Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

Statewide Emergency Medical Services Protocols for Status Epilepticus Management.

Although seizures are common in prehospital settings, standardized emergency medical services (EMS) treatment algorithms do not exist nationally. We examined nationwide variability in status epilepticus treatment by analyzing 33 publicly available statewide EMS protocols. All adult protocols recommend intravenous benzodiazepines (midazolam, n = 33; lorazepam, n = 23; diazepam, n = 24), 30 recommend intramuscular benzodiazepines (midazolam, n = 30; lorazepam, n = 8; diazepam, n = 3), and 27 recommend intranasal benzodiazepines (midazolam, n = 27; lorazepam, n = 3); pediatric protocols also frequently recommend rectal diazepam (n = 14). Recommended dosages vary widely, and first- and second-line agents are designated in only 18 and 2 states, respectively. Given this degree of variability, standardized national EMS guidelines are needed. ANN NEUROL 2021;89:604-609.

Effects of Oral Administration of Alprazolam and Lorazepam as Hypnotics on Cardiovascular Parameters in Hypertensive Patients.

BACKGROUND: Previous studies have suggested that evening intake of benzodiazepine affects blood pressure (BP) and/or heart rate (HR) in healthy and hypertensive subjects. The aim of this study was to compare the effect of chronic oral administration of alprazolam and lorazepam as hypnotics on ambulatory BP and HR in patients with mild hypertension. METHODS: Consecutive outpatients of both sexes with newly diagnosed, never-treated mild hypertension were randomized, after a 4-week placebo run-in period, to receive alprazolam 0.5 mg plus placebo, lorazepam 1 mg plus placebo, or placebo plus placebo for 2 weeks in 3 crossover periods, each separated by a 1-week placebo wash-out period. At the end of the initial placebo run-in and of each treatment period, 24-hour ambulatory BP and HR monitoring was performed using a noninvasive device. RESULTS: In the 32 patients, no treatment had any effect on 24-hour and daytime systolic BP (SBP), diastolic BP (DBP), and HR, which remained unchanged. During the nighttime, SBP and DBP values were unaffected by alprazolam, as compared with placebo, whereas DBP was significantly higher after treatment with lorazepam (+3.7%, P < 0.05 vs placebo). Nocturnal HR mean values were significantly increased by lorazepam (+10.1%, P < 0.01 vs placebo), whereas they did not change after alprazolam. CONCLUSIONS: In patients with mild hypertension, oral intake of alprazolam or lorazepam as hypnotics did not affect ambulatory BP or HR values. A slight increase in nighttime DBP was observed with lorazepam, whereas alprazolam showed no effect on nocturnal BP and HR, probably reflecting a stimulating effect of the drug on central α2-receptors.

Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial.

OBJECTIVE: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent. RESULTS: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures. SIGNIFICANCE: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.).

Concomitant lorazepam use and antidepressive efficacy of repetitive transcranial magnetic stimulation in a naturalistic setting.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective therapeutic intervention for the treatment of depression. Preliminary data suggest that the efficacy of rTMS is reduced in patients taking benzodiazepines (BZD). Here, we use real-world data from a large sample to investigate the influence of lorazepam on the effectiveness of rTMS. METHODS: From a retrospective cohort of clinically depressed patients that were treated with rTMS, we compared 176 patients not taking any BZD with 73 patients taking lorazepam with respect to changes in the Hamilton Depression Rating Scale (HRDS). RESULTS: Both groups improved during rTMS according to HRDS scores, but the amelioration of symptoms was significantly less pronounced in patients taking lorazepam (18% vs. 38% responders in the non-lorazepam group). We could not see any association of intake regimen of lorazepam with response in rTMS. CONCLUSION: Our observational study suggests that intake of lorazepam impedes the response to rTMS. The impact of lorazepam and other BZD on rTMS should receive more attention and be further investigated in prospective, hypothesis-based treatment studies to determine causal relationships between medication treatments and outcome. This could lead to specific recommendations for pharmacological treatment for depressed patients undergoing rTMS.

