Matsumoto H, Zhang B, GRADE: an emerging consensus on rating quality of evidence and strength of recommendations, Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). Delirium is a very common condition associated with significant morbidity, mortality, and costs. There is no enough evidence to determine whether benzodiazepines are effective when used to treat patients with delirium who are cared for in nonICU settings. Benzodiazepine Use in Older Adults: Dangers, Management, and Indeed, agitation is rated consistently as the most distressing manifestation for caregivers [13]. Our clinical approach to the management of agitation in patients with delirium in the palliative care is to treat any underlying cause, to optimize non-pharmacologic measures, and start neuroleptics for patients with restlessness/agitation. Minozzi S, Benzodiazepines for delirium - PubMed shortacting with an elimination halflife of less than six hours and longacting with an elimination halflife of more than 24 hours) (Dold 2012). We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register up to 10 April 2019. Hui 2017 reported that a modified intentiontotreat analysis including only participants who had begun the study intervention was specified a priori because of the nature of the study population. Because the two included studies differed in terms of the setting, participants, interventions, scales used to assess outcomes, and study designs (e.g., duration, time points), we did not pool any data, but presented results from each trial separately. Hui 2017 used a webbased simple randomisation procedure and allocation was concealed by using a secured web site that was only accessible to the study pharmacist. Benzodiazepines are currently used in clinical practice to treat behavioural disturbances associated with delirium but current guidelines do not recommend their use for this indication. In Breitbart 1996, hospitalised patients diagnosed with AIDS were assigned to treatment with haloperidol, chlorpromazine, or lorazepam, administered either orally or intramuscularly. Marcantonio ER, Only one clinical trial specifically examined agitation as the primary outcome [21], while the other two focused on delirium symptoms and severity. Schrijver EJ, Importantly, palliative sedation should be distinguished from the study above which used benzodiazepines as rescue only. Harrison JK, 1. Included RCTs had to assess the effect of benzodiazepines, at any dose and given by any route, compared with placebo or another drug intended to treat delirium. Both trials reported some of our outcomes of interest. Benzodiazepines for Agitation in Patients with Delirium: Selecting the We also included headtohead comparisons of benzodiazepines with another drug intended to treat delirium (e.g. Due to imprecision in the result, we are unable to determine whether there is a clinically important difference between groups in this outcome measured within a time period of eight hours (MD 2.10, 95% CI 0.96 to 5.16; participants = 50; Analysis 1.1; lowcertainty evidence). The diagnosis of delirium is usually based on observation of the patient and on information obtained from the nursing staff or caregivers. Controlled study of extrapyramidal reactions in the management of delirious, medically ill patients: intravenous haloperidol versus intravenous haloperidol plus benzodiazepines. To summarize, the Breitbart study supported the use of neuroleptics but not benzodiazepine, while the Agar study reached the opposite conclusion, resulting in significant confusion about the management of delirium [21,22]. Additionally, we extracted details of the funding source, declarations of interest of the primary investigators, and the methods used to control possible conflicts of interests. The American Psychiatric Association recommends that delirium assessment in clinical practice is best achieved when medical diagnosis is supplemented with observational assessment tools (Maldonado 2008). However, a sensitivity analysis was not feasible due to insufficient data. For health service organisations Ensure that policies and systems are in place to treat delirium and to support using non-drug strategies as first-line therapy. Baruch P. Efficacy of the combination of buspirone and carbamazepine in early posttraumatic delirium. The efficacy of benzodiazepines have been demonstrated in several systematic reviews . The certainty of the evidence