28/02/2019

譫妄症藥物治療的新指引(論文簡介及中英文新聞稿)

譫妄症藥物治療的新指引(論文簡介及中英文新聞稿)

蘇冠賓
中國醫藥大學 醫學院副院長
精神醫學及神經科學教授


由中國醫藥大學精神醫學教授蘇冠賓高雄文信診所曾秉濤醫師、與林口長庚復健科吳易澄醫師等人主導,結合日本國家癌症中心、英國倫敦國王學院及加拿大多倫多大學之國際知名團隊,對精神疾病的最嚴重之類型「譫妄症」的所有藥物治療納入研究主題,最新研究結果發表在國際知名期刊JAMA Psychiatry!他們的發現除了替臨床醫師帶來治療藥物選擇的根據之外,也為未來的譫妄症研究和治療指引提供新的方向!
A recent paper published in JAMA Psychiatry provides important findings of the missing piece of clinical uncertainty about treatment and prevention in delirium.
Delirium, commonly known as acute confusional state, can often be caused by one or more contributing factors, such as a severe or chronic medical illness, changes in metabolic balance, adverse effects from medication, systemic infection, surgery, or alcohol or drug intoxication or withdrawal. It’s critically important to identify and treat delirium because some of the contributing factors could be life-threatening. However, there is no sufficient evidence for choice of medication to treat or prevent the symptoms of delirium. 
A recent paper, Association of Delirium Response and Safety of Pharmacological Interventions for the Management and Prevention of Delirium A Network Meta-analysis, published in JAMA Psychiatry provides important findings of this missing piece in that important clinical uncertainty. The leading author of an international collaboration, Professor Kuan-Pin Su, at the China Medical University in Taichung, Taiwan, concludes the main finding about treatment/prevention of delirium: “In this report, we found that the combination of haloperidol and lorazepam demonstrated the best option for treatment of delirium, while ramelteon for prevention against delirium.” Hopefully, our findings would revise the chapter of treatments and prevention of delirium in the treatment guidelines. (https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2726609).
In addition to the superiority of “haloperidol plus lorazepam” and “ramelteon” in treatment and prevention to delirium, the paper also revealed an important result that both of these regimens did not associate with higher all-cause mortality rate than placebo/control did. That is, the safety of such regimen was similar with that of placebo/control, in aspect of risk of mortality.
Delirious symptoms have profound negative impacts to patients and their caregivers, and significant increase the mortality and morbidity. According to another main author, Dr Ping-Tao Tseng from the WinShine Clinics in Kaohsiung, Taiwan, “it is equally important to treat underlying diseases (e.g. dehydration, adverse drug reaction, or metabolic imbalances) and to treat the neuropsychiatric symptoms (psychosis, irritable and unstable mood, agitated and destructive behaviors… etc.) of delirium. Therefore, the rationale of this work was to provide a general principle of medication prescription to manage the delirium symptoms rather than the etiology behind the delirium.” In another word, the results of current network meta-analysis were aiming to delirious symptoms but not targeting their underlying causes as the recruited subjects had different baseline condition among these 58 RCTs.
In addition to the superiority of “haloperidol plus lorazepam” and “ramelteon” in treatment and prevention to delirium, the paper also revealed the important findings about safety. Their result revealed that both of these regimens did not associate with higher all-cause mortality rate than placebo/control.
In the study by Wu and colleagues in a coming issue of JAMA Psychiatry, the authors use a variant of meta-analysis (network meta-analysis [NMA]) to explore pharmacologic interventions for delirium. Another main author, Dr Yi-Cheng Wu, from the Chang Gung Memorial Hospital in Linkou, Taiwan, added, “single randomized controlled trial or traditional pairwise meta-analysis provides less information than NMA to synthesize direct and indirect evidence for decision-making.”
The Editorial in the same issue by Professor Blazer from Duke University Medical Center, North Carolina, pointed out that this NMA is of importance for at least 2 reasons. First, non-pharmacological approaches for delirium are time-consuming and costly to implement. A safe and effective pharmacologic intervention would be welcomed. Second, new agents and new approaches to pharmacologic treatment have emerged that can be empirically investigated for efficacy and safety in the treatment of delirium (https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2726605).
Indeed, non-pharmacological treatments are always important in the treatment and prevention in delirium. In fact, in this current NMA in JAMA Psychiatry, the authors have reported that the ramelteon, a melatonergic agonist, was ranked the best preventive regimen against delirium prevention. The authors added, “the action of melatonin agonists like ramelteon is to re-establish the disturbed circadian rhythm. Interestingly, the combination of simple behavioral interventions (e.g. exposure to diurnal light-dark cycles, familiar objects, clocks/calendars, …etc.) has been commonly advised to help to prevent delirium in clinical settings.