Front-loaded diazepam versus lorazepam for treatment of alcohol withdrawal agitated delirium.

BACKGROUND: Front-loaded diazepam is used to rapidly control agitation in patients with severe alcohol withdrawal syndrome (AWS). Our institution began using front-loaded lorazepam in August 2017 secondary to a nation-wide shortage of intravenous (IV) diazepam. Currently, there are no studies comparing lorazepam to diazepam for frontloading in severe AWS. METHOD: Retrospective cohort study of all adults presenting to the emergency department with a diagnosis of AWS and prescribed the institution's alcohol withdrawal agitated delirium protocol 8 months pre and post shortage of IV diazepam were eligible inclusion for the study. Of these, 106 patients were front-loaded with diazepam and 70 patients were front-loaded with lorazepam. RESULTS: There was no difference in the mean change in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised scores 24 h pre and post front-loading in the two groups (-13.9 ± -8.08 vs. -13.1 ± -8.91, p = 0.534). Patients who received front-loaded lorazepam had an increased incidence of ICU-delirium (positive for the Confusion Assessment Method in the ICU: 75% with lorazepam vs. 52.6% with diazepam, p = 0.009) and a higher risk of over-sedation, but this did not reach statistical significance (Richmond Agitation-Sedation Scale score < -1: 32.1% with lorazepam vs. 18.2% with diazepam, p = 0.063). CONCLUSION: Front-loaded lorazepam was similar to front-loaded diazepam in controlling AWS symptoms. Lorazepam's delayed onset of action should be considered when determining how quickly repeat doses are administered to avoid the potential for adverse drug events.

Treatment of opioid and alcohol withdrawal in a cohort of emergency department patients.

BACKGROUND: The safety of combining buprenorphine with a benzodiazepine or barbiturate in the treatment of concurrent alcohol and opioid withdrawal has not been well established. In this study we examine a cohort of patients treated with buprenorphine and phenobarbital or benzodiazepines for co-occurring opioid and alcohol withdrawal. METHODS: This is a retrospective cohort study of ED patients treated for opioid and alcohol withdrawal from January through December 2018. The primary outcome was unexpected airway intervention, or the administration of naloxone for respiratory depression. RESULTS: There were 16 patients treated for opioid and alcohol withdrawal. The mean age was 44.3 (standard deviation [SD] 13.1), 12 (75.0%) were male, and 8 (50.0%) of the patients were admitted to the hospital. For opioid withdrawal, six patients received intravenous buprenorphine, with doses between 0.3 mg to 1.8 mg; 12 patients received sublingual buprenorphine, with doses between 4 mg to 32 mg. For alcohol withdrawal, 10 patients received lorazepam with doses between 1 mg and 8 mg; 10 patients received phenobarbital with doses between 260 mg to 1040 mg. There were no unexpected airway interventions related to medications used for opioid or alcohol withdrawal. One patient with severe pneumonia was an expected intubation for respiratory failure. CONCLUSIONS: We describe a cohort of patients treated for opioid and alcohol withdrawal in the ED. There were no serious adverse events related to the medications used to treat opioid or alcohol withdrawal. Further work should assess optimal use of medical therapy for opioid and alcohol withdrawal and the transition to maintenance treatment for substance use disorders.

Efficacy of ketamine for initial control of acute agitation in the emergency department: A randomized study.

