Daily sedation interruption versus no daily sedation interruption for critically ill adult patients requiring invasive mechanical ventilation

  • Review
  • Intervention

Authors

  • Lisa Burry,

    Corresponding author
    1. Mount Sinai Hospital, Leslie Dan Faculty of Pharmacy, University of Toronto, Department of Pharmacy, Toronto, Ontario, Canada
    • Lisa Burry, Department of Pharmacy, Mount Sinai Hospital, Leslie Dan Faculty of Pharmacy, University of Toronto, 600 University Avenue, Room 18-377, Toronto, Ontario, M5G 1X5, Canada. lburry@mtsinai.on.ca.

    Search for more papers by this author
  • Louise Rose,

    1. University of Toronto, Lawrence S. Bloomberg Faculty of Nursing, Toronto, ON, Canada
    2. University of Toronto, Critical Care Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
    Search for more papers by this author
  • Iain J McCullagh,

    1. Newcastle Hospitals NHS Foundation Trust and University of Newcastle, Department of Perioperative and Critical Care Medicine, Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, UK
    Search for more papers by this author
  • Dean A Fergusson,

    1. Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, ON, Canada
    Search for more papers by this author
  • Niall D Ferguson,

    1. University Health Network and Mount Sinai Hospital, University of Toronto, Interdepartmental Division of Critical Care Medicine, Toronto, ON, Canada
    Search for more papers by this author
  • Sangeeta Mehta

    1. Mount Sinai Hospital, University of Toronto, Interdepartmental Division of Critical Care Medicine, Toronto, ON, Canada
    Search for more papers by this author

Abstract

Background

Daily sedation interruption (DSI) is thought to limit drug bioaccumulation, promote a more awake state, and thereby reduce the duration of mechanical ventilation. Available evidence has shown DSI to either reduce, not alter, or prolong the duration of mechanical ventilation.

Objectives

The primary objective of this review was to compare the total duration of invasive mechanical ventilation for critically ill adult patients requiring intravenous sedation who were managed with DSI versus those with no DSI. Our other objectives were to determine whether DSI influenced mortality, intensive care unit (ICU) and hospital lengths of stay, adverse events, the total doses of sedative drug administered, and quality of life.

Search methods

We searched, from database inception to February 2014, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1); MEDLINE (OvidSP); EMBASE (OvidSP); CINAHL (EBSCOhost); Latin American and Caribbean Health Sciences Literature (LILACS); Web of Science Science Citation Index; Database of Abstracts of Reviews of Effects (DARE); the Health Technology Assessment Database (HTA Database); trial registration websites, and reference lists of relevant articles. We did not apply language restrictions. The reference lists of all retrieved articles were reviewed for additional, potentially relevant studies.

Selection criteria

We included randomized controlled trials that compared DSI with sedation strategies that did not include DSI in mechanically ventilated, critically ill adults.

Data collection and analysis

Two authors independently extracted data and three authors assessed risk of bias. We contacted study authors for additional information as required. We combined data in forest plots using random-effects modelling. A priori subgroups and sensitivity analyses were performed.

Main results

Nine trials were used in the analysis (n = 1282 patients). These trials were found to be predominantly at low risk of bias. We did not find strong evidence of an effect of DSI on the total duration of ventilation. Pooled data from nine trials demonstrated a 13% reduction in the geometric mean, with relatively wide confidence intervals (CI) indicating imprecision (95% CI 26% reduction to 2% increase, moderate quality evidence). Similarly, we did not find strong evidence of an effect on ICU length of stay (-10%, 95% CI -20% to 3%, n = 9 trials, moderate quality evidence) or hospital length of stay (-6%, 95% CI -18% to 8%, n = 8 trials, moderate quality evidence). Heterogeneity for these three outcomes was moderate and statistically significant. The risk ratio for ICU mortality was 0.96 (95% CI 0.77 to 1.21, n = 7 trials, moderate quality evidence), for rate of accidental endotracheal tube removal 1.07 (95% CI 0.55 to 2.12, n = 6 trials, moderate quality evidence), for catheter removal 1.48 (95% CI 0.76 to 2.90, n = 4 trials), and for incidence of new onset delirium 1.02 (95% CI 0.91 to 1.13, n = 3 trials, moderate quality evidence). Differences in the doses of any drug used or quality of life score (Short Form (SF)-36) did not reach statistical significance. Tracheostomy was performed less frequently in the DSI group (RR 0.73, 95% CI 0.57 to 0.92, n = 6 trials, moderate quality evidence). Sensitivity analysis of unlogged data resulted in similar findings. Post hoc analysis to further explain heterogeneity, based on study country of origin, showed that studies conducted in North America resulted in a reduction in the duration of mechanical ventilation (-21%, 95% CI -33% to -5%, n = 5 trials).

Authors' conclusions

We have not found strong evidence that DSI alters the duration of mechanical ventilation, mortality, length of ICU or hospital stay, adverse event rates, drug consumption, or quality of life for critically ill adults receiving mechanical ventilation compared to sedation strategies that do not include DSI. We advise that caution should be applied when interpreting and applying the findings as the overall effect of treatment is always < 1 and the upper limit of the CI is only marginally higher than the no-effect line. These results should be considered unstable rather than negative for DSI given the statistical and clinical heterogeneity identified in the included trials.

Resumo

Interrupção versus não interrupção diária da sedação para adultos em ventilação mecânica invasiva na UTI

Introdução

Acredita-se que a interrupção diária da sedação (IDS) seria útil para reduzir o acúmulo de drogas, promover no paciente um estado de maior consciência e, assim, reduzir a duração da ventilação mecânica. A evidência disponível apresenta resultados inconsistentes, com estudos mostrando que a IDS pode reduzir, manter inalterada ou até prolongar a duração da ventilação mecânica.

Objetivos

O objetivo primário desta revisão foi avaliar o efeito da IDS sobre a duração total da ventilação mecânica invasiva em adultos na UTI (unidade de terapia intensiva) com sedação endovenosa. Os outros objetivos foram avaliar a influência da IDS na mortalidade, na duração da internação na UTI e na duração total da internação hospitalar, na ocorrência de eventos adversos, nas doses totais de drogas sedativas administradas e na qualidade de vida dos pacientes.