is very low. Seeling M, Key results: We did not find any important benefits for patients who took lorazepam instead of the other treatment in these two studies. The certainty of the evidence is very low. Individual side effects, such as falls and injuries, pressure sores, depression, disinhibition, hypotension, suppressed breathing, nausea and changes in appetite, blurred vision. Thompson J, Benzodiazepines (lorazepam) vs antipsychotics (chlorpromazine) for treatment of delirium in nonICU settings: Patient or population: adult AIDS patients with delirium Settings: general medical wards Intervention: benzodiazepine (lorazepam) Comparison: antipsychotic (chlorpromazine) Outcomes: Anticipated absolute effects* (95% CI) Relative . Levy MH, Currently, it is not clear if benzodiazepines are an effective treatment for patients with delirium or whether they can harm them. Vist GE, There are no certain benefits and possible harms of lorazepam compared to placebo, chlorpromazine or haloperidol. Symptom severity may have been measured using any validated scale, e.g. Shintani A, PDF Benzodiazepines for The Treatment of Delirium Tremens Conroy M, This study compared lorazepam to two different drugs that are sometimes used to treat delirium. the contents by NLM or the National Institutes of Health. The literature supports the use of benzodiazepines for persistent agitation in patients with terminal delirium and for patients with delirium tremens. The certainty of evidence was rated as low or very low, and there was very serious imprecision associated with effect estimates for all reported outcomes (severity of delirium, any adverse events, length of hospital admission, mortality from all causes, discharges, individual side effects). We cannot assume that results would apply to other populations at risk for delirium (such as postsurgical patients, or geriatric patients). A rating of very lowcertainty implies that we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. It provided strong preliminary evidence to support the clinical benefit of combination of lorazepam and haloperidol as a rescue for refractory agitation in the terminal delirium setting. liver failure, elderly). not dementia). In addition, considering that treatment advances for HIV since the 1990s have changed the course of this disease, our findings are probably not applicable to patients with AIDS today. We explored the clinical heterogeneity across studies based on differences in the characteristics of participants, interventions, comparators and outcomes. Supportive care and use of vitamins is essential in the management. We searched ALOIS (www.medicine.ox.ac.uk/alois), which is the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 10 April 2019. Each participant with delirium was evaluated hourly with the DRS and the Extrapyramidal Symptom Rating Scale. Almeida A, This was also the conclusion of an earlier systematic review, which found no adequately controlled trials to support the use of benzodiazepines in the treatment of delirium not related to alcohol withdrawal in hospitalised patients (Lonergan 2009). We expressed findings for continuous outcomes in terms of mean differences (MDs) and 95% CI or standardised mean differences (SMDs) for continuous outcomes if the included studies used different scales to measure the same outcome. Deppen S, Curtis M, The impact of delirium on the survival of mechanically ventilated patients, International Journal of Evidencebased Healthcare, Delirium in the acute care setting: characteristics, diagnosis and treatment. Nanayakkara PW. Clinicians need to carefully weigh the risks and benefits before prescribing benzodiazepines in patients with delirium and discuss the goals of care with family caregivers and patients (if possible). Management of moderate and severe alcohol withdrawal syndromes Davoli M. Diagnostic and Statistical Manual of Mental Disorders (DSM3), Diagnostic and Statistical Manual of Mental Disorders (DSM3R), Diagnostic and Statistical Manual of Mental Discorders (DSM4), Diagnostic and Statistical Manual of Mental Disorders, text revised (DSMIVTR), Diagnostic and Statistical Manual of Mental Disorders (DSM5). Therefore, it is uncertain whether lorazepam and chlorpromazine differ on this outcome (MD 7.12, 95% CI 0.43 to 14.67; participants = 19; Analysis 2.2). Sedation and Delirium in the Intensive Care Unit | NEJM The other study (Hui 2017) focused