BACKGROUND: Clinicians often encounter agitated patients, and current treatment options include benzodiazepines and antipsychotics. Ketamine rapidly induces dissociation, maintains cardiovascular stability, spontaneous respirations, and airway reflexes. There are no prospective, randomized studies comparing ketamine to other agents in the initial management of acute agitation in the Emergency Department (ED). OBJECTIVE: Determine the efficacy and safety of ketamine compared to parenteral haloperidol plus lorazepam for initial control of acute agitation. METHODS: This study was a prospective, single-institution, randomized, open-label, real world, standard of care pilot study. Adult patients with combative agitation were randomized to ketamine (4 mg/kg IM or 1 mg/kg IV) or haloperidol/lorazepam (haloperidol 5-10 mg IM or IV + lorazepam 1-2 mg IM or IV). The primary outcome was sedation within 5 min, and secondary outcomes included sedation within 15 min, time to sedation, and safety. RESULTS: Ninety three patients were enrolled from January 15, 2018 to October 10, 2018. Significantly more patients who received ketamine compared to haloperidol/lorazepam were sedated within 5 min (22% vs 0%, p = 0.001) and 15 min (66% vs 7%, p < 0.001). The median time to sedation in patients who received ketamine compared to haloperidol/lorazepam was 15 vs 36 min respectively (p < 0.001). Patients who received ketamine experienced a significant, but transient tachycardia (p = 0.01) and hypertension (p = 0.01). CONCLUSION: In patients with combative agitation, ketamine was significantly more effective than haloperidol/lorazepam for initial control of acute agitation, and was not associated with any significant adverse effects.

Neurochemical and behavioral effects of lorazepam: A dose related study.

Present study was designed to monitor the dose dependent effects of lorazepam; a benzodiazepine (CNS depressant). It is the primary drug of choice for treatment of anxiety and to produce calming effects. However, repeated administration of this lorazepam causes dependence and this might be caused by increased dopaminergic neurotransmission. Besides dopamine, 5-hydroxy tryptamine (5-HT) has also been reported to have pivotal role in the pathophysiology as well as treatment of anxiety and addiction. Repeated administration of lorazepam might involve altered 5-HT metabolism as well. Present study was therefore designed to monitor dose-dependent effects of lorazepam and to select its optimum dose for further experiments and pharmacological interventions. Effects of lorazepam were monitored on food intake, growth rate, activities in familiar and novel environments, light dark box activity, forced swim test and metabolism of dopamine and 5-HT. oral administration of lorazepam was done at the doses of 0mg/kg, 2mg/kg, 4mg/kg and 6mg/kg. Behaviors parameters were monitored following single administration of lorazepam. Rats were decapitated and whole brain samples were collected and stored at -70°C until neurochemical analysis by HPLC-EC. Findings from the present study could be implicated to increased therapeutic utility of lorazepam and related benzodiazepines.

Intranasal Lorazepam for Treatment of Severe Agitation in a Pediatric Behavioral Health Patient in the Emergency Department.

The treatment of severe agitation, aggression, and violent behavior in behavioral health patients who present to the emergency department (ED) often requires the intramuscular administration of a sedative. However, administering an intramuscular sedative to an uncooperative patient is associated with the risk of needlestick injuries to both patients and health care providers, and times to onset of sedation range from 15 to 45 minutes. Intranasal absorption is more rapid than intramuscular, with sedatives such as lorazepam reaching peak serum concentrations up to 6 times faster when administered intranasally. We present the first report of using intranasal lorazepam as a needle-free method of providing rapid and effective sedation to treat severe agitation in a pediatric behavioral health patient presenting to the ED.

Randomized open-label trial of intravenous brivaracetam versus lorazepam for acute treatment of increased seizure activity.