Métodos de busca

As buscas foram realizadas nas seguintes bases de dados eletrônicas, desde sua criação até fevereiro de 2014: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, fascículo 1); MEDLINE (OvidSP); Embase (OvidSP); CINAHL (EBSCOhost); Latin American and Caribbean Health Sciences Literature (LILACS); Web of Science, Science Citation Index; Database of Abstracts of Reviews of Effects (DARE); the Health Technology Assessment Database (Database HTA).Também fizemos buscas nas plataformas de registro de ensaios clínicos e nas listas de referências dos artigos relevantes. Não houve restrições de idiomas. As listas de referências de todos os artigos recuperados foram revistas para identificar estudos adicionais e potencialmente relevantes.

Critério de seleção

Foram incluídos ensaios clínicos randomizados que compararam a IDS com estratégias de sedação sem IDS em adultos em uso de ventilação mecânica internados na UTI.

Coleta dos dados e análises

Dois autores extraíram independentemente os dados e três autores avaliaram o risco de viés dos estudos incluídos. Entramos em contato com os autores dos estudos originais para obter informações adicionais, conforme necessário. Combinamos os dados em metanálises usando o modelo de efeitos aleatórios. Análises de subgrupos e de sensibilidade previamente estabelecidas foram realizadas.

Principais resultados

Nove estudos (n = 1.282 pacientes) foram incluídos nas análises. A maioria desses estudos tinha baixo risco de viés. Não conseguimos encontrar fortes evidências de um efeito da IDS sobre a duração total da ventilação. A combinação dos dados dos nove estudos mostrou que a IDS levou a uma redução média de 13% na duração da ventilação, porém o intervalo de confiança de 95% (95% CI) foi relativamente grande (95 CI -26% a 2%), o que indica imprecisão (evidência de qualidade moderada). Da mesma forma, não encontramos fortes evidências de um efeito da IDS sobre a duração da internação na UTI (-10%, 95% CI - 20% a 3%, 9 estudos, evidência de qualidade moderada) ou sobre a duração da internação hospitalar total (-6%, 95% CI -18% a 8%, 8 estudos, evidência de qualidade moderada). A heterogeneidade das metanálises para esses três desfechos foi moderada e estatisticamente significativa. O risco relativo (RR) para mortalidade na UTI foi de 0,96 (95% CI 0.77 a 1,21; 7 estudos, evidência de qualidade moderada); o RR para extubação acidental foi de 1,07 (95% CI 0,55 de 2,12, 6 estudos, evidência de qualidade moderada); o RR para a remoção do cateter foi de 1,48 (95% CI 0,76 a 2,90, 4 estudos) e o RR para surgimento de novos episódios de delírio foi de 1,02 (95% CI 0,91 a 1,13; 3 estudos, evidência de qualidade moderada). Não houve diferença estatística significativa entre os grupos para as doses de qualquer droga usada ou nos escores de qualidade de vida (Short Form-36, SF-36). A traqueostomia foi realizada com menos frequência no grupo de IDS (RR 0,73, 95% CI 0,57 a 0,92; 6 estudos, evidência de qualidade moderada). A análise de sensibilidade de dados não registrados resultou em conclusões semelhantes. Realizamos análise post hoc para investigar os motivos da heterogeneidade entre os estudos. A combinação dos resultados dos estudos conduzidos na América do Norte mostrou uma redução significativa na duração da ventilação mecânica (-21%, 95% CI -33% -5%, 5 estudos).

Conclusão dos autores

Não encontramos evdiências robustas de que a IDS reduza a duração da ventilação mecânica, a mortalidade, a duração da internação hospitalar ou na UTI, as taxas de eventos adversos, o consumo de drogas ou que melhore a qualidade de vida de adultos em ventilação mecânica, em comparação com estratégias de sedação que não incluem a IDS. Essas conclusões e sua aplicabilidade prática devem ser interpretadas com cuidado, já que o efeito global do tratamento foi sempre < 1, e o limite superior do IC ficou apenas um pouco acima da linha da nulidade. Devido à heterogeneidade estatística e clínica entre os estudos incluídos nesta revisão sistemática, estes resultados devem ser considerados inconsistentes em vez de negativos para a IDS.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva)

Plain language summary

Does daily sedation interruption reduce the time critically ill adults spend on breathing machines compared to other sedation strategies?

Background: critically ill patients require life-support technologies such as mechanical ventilation (breathing machines) and can experience pain, anxiety, and sleep deprivation related to their illness. Good pain control and adequate sedation are important but too much sedative drug can increase the time on breathing machines and the chance of harmful effects such as pneumonia.

Medications that are available have many properties that make them difficult to use in critically ill patients. Without careful adjustments these properties can lead to a build up of drug in the body. These medications are given as continuous infusions, so that blood levels remain stable, and dose changes are left to clinician judgement. In order to avoid drug build up, several methods can be used to adjust doses. Some studies claim that an interruption, or stopping the drug for a period of time each day, will allow the body to clear the drugs and lead to patients being more awake and ready for earlier liberation from the breathing machine.

Search date: current to February 2014.

Study characteristics: we included nine studies involving 1282 critically ill patients receiving mechanical ventilation. Studies compared daily sedation interruption to strategies that did not include an interruption. Studies were conducted worldwide and involved both medical and surgical critically ill patients.

Key results: we did not find strong evidence that daily sedation interruption reduced the duration of mechanical ventilation, length of stay in the intensive care unit (ICU) or hospital, death, or the amount of drug used. The effect on adverse events such as accidental removal of the breathing tube or invasive devices, or the rate of delirium was uncertain. However, tracheostomy was performed less often in those who were managed with daily sedation interruption. Sedation practices are known to vary worldwide, and as such an analysis of studies conducted in North America showed a reduction in time on the breathing machine for those who were managed with daily sedation interruption compared to those who were not.

Quality of the evidence: we advise caution should be applied when interpreting and applying our study findings. The results are based upon a small number of studies that were heterogeneous or not uniform in terms of methods, patients studied, and clinical management and our overall results only marginally crossed the no-effect line.

Резюме на простом языке

Уменьшает ли ежедневное прерывание седации время пребывания на дыхательных аппаратах у критически больных взрослых по сравнению с другими методиками седации?

Актуальность: пациентам в критическом состоянии требуется применение жизнеобеспечивающих технологий, таких как искусственная вентиляция легких (дыхательные аппараты), и [они] могут страдать от боли, тревоги и лишения сна, связанные с их заболеванием. Хороший контроль боли и адекватная седация важны, но избыточность седативного лекарства может увеличить время пребывания на дыхательных аппаратах и риск повреждающих эффектов, таких как пневмония.

