previously well-controlled hypertonia on a stable dosing regimen who have increased spasticity Evaluation includes a targeted history (onset, duration, course, exacerbating/relieving factors, medications, recent procedures), physical examination (neuromuscular, vital signs, mental status), radiologic/laboratory testing (catheter imaging, noxious stimuli, infection, rising CK levels), and pump telemetry (pump interrogation, reservoir volume). Rapidly progressing hypertonia with autonomic instability or hypotonia and somnolence require emergent care and perhaps hospitalization. The second algorithm was for emergent care and describes treatment of overdose or withdrawal, which requires immediate care in a monitored setting and restoration of ITB delivery. The previous dosing schedule can be used in withdrawal of short duration; 10-20 mg every six hours can be used in longer-duration withdrawal. Supportive care includes maintenance of airway, respiration, and circulation. Seizure prevention should be considered, along with pump reprogramming or interruption, cerebrospinal fluid drainage, and sequential lumbar punctures/drains. Physostigmine and flumazenil are not usually advised. Superficial infections can be treated with oral antibiotics, and deep infections with broad-spectrum IV antibiotics (e.g., cefazolin, clindamycin, vancomycin). Explantation is often required. A new pump can be implanted in a new site under IV antibiotic coverage. CONCLUSIONS: Orderly troubleshooting helps ensure patient safety.

Nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients.

BACKGROUND: While several analgesia and sedation guidelines and protocols have been developed and implemented for adults, there is still little evidence of clinical use of analgesia and sedation protocols and the impact on withdrawal symptoms in critically ill children. OBJECTIVE: The aim of this study was to evaluate the effects of a nurse-driven goal-directed analgesia and sedation protocol for mechanically ventilated pediatric patients (pASP) on duration of mechanical ventilation, pediatric intensive care unit (PICU) length of stay, total doses of opioids and benzodiazepines, and occurrence of withdrawal symptoms. PATIENTS AND METHODS: This is a before and after protocol implementation study in a 14-bed medical-surgical-cardiac pediatric intensive care unit at a university children's hospital. A total of 337 medical pediatric patients requiring mechanical ventilation with PICU length of stay for at least 24 h were included. Prior to implementation of the protocol, analgesia and sedation was managed by the attending physician's order. Afterwards, postimplementation, nurses managed analgesia and sedation following a pASP, including COMFORT 'behavioral' Scale, Nurse Interpretation Sedation Scale, and Sophia Observation Withdrawal Symptoms Scale. RESULTS: One hundred and sixty-five patients were included in the 15-month period before and 172 patients were included in the 15-month period after implementation of the pASP. Median duration of mechanical ventilation was 2.02 (0.96-25.0) days in the group preceding protocol implementation and 1.71 (0.96-66.0) days afterwards (P = 0.23). Median PICU length of stay was 5.8 (1-37.75) days in the preimplementation and 5.0 (1-120) days in the postimplementation group (P = 0.14). Total doses of opioids and benzodiazepines were 3.9 mg·kg(-1) ·day(-1) (0.1-70) vs 3.1 mg·kg(-1) ·day(-1) (0.05-56); P = 0.38 and 5.9 mg·kg(-1) ·day(-1) (0-82.0) vs 4.2 mg·kg(-1) ·day(-1) (0-66); P = 0.009 after implementation. Incidence of withdrawal was significantly lower over the postimplementation period (12.8% vs 23.6%; P = 0.005). CONCLUSION: Implementation of a nurse-driven pASP reduced the total dose of benzodiazepines and the occurrence of withdrawal symptoms significantly.

Nicotine replacement therapy in the intensive care unit: a systematic review.

OBJECTIVE: The objective of this review was to systematically review and evaluate available literature describing the effect of nicotine replacement therapy (NRT) on mortality and other outcomes in nicotine-dependent critically ill patients admitted to the intensive care unit (ICU). DATA SOURCES: A systematic search of the following databases was performed: MEDLINE (1948-August 2011), EMBASE (1980-August 2011), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts (1970-August 2011), Google, and Google Scholar. STUDY SELECTION: Studies that reported outcomes associated with any form of NRT in any intensive care setting were included. Studies were included regardless of design or number of participants reported. Studies published in languages other than English were excluded. DATA EXTRACTION: Data from each study were extracted using a standardized data extraction tool. Information included the study design, number of patients, classification of ICU, baseline characteristics, outcomes assessed, and overall results. DATA SYNTHESIS: Our search identified 8 studies, of which 7 met the inclusion criteria. These 7 studies were qualitatively reviewed and critically appraised for methodological quality, robustness of results, and internal and external validity. The results of similar studies and populations were compared in order to draw conclusions pertaining to specific intensive care settings. CONCLUSIONS: We conclude that NRT should not be routinely prescribed to patients admitted to intensive care settings. With only equivocal evidence of efficacy and signals suggesting increased toxicity, we believe that its use should be limited to selected patients where the potential benefit clearly outweighs the risk. There is a need for adequately powered randomized controlled trials to confirm the benefits and risks of NRT in the ICU overall but also in its unique subpopulations.