OBJECTIVE: The objective of the present trial was to assess efficacy and safety of intravenous (IV) brivaracetam (BRV) vs. lorazepam (LZP) in patients with epilepsy undergoing evaluation in an epilepsy monitoring unit (EMU) who experienced seizures requiring acute treatment. METHODS: This was a phase 2, open-label, randomized, active-control, proof-of-concept trial (EP0087; NCT03021018). Patients (18-70 years) admitted to EMU were randomized 1:1:1 to single-dose bolus IV LZP (dose per investigator's practice), IV BRV 100 mg, or IV BRV 200 mg. Trial medication had to be administered within 30 min of qualifying seizure. Primary efficacy outcome was time to next seizure (clinical observation with electroencephalogram [EEG] confirmation) or to rescue medication use within 12 h of trial medication administration. Secondary outcomes included seizure freedom and rescue medication use within 12 h of trial medication administration. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Overall, 46 patients were randomized, and 45 received trial medication for a qualifying seizure. Patients in the LZP arm had doses from 1 to 4 mg (median: 1 mg). Eleven of 45 patients had a seizure within 12 h of trial medication administration (LZP 5/15 [median time to next seizure: 5.55 h], BRV 100 mg 3/15 [5.97 h], BRV 200 mg 3/15 [3.60 h]). No patients received additional rescue medication to control their qualifying seizure. Most patients were seizure-free over 12 h (LZP 9/15 [60.0%], BRV 100 mg 12/15 [80.0%], BRV 200 mg 12/15 [80.0%]). Rescue medication use within 12 h was numerically higher for LZP (6/15 [40.0%]) vs. BRV 100 mg (1/15 [6.7%]) and vs. BRV 200 mg (2/15 [13.3%]). Treatment-emergent adverse events were reported by 5/16 (31.3%), 6/15 (40.0%), and 3/15 (20.0%) of LZP, BRV 100 mg, and BRV 200 mg patients; one LZP patient had a serious TEAE (seizure cluster). Most common TEAEs (≥10% of patients) were sedation and somnolence with LZP, and dizziness, headache, and nausea with BRV. SIGNIFICANCE: Intravenous LZP, IV BRV 100 mg, and IV BRV 200 mg showed similar efficacy in controlling acute seizure activity in the EMU. Treatment-emergent adverse events were as expected for each medication. Although this trial should be interpreted with caution because of small patient numbers, it suggests a possible role of BRV in the acute treatment of increased seizure activity.

Comparison of intranasal midazolam versus intravenous lorazepam for seizure termination and prevention of seizure clusters in the adult epilepsy monitoring unit.

OBJECTIVE: The objective of the study was to compare the performance of intravenous (IV) lorazepam (IVL) and intranasal midazolam (INM) for seizure termination and prevention of seizure clusters in adults admitted to the epilepsy monitoring unit (EMU) in whom seizures were captured on continuous video-electroencephalogram. METHODS: Retrospective cohort of consecutive adults (≥18 years) with epilepsy admitted to the EMU at a single tertiary academic center, who experienced epileptic seizures (confirmed electroencephalographically) and required rescue therapy. The study spanned from January 2015 until December 2016, which included one year before and one year after transitioning from IVL to INM as the standard rescue therapy at our institution. RESULTS: A total of 50 subjects received rescue therapy and were included in the analysis. In the first year, out of 216 patients with epilepsy admitted to the EMU, 27 (13%) received IVL; in the second year, 23/217 (11%) received INM. There were no differences in baseline characteristics and markers of epilepsy severity, the median duration of index seizure (1.7 min [interquartile range (IQR): 1.1-2.7] in IVL vs. 2.0 min [IQR: 1.5-2.6] in INM group, p = 0.20), or in the number of subjects requiring repeat benzodiazepine administrations (IVL 8/27 [29.6%] vs. INM 7/23 [30.4%], p = 0.95). There were no differences in the median number of recurrent seizures in 24 h (1 [IQR: 1-3] in IVL vs. 2 [IQR: 1-4] in INM, p = 0.27), occurrence of status epilepticus (IVL 4/27 [14.8%] subjects vs. INM 1/23 [4.3%] subjects, p = 0.36), incidence of seizure clusters (IVL 8/27 [29.6%] subjects vs. INM 7/23 [30.4%] subjects, p = 0.95), need for transfer to an intensive care unit (ICU), or other adverse events. SIGNIFICANCE: In our retrospective study, INM was comparable with IVL for seizure termination and prevention of seizure clusters in the adult EMU. Intranasal midazolam circumvents the need for IV access to be maintained throughout hospitalization and is an attractive alternative to IVL as a rescue therapy in this setting. Ideally, future large, prospective, randomized, and double blind studies are needed to confirm these findings.

Retrospective analysis of a gabapentin high dose taper compared to lorazepam in acute inpatient alcohol withdrawal.