中國醫藥大學蘇冠賓教授領導國際跨院合作之團隊研究提供譫妄治療新發現!

由中國醫藥大學精神醫學教授蘇冠賓以及幾位台灣精神科醫師主導,結合國際知名研究團隊,對精神疾病的最嚴重之類型「譫妄症」的所有藥物治療納入研究主題,最新研究結果發表在國際知名期刊JAMA Psychiatry!他們的發現除了替臨床醫師帶來治療藥物選擇的根據之外,也為未來的譫妄症研究和治療指引提供新的方向!

譫妄 (delirium)在重症治療中是一個相當重要的症候群,主要症狀包括突然其來嚴重的聽幻覺、視幻覺、及怪異妄想,合併意識混亂,讓照顧者以為患者中邪了。最新研究的報告指出(Pérez-Ros et al. Diseases 2019 Jan 30),譫妄在住院中老人盛行率高達27%,在其他重症病人中也非常常見(加護病房高達 35%, 如果使用上呼吸器更上達 80%;一般低風險手術後12%-13%;高風險手術後更高,例船冠狀心血管手術29%、重大腹部手術50%、心臟手術 51%;臨終病人高達85%!)由於譫妄患者死亡率高達20-30% (Lipowski NEJM 1989),其臨床意義非常重要,代表個案的病情相當嚴重,不容輕忽!

目前醫學界公認對於治療譫妄最重要的就是找出潛在生理病因並盡快矯正(例如藥物中毒或戒斷、代謝系統異常、急慢性內外科疾病或感染病…等等)。然而,譫妄症狀(例如幻覺及妄想所造成的對自我及他人之危險以及治療和照顧上的困難),嚴重影響病人的預後,雖然其病因仍未完全明朗,研究認為譫妄幻覺妄想症狀與腦內多巴胺、乙醯膽鹼、GABA等神經傳導物質異常、以及生物節律與醒睡中樞異常有關。遺憾的是,目前臨床研究證據相當有限,療效不足、副作用、都增加臨床治療困難;此外,譫妄的預防更是讓臨床醫師爭論不休的議題。臨床治療指引 (clinical guideline) 都強調:目前的臨床研究證據不足,無法有足夠確實的結論!

中國醫藥大學精神醫學教授蘇冠賓醫師、林口長庚復健科吳易澄醫師、與高雄文信診所曾秉濤醫師等人主導,結合日本國家癌症中心、英國倫敦國王學院及加拿大多倫多大學之國際知名團隊,把現存所有譫妄藥物治療納入研究主題,利用網路統合分析(NMA)的最新方法,發現:褪黑激素受體藥物ramelteon對於預防重病患者產生譫妄症有顯著的功效!在由於褪黑激素受體藥物可以矯正生物節率和晝夜週期(circadian rhythm),其效果類似其他矯正譫妄症的非藥物療法,例如光照療法、利用時鐘或日曆強化人時地定向感…等,因此藥物如果可以有效地達到類似的效果,應該具有相當重要的臨床價值。生物的晝夜週期(circadian rhythm)的正常運作,不僅是身心健康的重要指標、是大腦記憶功能的守門員、更是維持代謝、免疫、心血管、骨骼肌肉功能的重要生理機能。此外,蘇教授團隊更首度證實Haloperidol與lorazepam兩藥物的組合最能改善譫妄症的症狀,這份重大突破的研究成果也獎刊登在國際知名期刊JAMA Psychiatry!這樣的結果,甚至獲得國外審查專家的評論:「做為未來臨床指引制定之重要根據!」

Notes:

1. Lipowski, Z.J. Delirium in the elderly patient. N. Engl. J. Med. 1989, 320, 578–582. 
[The outcome for the majority of patients is full recovery, but in 20 to 30 percent, delirium is followed by death], [About 40 percent of patients with dementia who were 55 years of age or older were delirious on admission to the hospital, whereas 25 percent of those who were delirious had dementia], [In older long-term care residents, the reported prevalence varies between 15% and 70%]

2. Pérez-Ros P, Martínez-Arnau FM. Delirium Assessment in Older People in Emergency Departments. A Literature Review. Diseases. 2019 Jan 30;7(1). pii: E14. doi: 10.3390/diseases7010014.
[The prevalence of delirium in end-of-life patients approaches 85%], [In hospitalized older patients, delirium is the most frequent complication, with an approximate prevalence of 27%], [In postsurgical patients, the general surgery pose lesser risk, with a prevalence of 12%-13%, whereas the patients subjected to aortic, major abdominal, or cardiac surgery is much higher, up to 29%, 50%, and 51%, respectively], [In the ICU, the prevalence varies between 31% and 35%, being higher in patients subjected to mechanical ventilation and with comorbidities (up to 80%)], [The probability of delirium increasing by 45% in moderate dementias and 58% in severe dementias]. 


REPLY to valuable comments about the limitation of NMA:



Dear ~,
I am also very delighted to receive many valuable comments from excellent clinicians like you about our NMA in JAMA Psychiatry. They correctly pointed out the limitation of NMA and the caution of using FGS (haloperidol/lorazepem). I actually agree them all as well as the Editorial by Blazer in the same issue.
Although our study is strengthened by comparing different drugs with NMA, the generalization of our results are still highly limited and depending on the studies included in the NMA and the possible comparisons given the studies available. For example, there were many studies using haloperidol but only only one study compared haloperidol/lorazapam versus haloperidol/placebo. The result showing haloperidol/lorazapam the best because this combination was doing very well in Richmond Agitation-Sedation Scale (RASS) scores as compared to haloperidol/placebo in that single study.
In conclusion, we should always consider specific treatments in specific clinical conditions rather than applying only one general principle from a big picture of our NMA.


轉自共同作者曾秉濤醫師部落格:臨床困境與實證醫學的應用:譫妄症新紀元
https://tsengpt.blogspot.com/2019/02/blog-post.html

最近美國醫學會系列期刊 JAMA Psychiatry 刊出一篇非常重要的網路統合分析 (Network Meta-Analysis) 研究,這篇文章結合了來自世界各地許多位專家學者資深經驗薈萃,給出了許多關於臨床處理譫妄症狀 (delirium) 的重要臨床建議! 

譫妄症狀 (delirium) 是什麼?

患者因為內外科問題而導致身體狀況惡化時,有一定機率會出現譫妄症狀的併發症,這時患者會出現急性且起起伏伏的躁動 (agitation) 、幻覺 (hallucination) 、妄想 (delusion) 、日夜混亂 (circadian disturbance)、胡言亂語 (irrelevant and incoherent speech) 等,而這些症狀出現時,往往代表患者的身體出現重大狀況!



實證醫學告訴我們什麼:治療譫妄症方面

在我們這篇最新的研究中,我們發現到Haloperidol與lorazepam的組合,是所有藥物處方中最能緩解譫妄症狀的處方,另一方面,如果不考慮複方,Haloperidol則是所有單方 (single regimen) 裡面效果最好的處方!而且根據統計,這些處方和安慰劑/對照組 (placebo/control) 比較起來,並不會因此造成更高的患者最終死亡率 (all-cause mortality rate)。

實證醫學告訴我們什麼:預防譫妄症方面

另一方面,我們也嘗試討論是否有任何處方能夠預防 (或減少) 譫妄症的發生,我們的研究發現ramelteon 這個藥物對於預防譫妄症狀的發生,是所有處方之中效果最好的,而Olanzapine則是所有抗精神病劑 (antipsychotics) 中預防效果最好的,而且這兩種藥物和安慰劑/對照組 (placebo/control) 比較起來,並不會因此造成更高的患者最終死亡率 (all-cause mortality rate)。 (圖片資料整理自原始文章)

處理譫妄症狀的過程還是需要回歸根本

但是,我們還是要提醒所有臨床工作者,譫妄症狀的源頭還是來自於「患者的身體出狀況」,因此上述處方藥物只是協助緩解譫妄症狀的表面症狀,臨床工作人員還是要同時積極尋找與解決患者潛藏的身體問題,這才是治本之道! 