on drug treatment of delirium in a palliative care setting, comparing lorazepam with the antipsychotics chlorpromazine and haloperidol. It adds significantly to healthcare costs. Combining data from these two trials, a meta-analysis compared the prevalence of delirium between benzodiazepines and dexmedetomidine and reported that there was no statistically significant difference in this outcome (risk ratio 0.82, 95% 0.611.11, P=0.19) [35]. Li C, Hypoactive delirium is characterised by decreased responsiveness, withdrawal, and apathy, whereas hyperactive delirium is characterised by agitation, restlessness, and emotional lability (excessive emotional reactivity associated with frequent changes or swings in emotions and mood) (Meagher 2000). In addition, the end of treatment time point was not well reported. In a study examining agitation in delirium, the mean delirium-related distress level was 3.2 of 4 for patients (with 4 being the most severe), 3.75 of 4 for caregivers, and 3.1 of 4 for nurses [13,14]. Respiratory depression is a rare but very severe adverse effect of benzodiazepines in shortterm treatment (Dold 2012; Woods 1992). Benzodiazepines also have an established role in management of delirium secondary alcohol withdrawal. Buss MK, Because of the insufficient number of included studies, we did not perform metaanalysis, assessment of reporting biases, subgroup analysis, investigation of heterogeneity, and sensitivity analysis. Existing evidence supports the use of benzodiazepines in two specific delirium settings: persistent agitation in patients with terminal delirium and delirium tremens. sharing sensitive information, make sure youre on a federal Leonard M, Evidence supports the use of benzodiazepines only for the management of agitation in two . We included randomised controlled trials (RCTs) and quasiRCTs (those in which the method of allocation to treatment is known but is not strictly random, e.g. One study (Breitbart 1996) examined the efficacy and side effects of benzodiazepines (lorazepam) for the treatment of delirium in adult participants diagnosed with AIDS. Benzodiazepines are among the most commonly prescribed medications in the country. PDF By Sue Fosnight, BSPharm, BCPS, CGP - ACCP The median overall survival was 73 hours (95% CI 49 to 106 hours), with a median followup of 164 hours (95% CI 92 to 195 hours). Gozdalska J, conducted a crossover trial to compared 3 weeks of alprazolam to 3 weeks of haloperidol for the management of disruptive behavioral episodes in 48 nursing home patients with dementia, delirium, amnesia and other cognitive disorders [36]. After deduplication, 2981 unique references remained. Both studies used lorazepam; no other benzodiazepines were evaluated. Analyze patient drug regimens to determine the like- lihood that delirium or delirium-like symptoms are drug related. Others, such as anticonvulsants, barbiturates, adrenergic drugs, and GABA agonists have been tried and have evidence. In summary, the current evidence base is small, incomplete and of very limited applicability. we updated the expression of evidence ratings: "Rating evidence as high quality implies that we are very confident that the true effect lies close to that of the estimate of the effect. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (including MEDLINE, Embase, PsycINFO, CINAHL, LILACS), numerous trial registries (including national, international and pharmaceutical registries), and grey literature sources. Why Avoid Benzodiazepines Entirely? One important question relates to efficacy of combination therapy (benzodiazepine plus haloperidol) compared to either agent alone. Uncontrolled agitated delirium is also one of the most important reasons for prolonged hospital admissions and is the most common indication for palliative sedation [1518]. In patients with refractory agitation, benzodiazepines may be administered as scheduled doses or continuous infusion for palliative sedation. Because this study only examined a single dose and only enrolled cancer patients from a single center, further studies are needed to confirm its effect. However, age is a stronger predictor of delirium in nonICU than in ICU patients (Van Rompaey 2008). Fraser GL, Severity of delirium (we anticipated that this may have been measured differently in different trials. It is a frequent complication after surgery (e.g. the DRS (. preliminary report, Comparative evaluation