High doses of benzodiazepine predict analgesic and sedative drug withdrawal syndrome in paediatric intensive care patients.

AIM: Critically ill children can develop withdrawal syndrome after prolonged analgesia and sedation in a paediatric intensive care unit (PICU), when treatment is stopped abruptly or reduced quickly. The aim of this study was to evaluate the incidence of withdrawal syndrome in patients after three or more days of analgesic or sedative drug therapy, using a validated scale. We also analysed the association between withdrawal syndrome and the patients' outcome and factors related to analgesia and sedation treatment. METHODS: This prospective observational study analysed 89 periods of weaning from analgesia and sedation in 60 children between October 2010 and October 2011. Of these, 65% were less than six months old and 45% were admitted to the PICU after heart surgery. Withdrawal syndrome was assessed using the Withdrawal Assessment Tool-1 (WAT-1) scale. RESULTS: The incidence of withdrawal syndrome was 37%, and the only variable that predicted its presence was the highest administered dose of benzodiazepine. The duration of weaning, Sophia Observational Withdrawal Symptom scale score and nurse judgment were also associated with positive WAT-1 scores. CONCLUSION: Withdrawal syndrome should be considered after three or more days of analgesic or sedative treatment. A high dose of benzodiazepine increases the risk of developing withdrawal symptoms.

Post-Overdose Extended-Release Buprenorphine Initiation Facilitated by a Partnership Between Emergency Medical Services and an Outpatient Substance Use Disorder Observation Unit.

BACKGROUND: People who experience a nonfatal opioid overdose and receive naloxone are at high risk of subsequent overdose death but experience gaps in access to medications for opioid use disorder. The immediate post-naloxone period offers an opportunity for buprenorphine initiation. Limited data indicate that buprenorphine administration by emergency medical services (EMS) after naloxone overdose reversal is safe and feasible. We describe a case in which a partnership between a low-barrier substance use disorder (SUD) observation unit and EMS allowed for buprenorphine initiation with extended-release injectable buprenorphine after naloxone overdose reversal. CASE: A man in his 40's with severe opioid use disorder and numerous prior opioid overdoses experienced overdose in the community. EMS was activated and he was successfully resuscitated with intranasal naloxone, administered by bystanders and EMS. He declined emergency department (ED) transport and consented to transport to a 24/7 SUD observation unit. The patient elected to start buprenorphine due to barriers attending opioid treatment programs daily. His largest barrier was unsheltered homelessness. His severe opioid withdrawal symptoms were successfully treated with 16/4 mg sublingual buprenorphine/naloxone and 300 mg extended-release injectable buprenorphine (XR-buprenorphine), without precipitated withdrawal. Two weeks later, he reported no interval fentanyl use. DISCUSSION: We describe the case of a patient successfully initiated onto XR-buprenorphine in the immediate post-naloxone period via a partnership between an outpatient low-barrier addiction programs and EMS. Such partnerships offer promise in expanding buprenorphine access and medication choice, particularly for the high-risk population of patients who decline ED transport.

Clinical detoxification of bromazolam using diazepam: a case report.

An increasing number of new psychoactive substances (NPS), such as designer benzodiazepines, are becoming available on the recreational drug market. These are new unregistered substances and thereby an attempt to evade legislation. Often there is very limited clinical information available regarding these NPS, which could result in undesirable clinical outcomes in the management of intoxications, dependencies and withdrawals following NPS use. In this case report we describe a 23-year-old woman, who was admitted to our residential addiction care facility for the detoxification of the designer benzodiazepine bromazolam. Her daily use of 6 mg bromazolam was converted to 20 mg diazepam. Although we expected a higher dose would have been needed, 20 mg was sufficient and was tapered without complications. This case report demonstrates the safe conversion of 6 mg of bromazolam to 20 mg of diazepam by combining the use of fixed-dose and symptom-triggered-dose regimens. More clinical data is necessary to formulate advisory management for the detoxification of bromazolam and other designer benzodiazepines.