至於其餘各種藥物 (例如大家常用的quetiapine) 的效果,以及各種藥物的使用劑量與時間等細節,就請有興趣的讀者自行上雜誌網站買全文來看了! 最後,也提醒民眾,若真有遇到譫妄症狀的問題,切勿自行使用藥物,而應配合醫師接受積極檢查與治療方為上策唷! 

6 comments:

  1. Haloperidol plus lorazepam best treatment for delirium
    Healio.com (February 27, 2019)

    https://goo.gl/hpd43p

    Results from a large network meta-analysis found that haloperidol plus lorazepam appears to be the best treatment — and ramelteon the best preventive medicine — for patients with delirium.

    Although delirium is prevalent, particularly among elderly inpatients, it is underdiagnosed, and prior research has estimated that up to 40% of delirium cases may be preventable, according to Yi-Cheng Wu, MD, of Chang Gung Memorial Hospital at Linkou, Taiwan, and colleagues.

    “Despite the widespread use of various psychopharmacological agents for the management of delirium, the relative balance between benefit and harm of the various available treatments remains unclear,” they wrote in JAMA Psychiatry.

    To evaluate the available evidence, the researchers reviewed clinical online databases for randomized clinical trials (RCTs) examining pharmacological interventions for delirium treatment and prevention. Using a random-effects model, the investigators measured treatment response in patients with delirium and the incidence of delirium in patients at risk for delirium (primary outcomes).

    Of 58 trials included in the analysis, 20 RCTs encompassing 1,435 participants (mean age 63.5 years) compared the outcomes of treatment and 38 encompassing 8,168 participants (mean age 70.2 years) assessed the prevention of delirium.

    Network meta-analysis revealed that haloperidol plus lorazepam provided the best response rate for treatment on delirium (OR = 28.13; 95% CI, 2.38-333.08) compared with placebo/control. Other treatment medications (including rivastigmine tartrate, chlorpromazine hydrochloride, lorazepam, quetiapine fumarate, amisulpride, ziprasidone hydrochloride, olanzapine, etc.) did not show significantly better response rates when compared with placebo/control.

    For prevention, analysis revealed that only ramelteon (OR = 0.07; 95% CI, 0.01-0.66), olanzapine (OR = 0.25; 95% CI, 0.09-0.69), risperidone (OR = 0.27; 95% CI, 0.07-0.99) and dexmedetomidine hydrochloride (OR = 0.5; 95% CI, 0.31-0.8) demonstrated a significantly lower delirium occurrence rate than placebo/control. Moreover, midazolam hydrochloride was linkd to a greater rate of delirium occurrence than placebo/control.

    Other preventive interventions (including clonidine hydrochloride, melatonin, propofol, haloperidol, lorazepam, rivastigmine tartrate, suvorexant, etc.) did not result in different risks of delirium occurrence compared with placebo/control.

    Wu and colleagues also reported that no pharmacological treatments for delirium were significantly associated with a greater risk for all-cause mortality compared with placebo/control.

    “When delirium occurs, clinicians should not only prescribe medication to manage delirium symptoms but also begin surveillance to identify any potential abnormal physical conditions behind the delirium,” the researchers wrote. “Future large-scale RCTs investigating the treatment effect of haloperidol plus lorazepam and the preventive effect of ramelteon are warranted to corroborate the findings of our [network meta-analysis].”

    When drawing conclusions from network meta-analyses, clinicians should pay attention to the individual trials of participants, Dan G. Blazer, MD, MPH, PhD, from the department of psychiatry and behavioral science, Duke University Medical Center, wrote in a related editorial.

    “Given that the use of [network meta-analysis] will most probably become a much more widely used analytic tool in the future, scrutiny of the RCTs, the components of the analyses, is especially important,” Blazer wrote. – by Savannah Demko

    Disclosure: The authors and Blazer report no relevant financial disclosures.
    Blazer DG. JAMA Psychiatry. 2019;doi:10.1001/jamapsychiatry.2018.4276.
    Wu Y, et al. JAMA Psychiatry.2019;doi:10.1001/jamapsychiatry.2018.4365.