Имеющиеся лекарства обладают различными свойствами, которые делают их использование у критически больных затруднительным. Без тщательных корректировок эти свойства могут привести к накоплению лекарства в организме. Эти препараты вводят в виде непрерывной внутривенной инфузии таким образом, что их уровень в крови остается стабильным, а изменение дозы оставлено на усмотрение врача. Для того, чтобы избежать накопления лекарств, могут быть использованы несколько методов корректировки дозы. Некоторые исследования утверждают, что прерывание или остановка [введения] препарата на определенное время каждый день позволит очистить организм от лекарства, вести пациентов так, что они больше пребывают в состоянии бодрствования и готовы к более быстрому освобождению от дыхательного аппарата.

Дата поиска : Доказательства актуальны по февраль 2014 года.

Характеристики исследований: мы включили девять исследований с участием 1282 тяжелобольных пациентов, находящихся на искусственной вентиляции легких. Исследования сравнивали ежедневное прерывание седации с методиками, которые не включают прерывание. Исследования были проведены по всему миру и включали как терапевтических, так и хирургических больных в критическом состоянии.

Основные результаты: мы не нашли убедительных доказательств того, что ежедневное прерывание седации уменьшает продолжительность искусственной вентиляции легких, длительность пребывания в отделении интенсивной терапии (ОИТ) или в стационаре, смертность [пациентов] или количество использованного лекарства. Влияние на неблагоприятные события, такие, как случайное удаление дыхательной трубки или инвазивных аппаратов, или частоту развития делирия, было неопределенным. Однако, частота выполнения трахеостомии уменьшилась у тех пациентов, которых вели с ежедневным прерыванием седации. Практика седации, как известно, варьирует во всем мире, и, по существу, анализ исследований, проведенных в Северной Америке, показал сокращение времени искусственной вентиляции легких для тех [пациентов], кого вели с ежедневным прерыванием седации по сравнению с теми, кому это не проводилось.

Качество доказательств: мы советуем с осторожностью интерпретировать и применять результаты нашего исследования. Результаты основаны на небольшом числе исследований, которые были разнородными или не однородны с точки зрения методов изучения пациентов и клинического лечения, а также наши обобщенные результаты лишь незначительно пересекли линию отсутствия эффекта.

Заметки по переводу

Перевод: Кораблева Анна Александровна. Редактирование: Абакумова Татьяна Рудольфовна, Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет - аффилированный центр в Татарстане Северного Кокрейновского Центра. По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Laienverständliche Zusammenfassung

Vermindert eine tägliche Unterbrechung der Sedierung im Vergleich zu anderen Sedierungsstrategien die Dauer, die kritisch Kranke unter künstlicher Beatmung verbringen müssen?

Hintergrund: kritisch kranke Patienten benötigen lebenserhaltende Technologien, wie zum Beispiel künstliche Beatmung (Atemgeräte) und sie können Schmerzen, Angstgefühle und Schlafstörungen haben, die mit ihrer Krankheit zusammenhängen. Gute Schmerztherapie und ausreichende Sedierung sind wichtig, aber zu starke Medikamente können die Dauer der künstlichen Beatmung verlängern und die Wahrscheinlichkeit für gesundheitsschädliche Wirkungen, wie eine Pneumonie, erhöhen.

Verfügbare Medikamente haben viele Eigenschaften, die ihre Anwendung bei kritisch kranken Patienten erschweren. Ohne vorsichtige Anpassungen können diese Eigenschaften dazu führen, dass sich das Medikament im Körper ansammelt. Diese Medikamente werden als Dauerinfusion verabreicht, sodass ihre Konzentration im Blut stabil bleibt. Änderungen in der Dosierung unterliegen dem Ermessen des Klinikers. Um das Ansammeln des Medikamentes zu vermeiden, können verschiedene Methoden angewandt werden, um die Dosis anzupassen. Einige Studien behaupten, dass ein tägliches Unterbrechen oder Absetzen des Medikamentes über einen Zeitraum, es dem Körper erleichtert, das Medikament abzubauen und dazu führt, dass Patienten wacher und bereit für eine frühere Entwöhnung der künstlichen Beatmung sind.

Datum der letzten Suche: auf dem Stand von Februar 2014.

Studienmerkmale: wir schlossen neun Studien mit 1282 kritisch kranken Patienten ein, die künstliche Beatmung erhielten. Die Studien verglichen eine tägliche Unterbrechung der Sedierung mit Strategien, die keine Unterbrechung umfassten. Die Studien wurden weltweit durchgeführt und schlossen sowohl medizinisch als auch chirurgisch kritisch kranke Patienten ein.

Hauptergebnisse: Wir fanden keine starke Evidenz dafür, dass eine tägliche Unterbrechung der Sedierung die Dauer der künstlichen Beatmung, des Aufenthaltes auf der Intensivstation oder im Krankenhaus verkürzt und Todesfälle oder die Menge der gebrauchten Medikamente vermindert. Die Wirkung auf unerwünschte Ereignisse, wie beispielsweise die unbeabsichtigte Entfernung des Trachealtubus oder Katheters, oder die Rate der Delirien war unklar. Jedoch wurde eine Tracheotomie seltener bei Patienten durchgeführt, die mit täglichen Unterbrechungen sediert wurden. Es ist bekannt, dass Sedierungspraktiken weltweit variieren, und als solche zeigte eine Analyse der Studien, die in Nordamerika durchgeführt wurden, eine Verminderung der Dauer der künstlichen Beatmung bei allen, die mit täglichen Unterbrechungen sediert wurden, im Vergleich zu denen, deren Sedierung nicht täglich unterbrochen wurde.

Qualität der Evidenz: Wir raten zur Vorsicht in der Interpretation und Anwendung unserer Studienergebnisse. Die Ergebnisse basieren auf einer geringen Anzahl von Studien, die heterogen oder nicht einheitlich in Bezug auf ihre Methoden, Patienten, und die klinische Behandlung waren und unser Gesamtergebnis schnitt nur geringfügig die Keinen-Effekt-Linie.

Anmerkungen zur Übersetzung

K. Kunzweiler und I.Töws, Koordination durch Cochrane Schweiz.

Resumo para leigos

A interrupção diária da sedação, comparada a outras estratégias de sedação, reduz o tempo em que adultos entubados na UTI (unidade de terapia intensiva) precisam ficar ligados a aparelhos de ventilação artificial?

Introdução: Alguns pacientes em condições críticas podem precisar de aparelhos como os respiradores artificiais (ventilação mecânica) para continuar vivos e podem experimentar dor, ansiedade e privação do sono em decorrência da sua doença. Controle da dor e sedação adequada são importantes, mas o uso de uma grande quantidade de sedativos pode prolongar o tempo que esses pacientes ficam nos respiradores e a possibilidade de eles terem efeitos nocivos, como a pneumonia.