Background: Benzodiazepines have remained the standard of care for alcohol withdrawal syndrome; however, they have numerous unfavorable physiologic effects. Gabapentin has limited data to support a benefit in reducing benzodiazepine usage in alcohol withdrawal syndrome.Objectives: Evaluate the association of an institutional guideline and order set for alcohol withdrawal that incorporates high dose gabapentin tapers in acutely withdrawing patients. Methods: This retrospective study evaluated patients experiencing acute alcohol withdrawal. Two time periods were evaluated: a pre-protocol group assessed outcomes prior to implementation of a gabapentin backbone taper-based guideline (PRE-implementation), and a post-protocol group assessed post-guideline and order set introduction (POST-implementation). A total of 100 patients (50 PRE-implementation and 50 POST-implementation; 84% male, 16% female) were included in the analysis. Results: There was a significant difference in the median daily lorazepam usage in the PRE-implementation versus POST-implementation groups (9.48 [5.58-28.46] vs 6.52 [3.84-11.65] mg, P = 0.024) with a reduction observed in the POST-implementation group. There was also a significant difference in the mean hospital length of stay (LOS) in the PRE-implementation versus POST-implementation groups (9.92 ± 7.33 vs 7.04 ± 4.59 days, P = 0.021) in favor of the POST-implementation group. There was no difference in the number of rapid responses called, median intensive care unit (ICU) LOS, median number of days the patient was confusion assessment method for the ICU (CAM-ICU) positive or number of transfers to a higher level of care. Conclusions: Implementation of an institutional guideline and order set for alcohol withdrawal incorporating high dose gabapentin tapers was associated with a decreased median daily lorazepam use as well as hospital LOS; however, retrospective design and inherent limitations require larger prospective trials to validate results.

Active Seizures in Children Are Often Subtle and Unrecognized by Prehospital Providers.

Early recognition and treatment of seizures is essential for optimal patient outcomes. Seizure activity, particularly in young children, can be subtle and often go unrecognized by providers. This case series retrospectively identified 7 cases of pediatric patients (14 years and younger) who presented to the emergency department with active seizure activity that was unrecognized by the prehospital care providers. The presentation of these patients, their clinical signs of seizure, and emergency department disposition are highlighted in this series.

Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children.