    ReplyDelete
  2. Delirium: Treatment Options and Prevention Measures
    Posted on March 1, 2019
    https://medicalresearch.com/mental-health-research/delirium-treatment-options-and-prevention-measures/47687/

    MedicalResearch.com Interview with:
    Kuan-Pin Su, MD, PhD, China Medical University, Taichung, Taiwan

    MedicalResearch.com: What is the background for this study? What are the main findings?

    Response: Delirium, also known as acute confusional state, is a serious disturbance in mental abilities that results in confused thinking and reduced awareness of the environment. Delirium can often be traced to one or more contributing factors, such as a severe or chronic illness, changes in metabolic balance (such as low sodium), medication, infection, surgery, or alcohol or drug intoxication or withdrawal. It’s critically important to identify and treat delirium because some of the contributing factors could be life-threatening. However, there is no sufficient evidence for choice of medication to treat or prevent the symptoms of delirium.

    A recent paper, Association of Delirium Response and Safety of Pharmacological Interventions for the Management and Prevention of Delirium A Network Meta-analysis, published in JAMA Psychiatry provides important findings of this missing piece in that important clinical uncertainty. The leading author, Professor Kuan-Pin Su, at the China Medical University in Taichung, Taiwan, concludes the main finding about treatment/prevention of delirium: “In this report, we found that the combination of haloperidol and lorazepam demonstrated the best option for treatment of delirium, while ramelteon for prevention against delirium.


    MedicalResearch.com: What should readers take away from your report?

    Response: In addition to the superiority of “haloperidol plus lorazepam” and “ramelteon” in treatment and prevention to delirium, the paper also revealed an important result that both of these regimens did not associate with higher all-cause mortality rate than placebo/control did. That is, the safety of such regimen was similar with that of placebo/control, in aspect of risk of mortality.

    MedicalResearch.com: What recommendations do you have for future research as a result of this work?

    Response: In the result of the current network meta-analysis, it was not surprising the superiority of “haloperidol plus lorazepam” in treatment to delirium. However, the superiority of “ramelteon” in prevention to delirium worth further discussion. According to another main author, Dr Ping-Tao Tseng from the WinShine Clinics in Kaohsiung, Taiwan, “the disruptive circadian rhythm could be a major cause, while at the same time, consequence of delirium. Based upon this rationale, the correction of such abnormality might be one potential prevention strategy to delirium.” However, there lack of conclusive evidences to prove such a hypothesis. Future well-designed trials should be warranted to prove or refute this hypothesis.


    MedicalResearch.com: Is there anything else you would like to add?

    Response: Another main author, Dr Yi-Cheng Wu, from the Chang Gung Memorial Hospital in Linkou, Taiwan, added, “single randomized controlled trial or traditional pairwise meta-analysis provides less information than network meta-analysis to synthesize direct and indirect evidence for decision-making. Network meta-analysis might produce stronger evidence than pairwise meta-analysis did.” Finally, we want to reaffirm that the clinicians should, when the delirium occurred, pay more attention to survey and correct patients’ underlying diseases rather than simply prescribing medication for the set of delirium symptoms.

    ReplyDelete
  3. PRESS Interest: 聯合報「住院長者譫妄發生率高 台灣學界找到預防治療新方向」https://udn.com/news/story/7266/3672802
    2019-03-02 09:07聯合報 記者羅真╱即時報導

    每10名住院中老年人約有3人可能因疾病、代謝或中樞神經異常發生譫妄,住進加護病房者盛行率更高,影響疾病預後與死亡風險,但目前預防與治療的臨床研究證據有限。台灣學界主導的跨國研究找到新方向,研究發現,褪黑激素受體藥物ramelteon有顯著的預防之效,haloperidol與lorazepam兩藥物的組合則對嚴重譫妄病人最具療效。