of the effectiveness of various methods of treating delirium tremens, Acute respiratory insufficiency following treatment with chlordiazepoxide in patients with delirium tremens. We used an electronic data extraction form to extract information on source, eligibility, methods, participants, intervention, comparator, outcomes, results, and miscellaneous notes, according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, this study should be interpreted with caution because of its small sample size and the unique dosing schedule. For instance, lorazepam and clonazepam have high potency, diazepam has moderate potency, and temazepam has low potency. Comparison 1 Benzodiazepines (lorazepam) vs placebo, Outcome 5 Individual side effects (measured with UKU, higher = worse). Yan Li (YL): data screening after 2019 new search, data extraction, data entry, and data analysis after searching was updated, writing first draft of full review, revising the final full review, Jun Ma (JM): data screening after 2019 new search, data checking, writing first draft of full review, reviewing and revising the final full review, Nan Li (NL): initial data extraction before 2019 new search, Rui Zheng (RZ): data screening before 2019 new search, Wei Mu (WM): initial data extraction before 2019 new search, Jiaying Wang (JW): initial data extraction before 2019 new search, Jin Hua Si (JHS): data screening before 2019 new search, Hong Cai Shang (HCS): protocol development and revising the protocol, This review was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Dementia and Cognitive Improvement group. They may have frightening experiences, such as vivid hallucinations. Patients who present with refractory agitation may require palliative sedation with continuous infusion of benzodiazepine. The primary outcome, a composite score based on inappropriate behavior, inappropriate communication, and illusions and hallucinations, was significantly worse in the risperidone (0.48 units higher, P=0.02) and haloperidol (0.25 units higher, P=0.009) arms than in the placebo arm [22,28]. 2 Anzhen Road, BeijingChina, 100029. Inclusion in an NLM database does not imply endorsement of, or agreement with, Clinicians may prescribe benzodiazepines skillfully by selecting the right medication at the right dose for the right indication to the right patient at the right time. They can also be used for insomnia . This study compared lorazepam to two different drugs that are sometimes used to treat delirium. Lorazepam + haloperidol (n = 29): lorazepam (3 mg) given in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. For older people, it can lead to longer hospital stays and it has been associated with increased risks of death, disability, loss of independence, and later dementia. Therefore, it is uncertain whether there is a difference between groups on this outcome from the initiation of the protocol to one week after its completion (RR 1.83, 95% CI 0.34 to 9.92; participants = 17; Analysis 3.3). Current critical care guidelines recommend, first and foremost, the use of nonpharmacological strategies in both the prevention and treatment of delirium (Barr 2013). Therefore, it is uncertain whether there is a difference between groups on this outcome (day two after treatment: MD 4.85, 95% CI 0.03 to 9.67; at the study endpoint: MD 5.36, 95% CI 0.01 to 10.73; participants = 17; Analysis 3.1). Beijing Anzhen Hospital, Capital Medical University, Centerfor Anesthesiology, No.2 Anzhen Road, Chaoyang District, BeijingBeijingChina, 100029, Tianjin University of Traditional Chinese Medicine, Nursing, #312 West Anshan Road, TianjinChina, Tianjin University of Traditional Chinese Medicine, Tianjin Insititute of Clinical Evaluation, #88 Yuquan Road, Nankai District, TianjinTianjinChina, 300193, The 2nd Affiliated Hospital of Tianjin University of traditional Chinese Medicine, Clinical pharmacology, 861 Zhenli Road, Hebei District, TianjinTianjinChina, 300150, The Affiliated Wuxi Peoples Hospital of Nanjing Medical University, Rehabilitation and Acupuncture, No.299, Qingyang Road, Liangxi District, WuxiJiangsuChina, 214000, Tianjin University of Traditional Chinese Medicine, Library, #88 Yuquan Road, Nankai District, TianjinTianjinChina, 300193, Tianjin University of Traditional Chinese Medicine, Baokang Hospital, #88 Yuquan Road, Nankai District, TianjinTianjinChina, 300193, Dongzhimen