Os medicamentos disponíveis têm muitas propriedades que os tornam difíceis de usar em pacientes muito graves. Sem ajustes cuidadosos, essas propriedades podem levar a uma acumulação dessas drogas no corpo. Esses remédios geralmente são dados através de infusões contínuas diretamente na veia, para que os níveis sanguíneos permaneçam estáveis, e os médicos é que decidem como ajustar a dose desses remédios. Para evitar o acúmulo desses remédios, existem vários métodos para ajustar as doses. Alguns estudos afirmam que uma interrupção completa (suspender) das drogas por um período de tempo a cada dia, ajuda que o corpo as elimine, o que permite que os pacientes fiquem mais alertas e assim poderiam se livrar mais cedo do respirador artificial.

Data da busca: atualizada em fevereiro de 2014.

Características dos estudos: foram incluídos nove estudos, envolvendo 1.282 pacientes criticamente enfermos e em ventilação mecânica. Os estudos compararam a interrupção diária da sedação com estratégias que não incluíssem essa interrupção. Os estudos foram realizados em diversos países e incluíram tanto pacientes clínicos como cirúrgicos (depois de terem sido operados), todos eles em condições muito graves.

Principais resultados: não encontramos evidências fortes de que a interrupção diária da sedação reduza a duração da ventilação mecânica, o tempo de permanência na unidade de terapia intensiva (UTI) ou no hospital, a taxa de mortalidade ou a quantidade de droga usada. O efeito sobre os eventos adversos (como remoção acidental do tubo endotraqueal ou de outros aparelhos) e sobre a taxa de delírio mostrou-se incerto. No entanto, a traqueostomia foi realizada menos frequentemente nos pacientes que fizeram a interrupção diária da sedação. Como as práticas de sedação variam bastante em todo o mundo, fizemos uma análise apenas dos estudos realizados na América do Norte. Essa análise mostrou que a interrupção diária da sedação diminuiu o tempo que os pacientes permaneciam nos respiradores artificiais, em comparação com aqueles que não fizeram essa pausa diária.

Qualidade da evidência: É necessário cuidado na interpretação e aplicação prática dos nossos achados. Os resultados são baseados em um pequeno número de estudos que foram heterogêneos ou não uniformes em termos de métodos, pacientes estudados e condutas adotadas pelos médicos. Além disso, nossos resultados gerais ficaram muito próximos da linha de nenhum efeito (ou seja, foi pequena a diferença a favor da interrupção diária da sedação).

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva)

Summary of findings(Explanation)

Summary of findings for the main comparison. Daily sedation interruption compared to usual care or protocolized sedation strategies that do not include daily sedation interruption for critically ill adult patients requiring invasive mechanical ventilation
  1. 1 Daily sedation interruption is defined as a short-term suspension, hold, discontinuation, cessation, or interruption of intravenous sedatives (continuous infusions or fixed dose bolus), and in some cases, analgesic medications. The goal is to limit drug bioaccumulation, promote a more awake state, permit assessment of patient tolerance of drug discontinuation, neurological status, and readiness for liberation from mechanical ventilation.
    2 The assumed risks are derived from the large epidemiological study of characteristics and outcomes in patient (n = 4968) receiving mechanical ventilation by Esteban 2008. Reported medians are used as an approximation for the means used for illustrative comparisons of continuous variables.

Daily sedation interruption compared to usual care or protocolized sedation strategies that do not include daily sedation interruption for critically ill adult patients requiring invasive mechanical ventilation
Patient or population: critically ill adult patients requiring invasive mechanical ventilation
Settings: intensive care units
Intervention: daily sedation interruption1
Comparison: usual care or protocolized sedation strategies that do not include daily sedation interruption
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Usual care or protocolized sedation strategies that do not include daily sedation interruption Daily sedation interruption
Total duration of mechanical ventilation (days)
Follow-up: 0 to 90 days
Mean 4.0 days2Mean 3.5 daysGeometric mean difference - 13% (-26%, 2%)1282
(9 studies)
⊕⊕⊕⊝
moderate

We detected substantial heterogeneity explained only in part by differences in study population

We also detected a wide confidence interval suggesting imprecision

ICU length of stay (days)
Follow-up: 0 to 90 days
Mean 8.0 days2Mean 7.5 daysGeometric mean difference - 6% (-19%, +8%)1282
(9 studies)
⊕⊕⊕⊕
moderate
 
Hospital length of stay (days)
Follow-up: 0 to 90 days
Mean 17.0 days2Mean 16.7 daysGeometric mean difference -2% (-16% to +14%)1232
(8 studies)
⊕⊕⊕
moderate
 
Tracheostomy
Follow-up: 0 to 90 days
Moderate2RR 0.73
(0.57 to 0.92)
1061
(6 studies)
⊕⊕⊕
moderate
We detected a wide confidence interval suggesting imprecision
4.1%3.0%
Accidental removal of ETT
Follow-up: 0 to 90 days
Moderate2RR 1.07
(0.55 to 2.12)
1108
(6 studies)
⊕⊕⊕
moderate
We detected a wide confidence interval suggesting imprecision
3.5%3.7%
ICU mortalityModerate2RR 0.96
(0.77 to 1.21)
815
(7 studies)
⊕⊕⊕
moderate
We detected a wide confidence interval suggesting imprecision
31.0%29.8%
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; ICU: intensive care unit
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Critically ill patients require life-support technologies such as invasive mechanical ventilation and the patients experience pain, sleep deprivation, and anxiety related to their acute illness. Analgesics and sedatives are commonly used in the intensive care unit (ICU) to promote patient comfort and safety. An international audit of sedation practices in more than 5000 patients in 361 ICUs across 20 countries found that 68% of patients received a sedative while mechanically ventilated; the use of sedatives was associated with longer durations of mechanical ventilation and ICU stay (Arroliga 2005). Over the last 10 years, numerous studies have confirmed the link between sedation and other adverse patient consequences including delirium, delayed mobilization, long-term psychological morbidity, and cognitive impairment (Girard 2007; Jackson 2007; Kress 2003; Pandharipande 2007; Riker 2007; Samuelson 2006; Schweickert 2004).