    這項研究由中國醫藥大學精神醫學教授蘇冠賓、林口長庚復健科醫師吳易澄、高雄文信診所醫師曾秉濤等人主導,並與日本國家癌症中心、英國倫敦國王學院與加拿大多倫多大學合作,研究成果剛於2月27日刊登於國際期刊《美國醫學會雜誌—精神病學》(JAMA Psychiatry),國際審查委員認為這是未來臨床指引制定的重要根據。

    蘇冠賓說明,譫妄是重症患者容易出現的症候群,住院中老年人的盛行率為27%,加護病房重症患者達35%,使用呼吸器者更高達80%。患者可能因感染、代謝異常、藥物中毒或戒斷、急慢性內外科疾病等因素,影響腦內多巴胺、乙醯膽鹼、GABA等神經傳導物質異常,以及生理時鐘與醒睡中樞異常,進而引起相關的症候群。

    譫妄的主要症狀猶如中邪,包括突然其來的嚴重聽幻覺、視幻覺、怪異妄想、意識混亂等,這會影響患者自身與他人的危險,增加治療與照顧困難、提升死亡風險,但目前預防與治療的臨床研究證據有限。

    蘇冠賓等人運用系統回顧和統合分析(NMA)方法,分析58個有關譫妄預防或治療的臨床試驗,其中包含的受試患者共9603名。分析結果顯示,在預防方面,可調節生理時鐘的褪黑激素受體藥物ramelteon具顯著效果;在治療方面,haloperidol與lorazepam兩藥物的組合適用於嚴重的急性譫妄症患者,療效相對其他藥物明顯。

    蘇冠賓說,生理時鐘的穩定性是維持大腦意識功能的關鍵,而譫妄患者普遍有生理時鐘失調的情形,因此重症病人若開始出現日夜顛倒、晚上發生意識障礙等狀況,可及早透過褪黑激素受體藥物來預防譫妄的發生。

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  4. PRESS RELEASE (20190304-5)
    中國醫藥大學全球資訊網 校園新聞 China Medical University, Taiwan
    中央社新聞網: http://www.cna.com.tw/postwrite/Detail/249967.aspx
    焦點新聞網:http://focusnews.tw/2019/03/04/p52976/
    ENN 台灣電報: http://enn.tw/?p=982
    17news 民生好報: http://17news.net/?p=34003
    TNN台灣新聞 : http://news.tnn.tw/news.html?c=5&id=133459
    台中地方新聞 : http://tc.news.tnn.tw/news.html?c=5&id=133459
    联合報 : https://udn.com/news/story/7266/3675987
    民時新聞網:http://www.lifetimes.tw/?p=338092
    大宇宙新聞時報 : http://www.macrocosm.tw/indexmain.php?mmenu=18000&sid=80011&cateid=10&imp=1
    中國新聞記者協會 : http://chnews.ihandle.com.tw/read.php?22082
    台灣省新聞記者協會 : http://twnews.ihandle.com.tw/read.php?20159
    新華報導 : https://ccss3172.blogspot.com/2019/03/jama-psychiatry.html
    工商時報 : 中國醫藥大學蘇冠賓教授結合國際跨院合作團隊研究譫妄症預防與治療新發現 - 工商時報

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  5. Study Identifies Medications Effective for Treating, Preventing Delirium
    Psychiatric News Monday, March 4, 2019
    https://goo.gl/zKCCGN

    Delirium—an acute brain state characterized by confused thoughts and emotions—is a common problem among elderly inpatients and patients in intensive care. A meta-analysis published in JAMA Psychiatry suggests that a combination of haloperidol and lorazepam may be the best option to treat patients with delirium, while ramelteon may be the best medication to prevent delirium.

    Yi-Cheng Wu, M.D., of Linkou Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues compiled data from 58 clinical trials for delirium; these included 20 trials assessing therapeutic interventions for delirium and 38 assessing preventive interventions. The trials involved more than 9,600 individuals who had delirium due to a variety of possible causes such as being in critical care, undergoing major surgery, having a chronic illness like cancer, or being of advanced age.

    Among the studies testing medications to treat delirium, only patients given haloperidol (currently the most commonly used medication for delirium) or haloperidol plus lorazepam had better response rates (fewer delirium-related symptoms) than those given placebo. The haloperidol-lorazepam combination was superior, according to the analysis; patients prescribed haloperidol plus lorazepam were 28 times more likely to respond than those prescribed placebo, while patients prescribed haloperidol were about 2.4 times as likely to achieve a response than those prescribed placebo.