BACKGROUND: Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and require urgent and appropriate anticonvulsant treatment. International consensus is that an anticonvulsant drug should be administered for any tonic-clonic convulsion that has been continuing for at least five minutes. Benzodiazepines (diazepam, lorazepam, midazolam) are traditionally regarded as first-line drugs and phenobarbital, phenytoin and paraldehyde as second-line drugs. This is an update of a Cochrane Review first published in 2002 and updated in 2008. OBJECTIVES: To evaluate the effectiveness and safety of anticonvulsant drugs used to treat any acute tonic-clonic convulsion of any duration, including established convulsive (tonic-clonic) status epilepticus in children who present to a hospital or emergency medical department. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (23 May 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 May 2017), MEDLINE (Ovid, 1946 to 23 May 2017), ClinicalTrials.gov (23 May 2017), and the WHO International Clinical Trials Registry Platform (ICTRP, 23 May 2017). SELECTION CRITERIA: Randomised and quasi-randomised trials comparing any anticonvulsant drugs used for the treatment of an acute tonic-clonic convulsion including convulsive status epilepticus in children. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. We contacted study authors for additional information. MAIN RESULTS: The review includes 18 randomised trials involving 2199 participants, and a range of drug treatment options, doses and routes of administration (rectal, buccal, nasal, intramuscular and intravenous). The studies vary by design, setting and population, both in terms of their ages and also in their clinical situation. We have made many comparisons of drugs and of routes of administration of drugs in this review; our key findings are as follows:(1) This review provides only low- to very low-quality evidence comparing buccal midazolam with rectal diazepam for the treatment of acute tonic-clonic convulsions (risk ratio (RR) for seizure cessation 1.25, 95% confidence interval (CI) 1.13 to 1.38; 4 trials; 690 children). However, there is uncertainty about the effect and therefore insufficient evidence to support its use. There were no included studies which compare intranasal and buccal midazolam.(2) Buccal and intranasal anticonvulsants were shown to lead to similar rates of seizure cessation as intravenous anticonvulsants, e.g. intranasal lorazepam appears to be as effective as intravenous lorazepam (RR 0.96, 95% CI 0.82 to 1.13; 1 trial; 141 children; high-quality evidence) and intranasal midazolam was equivalent to intravenous diazepam (RR 0.98, 95% CI 0.91 to 1.06; 2 trials; 122 children; moderate-quality evidence).(3) Intramuscular midazolam also showed a similar rate of seizure cessation to intravenous diazepam (RR 0.97, 95% CI 0.87 to 1.09; 2 trials; 105 children; low-quality evidence).(4) For intravenous routes of administration, lorazepam appears to be as effective as diazepam in stopping acute tonic clonic convulsions: RR 1.04, 95% CI 0.94 to 1.16; 3 trials; 414 children; low-quality evidence. Furthermore, we found no statistically significant or clinically important differences between intravenous midazolam and diazepam (RR for seizure cessation 1.08, 95% CI 0.97 to 1.21; 1 trial; 80 children; moderate-quality evidence) or intravenous midazolam and lorazepam (RR for seizure cessation 0.98, 95% CI 0.91 to 1.04; 1 trial; 80 children; moderate-quality evidence). In general, intravenously-administered anticonvulsants led to more rapid seizure cessation but this was usually compromised by the time taken to establish intravenous access.(5) There is limited evidence from a single trial to suggest that intranasal lorazepam may be more effective than intramuscular paraldehyde in stopping acute tonic-clonic convulsions (RR 1.22, 95% CI 0.99 to 1.52; 160 children; moderate-quality evidence).(6) Adverse side effects were observed and reported very infrequently in the included studies. Respiratory depression was the most common and most clinically relevant side effect and, where reported, the frequency of this adverse event was observed in 0% to up to 18% of children. None of the studies individually demonstrated any difference in the rates of respiratory depression between the different anticonvulsants or their different routes of administration; but when pooled, three studies (439 children) provided moderate-quality evidence that lorazepam was significantly associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93).Much of the evidence provided in this review is of mostly moderate to high quality. However, the quality of the evidence provided for some important outcomes is low to very low, particularly for comparisons of non-intravenous routes of drug administration. Low- to very low-quality evidence was provided where limited data and imprecise results were available for analysis, methodological inadequacies were present in some studies which may have introduced bias into the results, study settings were not applicable to wider clinical practice, and where inconsistency was present in some pooled analyses. AUTHORS' CONCLUSIONS: We have not identified any new high-quality evidence on the efficacy or safety of an anticonvulsant in stopping an acute tonic-clonic convulsion that would inform clinical practice. There appears to be a very low risk of adverse events, specifically respiratory depression. Intravenous lorazepam and diazepam appear to be associated with similar rates of seizure cessation and respiratory depression. Although intravenous lorazepam and intravenous diazepam lead to more rapid seizure cessation, the time taken to obtain intravenous access may undermine this effect. In the absence of intravenous access, buccal midazolam or rectal diazepam are therefore acceptable first-line anticonvulsants for the treatment of an acute tonic-clonic convulsion that has lasted at least five minutes. There is no evidence provided by this review to support the use of intranasal midazolam or lorazepam as alternatives to buccal midazolam or rectal diazepam.

Implementation of a Risk-Stratified Opioid and Benzodiazepine Weaning Protocol in a Pediatric Cardiac ICU.