Achieving optimal sedation for critically ill patients is challenging because of factors such as fluctuating acuity of illness, disease-associated encephalopathy, pre-morbid psychiatric disorders, drug or alcohol consumption, and unpredictable pharmacokinetics associated with organ dysfunction (for example, renal or hepatic dysfunction, hypoalbuminaemia). Characteristics of the ideal drug for critically ill patients include minimal bioaccumulation, ease of dose adjustment, tolerable adverse effects, few drug interactions, and low cost. None of the currently available sedative agents satisfy all of these criteria. Sedation administration strategies that potentially address the limitations of available drug therapies include use of agents with ultra-short therapeutic half-lives, sedation minimization with intermittent bolus dosing rather than continuous infusions, sedation protocols, and daily sedation interruption (DSI). The primary goal of these strategies is to reduce drug bioaccumulation and therefore limit the potential for oversedation and associated consequences. 

Description of the intervention

DSI is defined as a short-term suspension, hold, discontinuation, cessation, or interruption of intravenous sedatives (continuous infusions or fixed dose bolus) and, in some cases, analgesic medications. The goal of DSI is to limit drug bioaccumulation; promote a more awake state; and permit assessment of neurological status, patient tolerance of drug discontinuation, and readiness for liberation from mechanical ventilation. Sedation is typically interrupted in the morning, but timing may be based on practicalities such as ward rounds, workload, and other required procedures. The intervention involves suspending drug therapy during which time the patient is observed until either awake, uncomfortable, or agitated, based on a sedation assessment scale or physiologic signs such as tachypnoea and tachycardia. 'Awake' is typically defined as being able to obey simple commands such as opening eyes, visually tracking the care provider, sticking out the tongue, and squeezing a hand. If the patient is awake and comfortable, infusions are not recommenced. If ongoing sedation is required the drug is typically restarted at 50% of the previous dose, with subsequent titration using a sedation score.

How the intervention might work

Continuous drug administration provides more consistent plasma concentrations than intermittent dosing, thereby optimizing patient comfort. However, this strategy may result in drug bioaccumulation and associated oversedation, particularly when using medications that have active metabolites or have long therapeutic half-lives. DSI decreases the potential for bioaccumulation and provides an opportunity to evaluate ongoing drug requirements, as well as weaning and extubation readiness. Thus total drug consumed should be lower.

Why it is important to do this review

DSI has been evaluated in several randomized trials, with varied results. The first trial evaluating DSI reported a 2.4 day reduction in the duration of mechanical ventilation and a 3.5 day reduction in ICU stay compared to usual sedation practice (that is non-standardized) that did not include DSI (Kress 2000). Results of subsequent trials have been inconsistent as DSI has been shown to shorten (Girard 2008), not alter (Mehta 2012), or prolong (de Wit 2008) the duration of mechanical ventilation. Augustes and Ho conducted a meta-analysis of trials comparing DSI with no interruption in critically ill mechanically ventilated patients (Augustes 2011). Their analysis included trials published up to April 2010; five trials met the analysis inclusion criteria, for a total of 699 patients. Pooled results showed that DSI was not associated with a significant reduction in duration of mechanical ventilation (odds ratio (OR) 0.72 days, 95% confidence interval (CI) -2.49 to 3.92, P = 0.66, I2 = 71%), length of ICU stay (OR 0.16 days, 95% CI -3.30 to 3.62, P = 0.93, I2 = 84%), or mortality (OR 0.84, 95% CI 0.58 to 1.21, P = 0.35, I2 = 19%); or an increased risk of self-extubation (OR 1.3, 95% CI 0.41 to 4.10, P = 0.65, I2 = 49%). DSI was associated with a reduced risk of requiring tracheostomy (OR 0.57, 95% CI 0.35 to 0.92, P = 0.02, I2 = 3%).

The 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit that were developed by the Society of Critical Care Medicine recommend the use of either targeted minimal sedation or DSI unless clinically contraindicated (Barr 2013). Other professional societies (Martin 2010; Mattia 2006) and organizations promoting uptake of evidence-based healthcare and patient safety initiatives (for example, IHI) also recommend the use of DSI. International surveys of perceived practice have reported variable adoption of sedation minimization strategies with generally low utilization of DSI (Burry 2009; Bertolini 2001; Martin 2006; Mehta 2009; Payen 2007; Varney Gill 2012; Woien 2012). Reported reluctance to routinely apply DSI relates to concerns about patient pain and discomfort, clinical instability and respiratory compromise, accidental removal of endotracheal tubes and catheters, and the perceived need for constant observation during the interruption and associated increased work load (Burry 2011b; Roberts 2010; Tanios 2009). At present it is unclear if DSI for critically ill adults is more effective than other sedative administration strategies in minimizing sedation doses and reducing the duration of mechanical ventilation without increasing adverse events and workload. Given the varied results of previous trials and endorsement by professional societies yet poor clinical adoption due to clinicians' concerns of safety, an updated systematic review is warranted to provide clinicians with clarity on the benefits as well as reassurance about the safety of DSI.

Objectives

The primary objective of this review was to compare the total duration of invasive mechanical ventilation for critically ill adult patients requiring intravenous sedation who were managed with DSI versus those with no DSI. Our other objectives were to determine whether DSI influenced mortality, ICU and hospital lengths of stay, adverse events, the total doses of sedative drug administered, and quality of life.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials (RCTs) that compared DSI with other sedation administration strategies including sedation protocols, usual care, and targeting of sedation to a sedation assessment scale. We excluded quasi-randomized and non-randomized studies.

Types of participants

We included adult patients (≥ 16 years of age) receiving any type of invasive mechanical ventilation and sedation in an intensive care setting.

Types of interventions

We compared two sedation administration strategies: DSI (as defined by study authors) and sedation strategies that did not include DSI. Other sedation strategies for comparison included:

  1. usual sedation practice existing in the ICU (as stated by the authors) that did not incorporate DSI; and

  2. sedation protocols, guidelines, and sedation assessment tools without DSI. 

Intravenous sedation and analgesia used as continuous infusions or fixed frequency bolus doses in the critical care setting included: midazolam, lorazepam, diazepam, propofol, clonidine, dexmedetomidine, ketamine, tramadol, morphine, fentanyl, hydromorphone, sufentanil, alfentanil, and remifentanil. A priori, we anticipated that the selection of continuous infusions to suspend during DSI would be variable (sedative only versus sedative and analgesic).

Types of outcome measures

Primary outcomes

The primary outcome was the total duration of invasive mechanical ventilation (time in days from intubation to successful extubation, defined as no requirement for either reintubation or recommencement of mechanical ventilation in the case of tracheostomy for 48 hours, or as defined by study authors, or death).