    Among the 38 preventive studies, four treatments were found superior to placebo at reducing the risk of delirium: dexmedetomidine hydrochloride, olanzapine, ramelteon, and risperidone. Of these, ramelteon had the strongest preventive effect, reducing the risk of delirium by 93% relative to placebo.

    The study authors cautioned, however, that haloperidol-lorazepam and ramelteon were studied in only one trial each. “Future large-scale RCTs investigating the treatment effect of haloperidol plus lorazepam and the preventive effect of ramelteon are warranted to corroborate the findings,” they concluded.

    To read more about the management of delirium, see the Psychiatric News article “Common Delirium Medications Found Not Effective in Critically Ill Patients” and the Journal of Neuropsychiatry and Clinical Neurosciences article “Responding to Ten Common Delirium Misconceptions With Best Evidence: An Educational Review for Clinicians.”

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  6. PRESS from Reuters:

    MEDSCAPE: https://www.medscape.com/viewarticle/910192

    MDLins: https://www.mdlinx.com/pharma-news/top-medical-news/article/2019/03/11/7560298/

    Ramelteon and Combination Haloperidol/Lorazepam May Curb Delirium
    By Marilynn Larkin

    March 12, 2019

    NEW YORK (Reuters Health) - For delirium, haloperidol plus lorazepam may be the best treatment and ramelteon, the best preventive medication, researchers say.

    Dr. Kuan-Pin Su of China Medical University in Taiwan and colleagues analyzed 58 randomized controlled trials of delirium treatment or prophylaxis in patients with varied conditions, including hospitalization in general wards or ICUs, cancer, extreme old age, major surgical procedures, and hospice care.

    Twenty trials compared outcomes of treatment in 1,435 participants (mean age, 63.5; 65% men) and 38 trials examined pharmacologic approaches to prevention in 8,168 participants (mean age 70; 53.4% women).

    As reported online February 27 in JAMA Psychiatry, the team's network meta-analysis demonstrated that haloperidol plus lorazepam provided the best response rate for treatment (odds ratio, 28.13) compared with placebo/control. No statistically significant differences in all-cause mortality were found across the tested medications.

    "The rationale of this work was to provide a general principle of medication prescription to manage delirium symptoms rather than the etiology behind the delirium," Dr. Kuan-Pin Su of China Medical University in Taiwan told Reuters Health on behalf of the authors.

    "It is important to treat underlying diseases (that contribute to delirium) - e.g. dehydration, adverse drug reaction, or metabolic imbalances - as well as the neuropsychiatric symptoms," he said by email.

    With respect to prevention, he added, "the action of melatonin agonists like ramelteon is to re-establish a disturbed circadian rhythm. A combination of simple behavioral interventions - e.g. exposure to diurnal light-dark cycles, familiar objects, clocks/calendars, etc. - has been commonly recommended to help prevent delirium in clinical settings."

    Dr. Dan Blazer of Duke University Medical Center in Durham, author of a related editorial, told Reuters Health, "Delirium is one of the most frequent and frustrating disorders which physicians encounter in the hospital. We are constantly seeking new treatments, and our desire for an effective pharmacological intervention may lead us to draw conclusions which jump ahead of the empirical studies available."

    "For this reason, we must carefully review data which support novel treatments," he said by email. "A detailed review of the individual randomized clinical trials supporting a new treatment derived from a meta-analysis is therefore essential to delivering appropriate care to our patients."

    Dr. Peter Shapiro, Professor of Psychiatry at Columbia University Irving Medical Center in New York City, commented, "It may be that determining effectiveness depends on the patient population and the very specific criteria used to define a good response."

    "This study has blurred together many kinds of patients and many definitions of good response," he said by email. "Still, overall, I think it will tend to reinforce the practice of using haloperidol, maybe with the addition lorazepam more often now, at least to calm delirious patients with severe agitation that puts them at risk of injuring themselves, for example by pulling out IV lines and endotracheal tubes."

    Reuters Health Information © 2019

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