Practices and Outcomes Associated With Sublingual Buprenorphine Use in a Critically Ill Population.

IMPORTANCE: Buprenorphine for opioid use disorder (OUD) is commonly used in the outpatient setting with increasing use in hospitalized patients. However, there is limited literature describing its use in critically ill populations. OBJECTIVES: The primary objective was to report the practices of buprenorphine prescribing among ICU teams. We also assessed the effect of a novel initiation strategy on opioid requirements in the ICU and the incidence of precipitated withdrawal. DESIGN SETTING PARTICIPANTS: Single-center, retrospective, descriptive study of patients receiving buprenorphine in the ICU. MAIN OUTCOMES AND MEASURES: The main outcome was to describe the use of buprenorphine in ICU patients through indication, initiation strategy, dosing information, and time from ICU admission to the first dose. We also detailed the incidence of precipitated withdrawal overall and the difference in opioid requirements before and after a low-dose induction strategy (buprenorphine initiated while receiving full agonist opioids [5-d titration from 150 µg to 4 mg four times daily]). RESULTS: A total of 153 patients were included. Most patients (86.3%) received buprenorphine for treatment of OUD. Of the 75 patients taking buprenorphine before admission, 46 (61%) had it restarted within 24 hours of ICU admission. Among 95 patients requiring buprenorphine induction, 57 (60%) underwent standard induction and 38 (40%) underwent low-dose induction, with only one instance of precipitated withdrawal. Median morphine milligram equivalents (MMEs) of concomitant full agonist opioids in patients completing low-dose induction decreased from 1057.5 mg to 262.5 mg in the 24 hours before initiation compared with the 24 hours after target buprenorphine dose was reached (p < 0.005). CONCLUSIONS AND RELEVANCE: Use of sublingual buprenorphine was most often in patients with OUD. Timely continuation of home buprenorphine in the ICU was suboptimal. Both standard and low-dose induction strategies appear to be safe with a low risk of precipitating withdrawal. When implemented appropriately, low-dose buprenorphine induction may lead to significant reduction in full agonist opioids in critically ill patients.

Alcohol Withdrawal Severity Measures for Identifying Patients Requiring High-Intensity Care.

OBJECTIVES: Alcohol withdrawal syndrome (AWS) may progress to require high-intensity care. Approaches to identify hospitalized patients with AWS who received higher level of care have not been previously examined. This study aimed to examine the utility of Clinical Institute Withdrawal Assessment Alcohol Revised (CIWA-Ar) for alcohol scale scores and medication doses for alcohol withdrawal management in identifying patients who received high-intensity care. DESIGN: A multicenter observational cohort study of hospitalized adults with alcohol withdrawal. SETTING: University of Chicago Medical Center and University of Wisconsin Hospital. PATIENTS: Inpatient encounters between November 2008 and February 2022 with a CIWA-Ar score greater than 0 and benzodiazepine or barbiturate administered within the first 24 hours. The primary composite outcome was patients who progressed to high-intensity care (intermediate care or ICU). INTERVENTIONS: None. MAIN RESULTS: Among the 8742 patients included in the study, 37.5% (n = 3280) progressed to high-intensity care. The odds ratio for the composite outcome increased above 1.0 when the CIWA-Ar score was 24. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at this threshold were 0.12 (95% CI, 0.11-0.13), 0.95 (95% CI, 0.94-0.95), 0.58 (95% CI, 0.54-0.61), and 0.64 (95% CI, 0.63-0.65), respectively. The OR increased above 1.0 at a 24-hour lorazepam milligram equivalent dose cutoff of 15 mg. The sensitivity, specificity, PPV, and NPV at this threshold were 0.16 (95% CI, 0.14-0.17), 0.96 (95% CI, 0.95-0.96), 0.68 (95% CI, 0.65-0.72), and 0.65 (95% CI, 0.64-0.66), respectively. CONCLUSIONS: Neither CIWA-Ar scores nor medication dose cutoff points were effective measures for identifying patients with alcohol withdrawal who received high-intensity care. Research studies for examining outcomes in patients who deteriorate with AWS will require better methods for cohort identification.