Secondary outcomes
  1. Mortality (ICU mortality; 28-day, 60-day, or 90-day mortality; hospital mortality)

  2. Length of stay (ICU, hospital)

  3. Time to first extubation (time in days from intubation to first extubation)

  4. Number of patients experiencing adverse events including accidental removal of endotracheal tube or catheter, new onset of delirium, cardiac events (ST-elevation myocardial infarction (STEMI) or non-STEMI)

  5. Total sedative and analgesic doses

  6. Quality of life (after hospital discharge, three-month, six-month, one-year) as reported by study authors

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1); MEDLINE (OvidSP) (1950 to February 2014); EMBASE (OvidSP) (1980 to February 2014); CINAHL (EBSCOhost) (1982 to February 2014); and Latin American and Caribbean Health Sciences Literature (LILACS) (1986 to February 2014). We conducted citation searching using the Web of Science Citation Index. We searched the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database) for published reviews pertinent to our topic. We combined our search terms in MEDLINE with the Cochrane highly sensitive search strategy for identifying randomized controlled trials (Appendix 1). We adapted our MEDLINE search strategy for other databases (Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8). We limited our searches to RCTs, systematic reviews, and meta-analyses and applied a filter to limit to humans. We did not impose a language restriction.

Searching other resources

We searched conference proceedings using the Web of Science ISI Proceedings (2001 to February 2014). We handsearched the conference proceedings of the annual congresses of the European Society of Intensive Care Medicine, the Society of Critical Care Medicine, American Association of Critical Care Nurses, Australian New Zealand Intensive Care Society, and the American Thoracic Society (from 2005 to 2013). 

We searched for unpublished studies and ongoing trials on the following websites:

  1. clinicaltrials.gov/;

  2. www.controlled-trials.com/mrct/; and

  3. www.who.int/trialsearch.

We handsearched the reference lists of all retrieved studies for additional, potentially relevant studies. We contacted the corresponding author of eligible trials as well as content experts to identify other potentially relevant studies.

Data collection and analysis

Selection of studies

One author (LB) piloted the study selection form on a sample of five studies (Appendix 9). Two authors (LB and LR) independently examined each title and abstract retrieved from the electronic and manual searches using the study selection form to identify potentially eligible studies. References were organized in the reference manager EndNote (Version X6, Thomson Reuters, Carlsbad, CA, USA) with reasons for exclusion documented in the notes field. Full-texts of articles selected by either author from the review of the title and abstract were examined independently to determine inclusion. We resolved disagreements by discussion without the need to refer to our independent arbiter (NF).

Data extraction and management

We (LB, LR) developed a data extraction form and one author (LB) evaluated it on five studies to ensure all required data were collected (Appendix 10). Two authors (SM and IM) independently extracted the data using the standardized data extraction form, on: first author, year of publication, study design, inclusion and exclusion criteria, study population and setting, patient characteristics, detailed description of the study interventions, and outcomes. We also extracted data on randomization methods, allocation concealment, blinding, frequency and handling of missing data, adherence to intention to treat, and selective reporting of outcomes (Higgins 2011). We (SM, LB) attempted to contact corresponding authors to seek clarification on issues of reporting or to obtain further study details. Given our familiarity with the literature we did not blind data extractors to the names of study authors.

Assessment of risk of bias in included studies

Two authors (SM, IM) independently assessed the quality of included studies; quality was verified by a third author (LB). Quality of included studies was assessed based on the domain-based evaluation as recommended by The Cochrane Collaboration (Higgins 2011). These domains include:

  1. random sequence generation (selection bias);

  2. allocation concealment (selection bias);

  3. blinding of participants and personnel (performance bias);

  4. blinding of outcomes assessment (detection bias);

  5. incomplete outcome data (attrition bias);

  6. selective reporting (selective reporting);

  7. other bias.

For each domain we assessed the risk of bias as 'low risk', ‘high risk', or 'unclear’ if insufficient detail was reported. Once quality assessment was agreed upon we assigned studies to the following categories:

  1. low risk of bias, describes studies for which all domains are scored as ‘low risk of bias’;

  2. high risk of bias, two or more domains scored as high risk of bias; and

  3. unclear risk of bias, one or more domains scored as unclear.

We generated a risk of bias graph and risk of bias summary. As anticipated, blinding was rarely applied.

Measures of treatment effect

We described treatment effect using risk ratios (RR) for dichotomous data and mean differences (MD) and 95% confidence intervals (CI) for continuous data. Continuous variables (duration of mechanical ventilation, ICU and hospital LOS) were log transformed due to expected skewness. We calculated pooled estimates using the random-effects model (REM) to allow for adjustments due to heterogeneity and to incorporate variation both within and between studies (DeMets 1987).

We had planned to calculate the ratio of mean values to account for missing standard deviations (Friedrich 2008) but this was not required as standard deviations were available for all included trials. We considered (two-sided) P < 0.05 as significant.

Unit of analysis issues

The unit of analysis was individual participants in each trial arm. As anticipated, all included trials were parallel-group design so no adjustment was necessary for crossover or clustering.

Dealing with missing data

For missing data, we sent a maximum of three e-mails to the corresponding author to request missing information.

Assessment of heterogeneity

We assessed each included trial for statistical and clinical heterogeneity. We evaluated statistical heterogeneity using the I2 statistic and the Chi2 test, with P < 0.05 indicative of heterogeneity. We applied the categorisation values described by Higgins who assigned the descriptors of low, moderate, and high heterogeneity to I2 values of 25%, 50%, and 75% respectively (Higgins 2003). It is known that sedation practices vary greatly internationally (Mehta 2009), and as such included trials may have had vastly different sedation practices in the control group. We planned to describe clinical heterogeneity qualitatively by examination of the country of study origin as well as the sedation and weaning methods provided in each trial. The use of sedation minimization strategies to avoid the ill effects of prolonged sedation has been endorsed by professional societies since 2002 and so we planned to examine the year of study publication. Only one trial was published prior to 2002 so there were insufficient data to conduct further analysis.

Assessment of reporting biases

Reporting biases occur due to an increased likelihood of positive trials, large or small, being published compared to negative trials. We constructed and visually inspected funnel plots to assess for possible publication bias in Review Manager 5.2 (RevMan 5.2). We tested for funnel plot asymmetry using the test proposed by Egger due to the continuous nature of our primary outcome variable (Egger 1997).

Data synthesis

One author (LB) entered data in Revman 5.2 (RevMan 5.2). Two authors (LB, DF) conducted the analyses and reported summary statistics for the data. Due to considerable skewness of our continuous variables we log transformed the data. Corresponding authors of four trials (Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011) transformed the raw data to provide means and standard deviations on the log scale. One author (de Wit 2008) provided raw data which we log transformed. For four studies (Anifantaki 2009; Girard 2008; Kress 2000; Yilmaz 2010) approximations were used to log transform means and standard deviations obtained from study authors, using the method described by Higgins 2011.