OBJECTIVES: Opioids and benzodiazepines are commonly used to provide analgesia and sedation for critically ill children with cardiac disease. These medications have been associated with adverse effects including delirium, dependence, withdrawal, bowel dysfunction, and potential neurodevelopmental abnormalities. Our objective was to implement a risk-stratified opioid and benzodiazepine weaning protocol to reduce the exposure to opioids and benzodiazepines in pediatric patients with cardiac disease. DESIGN: A prospective pre- and postinterventional study. PATIENTS: Critically ill patients less than or equal to 21 years old with acquired or congenital cardiac disease exposed to greater than or equal to 7 days of scheduled opioids ± scheduled benzodiazepines between January 2013 and February 2015. SETTING: A 24-bed pediatric cardiac ICU and 21-bed cardiovascular acute ward of an urban stand-alone children's hospital. INTERVENTION: We implemented an evidence-based opioid and benzodiazepine weaning protocol using educational and quality improvement methodology. MEASUREMENTS AND MAIN RESULTS: One-hundred nineteen critically ill children met the inclusion criteria (64 post intervention, 55 pre intervention). Demographics and risk factors did not differ between groups. Patients in the postintervention period had shorter duration of opioids (19.0 vs 30.0 d; p < 0.01) and duration of benzodiazepines (5.3 vs 22.7 d; p < 0.01). Despite the shorter duration of wean, there was a decrease in withdrawal occurrence (% Withdrawal Assessment Tool score ≥ 4, 4.9% vs 14.1%; p < 0.01). There was an 8-day reduction in hospital length of stay (34 vs 42 d; p < 0.01). There was a decrease in clonidine use (14% vs 32%; p = 0.02) and no change in dexmedetomidine exposure (59% vs 75%; p = 0.08) in the postintervention period. CONCLUSIONS: We implemented a risk-stratified opioid and benzodiazepine weaning protocol for critically ill cardiac children that resulted in reduction in opioid and benzodiazepine duration and dose exposure, a decrease in symptoms of withdrawal, and a reduction in hospital length of stay.

Evaluation of IV to Enteral Benzodiazepine Conversion Calculations in a Pediatric Intensive Care Setting.

OBJECTIVES: To evaluate if institutionally established calculations for transitioning continuous IV midazolam to enteral benzodiazepines maintain Withdrawal Assessment Tool-Version 1 scores equal to or less than preconversion values. DESIGN: Retrospective cohort study evaluating the effectiveness and safety of benzodiazepine conversion calculations embedded within an institution-specific clinical pathway for sedation and weaning of mechanically ventilated pediatric patients. SETTING: A 55-bed, mixed-medical, noncardiac surgical PICU in a tertiary care children's hospital. PATIENTS: All patients age 6 months to 18 years who received continuous midazolam for 5 days or longer while mechanically ventilated for 5-21 days and were then converted to either enteral diazepam or lorazepam following extubation (or return to baseline ventilator settings in tracheostomy-dependent patients) between January 1, 2015, and June 30, 2016. INTERVENTIONS: Benzodiazepine conversion calculations were applied according to institutional clinical pathway guidance. MEASUREMENTS AND MAIN RESULTS: Withdrawal Assessment Tool-Version 1 scores were compared pre and post benzodiazepine conversion. Patient demographics, benzodiazepine dose escalations, as needed benzodiazepine requirements, and severe adverse events within 48 hours of conversion were assessed. Seventy-one patient encounters were analyzed (median age, 2.5 yr; interquartile range, 1.2-5.3). The median Withdrawal Assessment Tool-Version 1 scores pre conversion and post conversion were not significantly different (1 [interquartile range, 0.75-2] and 1 [interquartile range, 0.25-2], respectively, p = 0.1). As needed benzodiazepine doses were administered in 38% of encounters post conversion, but escalation of a scheduled enteral benzodiazepine regimen was only required in 2.8% of encounters. Post conversion, one patient (1.4%) had increased seizure activity, and four patients (5.6%) required fluid boluses secondary to tachycardia or dehydration, but not hypotension. CONCLUSIONS: These findings suggest that standardized benzodiazepine conversions successfully achieved consistent Withdrawal Assessment Tool-Version 1 scores compared with preconversion values. Severe adverse events associated with oversedation and/or withdrawal were minimal and confounded by underlying disease states.

A Symptom-Triggered Benzodiazepine Protocol Utilizing SAS and CIWA-Ar Scoring for the Treatment of Alcohol Withdrawal Syndrome in the Critically Ill.