Hospital, Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education, Haiyuncang Lane, Dongcheng District, BeijingChina, 100700, Beijing Anzhen Hospital, Capital Medical University, Center for Anesthesiology, No. Due to very serious imprecision, all evidence was of low certainty. Taylor J, Si JH, Comparison 2 Benzodiazepines (lorazepam) vs chlorpromazine, Outcome 2 Any adverse events (measures with ESRS, higher = worse). Walther T, Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and metaanalysis. Benzodiazepines: Benzodiazepines can worsen the cognitive functions and lead to excessive sedation. However, Breitbart 1996 found that all six participants who received lorazepam developed treatmentlimiting side effects, including oversedation, disinhibition, ataxia, and increased confusion, leading to either a refusal to take the drug or a requirement to discontinue the drug. Peterson J, All of the participants had delirium, were treated with haloperidol, and were randomised to receive either lorazepam or placebo in combination with it. Results were reported for all stated outcomes. Clinicians may prescribe benzodiazepines skillfully by selecting the right medication at the right dose for the right indication to the right patient at the right time. Benzodiazepines are medicines that are often used as sedatives. DOI: 10.1002/14651858.CD012670.pub2, Copyright 2023 The Cochrane Collaboration. They may have frightening experiences, such as vivid hallucinations. Derevenco M, Adamis D, Once delirium is established, its management should address both the underlying causes and the symptoms. Patients who took it did not have better outcomes. Araujo KL, Clegg A, Costs associated with delirium in mechanically ventilated patients. Although we endeavoured to include unpublished studies, we cannot be sure whether other randomised studies have been carried out or whether they have been published or disseminated publicly. government site. et al. We wanted to know if benzodiazepines are a helpful treatment option for delirium in any healthcare setting except ICU (patients in ICU are very sick and they may need different kinds of treatment). ", Quote: "Research staff conducting the study assessments, bedside nurses, attending physicians, patients, and caregivers were blinded to the allocation of the study medication and study outcomes throughout the entire study. 1. Accessibility Author David Phillip Alldred 1 Affiliation adinazolam or alprazolam or bentazepam or benzodiazepine* or bromazepan or brotizolam or camazepam or chlordiazepoxide or clobazam or clotiazepam or cloxazolam or diazepam or etizolam or flunitrazepam or flurazepam or flutoprazepam or halazepam or ketazolam or loflazepate or loprazolam or lormetazepam or metaclazepam or midazolam or nitrazepam or oxzepam or prazepam or propazepam or ripazepam or serazepine or temazepan or tofisopam or triazolam, CENTRAL (The Cochrane Library) http://crso.cochrane.org, MEDLINE Inprocess and other nonindexed citations and MEDLINE 1950present (Ovid SP), 1 (MH "antianxiety agents, benzodiazepine+"), ISI Web of Science all databases [includes: Web of Science (1945present); BIOSIS Previews (1926present); MEDLINE (1950present); Journal Citation Reports], (benzodiazepine* OR diazepam OR temazepan OR lorazepam OR alprazolam OR bromazepam OR nitrazepam OR clonazepam) AND TOPIC: (deliri* OR "acute confusion*" OR "acute organic psychosyndrome" OR "acute brain syndrome" OR "metabolic encephalopathy" OR "acute psychoorganic syndrome" OR "clouded state" OR "clouding of consciousness" OR "exogenous psychosis" OR "toxic psychosis" OR "toxic confusion" OR obnubilat*) ANDTOPIC: (random* or placebo or "doubleblind" or trial OR groups OR "controlled study" OR "time series" OR "comparative study" OR "pretestposttest design"), benzodiazepine* OR diazepam OR temazepan OR lorazepam OR alprazolam OR bromazepam OR nitrazepam OR clonazepam [Words] and and delirium OR delious OR deliria OR delirio OR loucura [Words], delirium OR toxic psychosis OR toxic confusion OR metabolic encephalopathy OR clouded state OR exogenous psychosis | benzodiazepine* OR diazepam OR temazepan OR lorazepam OR alprazolam OR bromazepam OR nitrazepam OR clonazepam, TOTAL after first assessment by information specialist, Diagnosis: adult patients who met the case definition for AIDS of the Centers for Disease Control and were undergoing treatment for acquired immune deficiency syndrome (AIDS)related medical problems.