We identified sufficient studies to perform meta-analyses of our primary and secondary outcomes. The difference in the mean of a variable on the log scale between the intervention and control groups was exponentiated to provide the ratio of geometric means on the unlogged scale. We reported this as a percentage increase or reduction in geometric mean in the treatment group versus the control group for ease of understanding (Bland 1996). Findings are presented in the summary of findings table.

Subgroup analysis and investigation of heterogeneity

We conducted the following subgroup analyses.

  1. Use of a co-intervention that may influence patient outcomes. Specifically use of (a) a sedation guideline or protocol and (b) strategies to facilitate timely weaning including weaning protocols or spontaneous breathing trials, or both, in the control arm.

  2. Use of sedative or analgesic agents, or both, that have minimal risk of bioaccumulation or no active metabolites (propofol, remifentanil, dexmedetomidine).

  3. Exposure to DSI (compliance), defined as the number of DSIs per days of ventilation. There was insufficient reporting to conduct this analysis.

Sensitivity analysis

We conducted two sensitivity analyses:

  1. to explore the effect on total duration of mechanical ventilation, length of ICU stay, and length of hospital stay prior to log-transforming the data; and

  2. to assess the effect of excluding studies with high risk of bias on the pooled estimate of the duration of mechanical ventilation.

Summary of findings table

We assessed the quality of the evidence associated with the total duration of invasive mechanical ventilation, mortality, ICU and hospital lengths of stay, the number of patients experiencing adverse events, total sedation dose, and quality of life using the principles of the GRADE system (Guyatt 2008). The GRADE system assesses within-study risk of bias (methodological quality), directness of evidence, data heterogeneity, precision of effect estimates, and risk of publication bias. We presented our findings using a 'Summary of findings' (SoF) table (Summary of findings for the main comparison).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

We included RCTs of adult patients receiving invasive mechanical ventilation and sedation in ICUs. We identified eligible RCTs with an intervention arm that included DSI as part of the sedation management strategy. Sedation management for control arms included usual care (that is usual methods of sedation management at the study sites) and written sedation strategies such as titration protocols that did not include DSI. We excluded quasi-randomized or non-randomized studies.

Results of the search

See: Figure 1.

Figure 1.

Study flow diagram.

The electronic database search described above identified 7041 citations. We retrieved 23 references for full-text assessment. Nine of these studies met the inclusion criteria. Quality of life was reported for three trials (Girard 2008; Kress 2000; Mehta 2012) but in separate subsequent publications (Jackson 2010; Kress 2003; Rose 2013). We excluded three abstracts (Carson 2005; de Wit 2006; Anifantaki 2007) identified from conference proceedings; these abstracts were subsequently published in full-text and were identified within the 23 references retrieved for full-text assessment. The remaining eight studies did not meet the inclusion criteria.

From trial registries we identified six citations for further consideration. One trial was published and already identified in our electronic database search; one was eligible and ongoing; and one was eligible, completed but not yet published, however, the authors supplied unpublished data for analysis, and the study has since been published (Nassar 2014). Three trials were not eligible for inclusion: one did not include DSI in either study group; one included DSI in both study groups; and one was an observational study. Two abstracts were identified by experts in the field: one abstract reporting quality of life conducted by members of our authorship team (Rose 2013) and one abstract reporting on the primary endpoint, which was duration of mechanical ventilation (Binnekade 2009).

Included studies

See: Characteristics of included studies table.

We included nine trials with 1282 participants. We have provided detailed descriptions of the trials in the 'Characteristics of included studies' table. Sample sizes of these trials ranged from 50 to 430 participants. Four trials were multi-centre studies (Girard 2008; Mehta 2008; Mehta 2012; Weisbrodt 2011) and the remainder were conducted in a single ICU. Two trials (de Wit 2008; Kress 2000) enrolled only medical patients and the remainder (Anifantaki 2009; Girard 2008; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011; Yilmaz 2010) enrolled mixed ICU populations that included medical, surgical, and trauma patients. No trial was conducted in just surgical or cardiac ICU patients. Nine trials reported the duration of mechanical ventilation, which was our primary outcome measure. Quality of life was reported for three trials (Girard 2008; Kress 2000; Mehta 2012) but in separate subsequent publications (Jackson 2010; Kress 2003; Rose 2013). 

For all trials the process of DSI involved interruption of continuous sedation until the patient was awake and able to follow simple commands (for example, open eyes). One trial applied a maximum duration of interruption of six hours (Weisbrodt 2011); in all other trials the duration of interruption was not directed by the study protocol. All trials interrupted sedative agents and six trials also interrupted continuous opioid infusions (de Wit 2008; Kress 2000; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011). One trial reduced the opioid dose but did not interrupt the opioid (Anifantaki 2009), one trial allowed analgesia for active pain during sedation interruption (Girard 2008), and one trial did not describe whether opioids were interrupted (Yilmaz 2010). In all trials medications were restarted at 50% of the previous dose and re-titrated if the patient required ongoing therapy.

Clinical practices such as those related to the drug classes administered, use of sedation protocols, management of agitation and use of physical restraints, staffing ratios, open versus closed ICU model, hierarchy of decision making, and use of weaning protocols varied between studies and should be considered when examining the included studies. Some of these factors have been shown in surveys to differ greatly based on the country examined. We have summarized key clinical practices in the studies identified that may have influenced individual study findings (Table 1). The majority of trials were conducted in North America: USA (de Wit 2008; Girard 2008; Kress 2000) and Canada (Mehta 2008; Mehta 2012). Other trials were conducted in Australia (Weisbrodt 2011), Greece (Anifantaki 2009), Turkey (Yilmaz 2010), and Brazil (Nassar 2014). Four trials used ‘usual sedation practices’ in the control arm with sedation and analgesia managed at the clinical team’s discretion (Anifantaki 2009; Girard 2008; Kress 2000; Weisbrodt 2011). A sedation protocol was used in the control arm for five trials (de Wit 2008; Mehta 2008; Mehta 2012; Nassar 2014; Yilmaz 2010); two applied the same protocol in the DSI group (Mehta 2008; Mehta 2012). All trials included a sedation assessment scale for management of sedation in both the control and intervention arms; frequency of assessment ranged from hourly to every eight hours. No trial used a pain assessment scale. A standardized approach to assessing readiness for extubation was used in five trials (de Wit 2008; Girard 2008; Mehta 2008; Mehta 2012; Nassar 2014). The drug regimens selected for each study protocol varied: four trials permitted only benzodiazepines and opioids (de Wit 2008; Mehta 2008; Mehta 2012; Weisbrodt 2011), two trials used propofol or a benzodiazepine for sedation and an opioid for analgesia (Kress 2000; Nassar 2014), two trials allowed the clinician's discretion for the choice of sedative or analgesic (Girard 2008; Yilmaz 2010), and one trial allowed use of any drug but suggested the first choice should be the short-acting agents propofol and remifentanil (Anifantaki 2009).