BACKGROUND: There are limited data on the efficacy of symptom-triggered therapy for alcohol withdrawal syndrome (AWS) in the intensive care unit (ICU). OBJECTIVE: To evaluate the safety and efficacy of a symptom-triggered benzodiazepine protocol utilizing Riker Sedation Agitation Scale (SAS) scoring for the treatment of AWS in the ICU. METHODS: We performed a before-and-after study in a medical ICU. A protocol incorporating SAS scoring and symptom-triggered benzodiazepine dosing was implemented in place of a protocol that utilized the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scale and fixed benzodiazepine dosing. RESULTS: We enrolled 167 patients (135 in the preintervention and 32 in the postintervention group). The median duration of AWS was shorter in the postintervention (5, interquartile range [IQR] = 4-8 days) than in the preintervention group (8, IQR = 5-12 days; P < 0.01). Need for mechanical ventilation (31% vs 57%, P = 0.01), median ICU length of stay (LOS; 4, IQR = 2-7, vs 7, IQR = 4-11 days, P = 0.02), and hospital LOS (9, IQR = 6-13, vs 13, IQR = 9-18 days; P = 0.01) were less in the postintervention group. There was a reduction in mean total benzodiazepine exposure (74 ± 159 vs 450 ± 701 mg lorazepam; P < 0.01) in the postintervention group. CONCLUSION: A symptom-triggered benzodiazepine protocol utilizing SAS in critically ill patients is associated with a reduction in the duration of AWS treatment, benzodiazepine exposure, need for mechanical ventilation, and ICU and hospital LOS compared with a CIWA-Ar-based protocol using fixed benzodiazepine dosing.

Intramuscular Lorazepam for Status Epilepticus in Children With Complex Medical and Physical Disabilities.

BACKGROUND: A protocol was developed to achieve status epilepticus (SE) resolution: step 1, intramuscular (IM) lorazepam; step 2, repeat IM lorazepam; step 3, rectal diazepam. OBJECTIVE: The primary objective was to identify the number of patients with SE resolution after step 1. Secondary objectives included categorization of mean number of IM doses per episode and patient factors associated with SE resolution. METHODS: This was a retrospective study of patients <21 years old with complex medical and physical disabilities admitted over 5 years. For analysis, IM dosing was categorized as high dose (>0.05 mg/kg/dose) and low dose (≤0.05 mg/kg/dose). A generalized linear mixed-model regression was used to assess the relationship with SE resolution at step 1 and patient characteristics. RESULTS: A total of 44 patients were included (n = 162 episodes). SE resolution was noted in 68.5% of episodes after step 1. Models were stratified by gender to present odds of SE resolution at step 1 versus step 2/3. For women, no covariate was significant. For men, the odds of SE resolution at step 1 were 14.9 times higher in those receiving 2 versus 4 maintenance antiepileptics, adjusting for covariates. Additionally, odds of resolution at step 1 was 3.1 times higher for high-dose versus low-dose lorazepam in males, adjusting for covariates, but was not statistically significant. CONCLUSIONS: SE resolution was noted in 68.5% after step 1. Unadjusted, females had a higher odds of SE resolution at step 1 than males. In males, high-dose lorazepam had higher odds of SE resolution at step 1 than low-dose lorazepam, though not significantly different.

Effects of Intramuscular Midazolam and Lorazepam on Acute Agitation in Non-Elderly Subjects - A Systematic Review.

Benzodiazepines are commonly used for the treatment of acute agitation in a psychiatric setting.We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant publications. Randomized trials evaluating intramuscular (IM) midazolam or lorazepam given as monotherapy or as add-on treatment, with more than 10 patients aged 18-65 years, conducted in a psychiatric setting, and published between January 1, 1980, and February 3, 2016, were included. 16 studies from a search result of 5 516 studies were included. In total, 577 patients were treated with lorazepam IM 2-4 mg, and 329 patients were treated with midazolam IM 5-15 mg. It is unclear whether lorazepam IM or midazolam IM is as efficacious as an antipsychotic IM. It is a bit more certain that the combination of benzodiazepines IM and a low dose antipsychotic IM is more efficacious than the benzodiazepine and the antipsychotic alone. However, there is no doubt that benzodiazepines are less likely to be associated with treatment emergent side effects, as compared to antipsychotics.