Table 1. Factors that may explain study heterogeneity
StudyOpen vs. closed ICUNurse staffing ratioSedation decision making in the control armTraining prior to study initiationCompliance with initiating DSIManagement of agitationUse of physical restraintsStandardized mechanical ventilation or weaning strategies
Anifantaki 2009Not reported1:2 or 1:2.5Usual care - physicians driven

Not reported. DSI

intervention by

study personnel

75.5% of study

days; Note - DSI applied to 46.% of

control group

Not reportedNot reportedNot reported
de Wit 2008ClosedNot reportedNurse directed protocolYes, 2 month training programReported as 79 of 179 screening episodes

Study drugs resumed @ 50% and re-titrated;

Use of other medications

permitted but not reported

Not reportedYes
Girard 2008ClosedNot reportedUsual care - physician & nurse drivenNot reported90% complianceStudy drugs resumed @ 50% and re-titratedNot reportedYes
Kress 2000Open1:1 or 1:2Usual care - physician drivenNot reported100% in DSI group; 18 of 60 in the control group had infusions interrupted temporarilyStudy drugs resumed @ 50% and re-titratedNot reportedNot reported
Mehta 2008Closed1:1 or 1:2Nurse directed protocolYes, inservices82.2%

Study drugs resumed @ 50% and re-titrated; If pt because extremely agitated

sedative therapy could deviate from protocol as directed by clinical team

Not reportedYes
Mehta 2012Closed1:1 or 1:2Nurse directed protocolYes, inservices72.2%Study drugs resumed @ 50% and re-titrated; antipsychotics permitted˜ 75% both groupsYes
Nassar 2014Closed1:4Attending nurse titrated based on pain scaleNot reportedNot reportedStudy drugs resumed @ 50% and re-titrated; antipsychotic permitted for deliriumNot reportedYes
Weisbrodt 2011Closed1:1Usual care by clinical teamNot reportedreported as 30% of eligible daysStudy drug stopped and prescribed sedative restartedNot reportedNo
Yilmaz 2010Not reportedNot reportedNurse titrated protocol based on physician directionNot reportedNot reportedStudy drugs could be increased if sedation score indicated agitation and additional drugs could be used if patient still agitatedNot reportedNo

Excluded studies

See: Characteristics of excluded studies table.

We excluded eight RCTs. In six trials DSI was included in both the control and the intervention arms (Amor 2007; Carson 2006; Ruokonen 2009; Strom 2010) or not included in either study arm (Bein 2008; Brook 1999). One study was deemed to be a duplicate as it presented a re-analysis of data already published and included in this review (Kress 2001). We also excluded one study (Oto 2011) as it evaluated a different question than we had selected (the study evaluated sleep architecture from a single night polysomnography). We also excluded three abstracts from conference proceedings as they were already published in full and were identified in the 23 retrieved references (Carson 2005; de Wit 2006; Anifantaki 2007).

Risk of bias in included studies

The ‘Risk of bias’ tables present details of the performance of trials for each domain. Figure 2 and Figure 3 provide a visual summary of the judgement of the methodological quality. Most trials were assessed as low risk of bias across the six domains with the exception of blinding of participants and personnel. As anticipated, blinding was rarely applied (Figure 2; Figure 3).

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We judged the risk of bias due to random sequence generation to be low in eight trials and unclear in one (Anifantaki 2009). Three trials used central allocation (Girard 2008; Mehta 2008; Mehta 2012) and five used sequentially numbered sealed, opaque envelopes (de Wit 2008; Kress 2000; Nassar 2014; Weisbrodt 2011; Yilmaz 2010). In one trial (Anifantaki 2009) we were unable to obtain information regarding allocation concealment.     

Blinding

Given the nature of the intervention, blinding of participants and personnel was problematic. In seven trials clinicians were unblinded to allocation group (Anifantaki 2009; de Wit 2008; Girard 2008; Mehta 2008; Mehta 2012; Nassar 2014; Yilmaz 2010). Lack of blinding may have influenced the duration of the DSI, the amount of drug delivered if titration was not according to a protocol, and more importantly the decision to extubate. Therefore, we judged the risk of bias due to lack of blinding of clinicians as high for these trials. In two trials ICU clinicians were blinded to allocation group. One trial provided a blinded study infusion bag (placebo or sedation) during the DSI (Weisbrodt 2011). However, clinicians may have suspected treatment allocation due to changes in patient behaviour as the drug effect wore off during DSI. In the other trial (Kress 2000) the patients' allocation to DSI or control was known only to study personnel; research personnel not directly involved in the patients' clinical care performed the DSI. It was unclear how blinding was maintained as sedatives and analgesics were administered on an open-label basis and what role the clinical nurses played in the care of the patients during the DSI. The investigators also attempted to minimize risk of bias due to lack of blinding by not disclosing study endpoints to clinicians. This may have influenced open label sedation management practices, mechanical ventilation decisions, and outcome assessments.

No trial used blinded outcome assessment. However, outcomes such as duration of mechanical ventilation, length of stay, and mortality are not subject to interpretation and thus we considered the risk of bias to be unclear for all nine trials.

Incomplete outcome data

We judged all trials to be at low risk of attrition bias as all used intention-to-treat analysis or had no missing data.  

Selective reporting

We judged all trials to be at low risk of reporting bias as reported primary and secondary outcomes were consistent with described methods. 

Other potential sources of bias

Of the nine trials included in the pooled analysis, all appeared to be free of other sources of bias. A priori sample size calculations were available for six trials (Anifantaki 2009; de Wit 2008; Girard 2008; Kress 2000; Mehta 2012; Nassar 2014), two trials were feasibility studies and thus not powered to the primary endpoint we had selected (Mehta 2008; Weisbrodt 2011); sample size calculations were not available for one trial (Yilmaz 2010).

Effects of interventions

See: Summary of findings for the main comparison Daily sedation interruption compared to usual care or protocolized sedation strategies that do not include daily sedation interruption for critically ill adult patients requiring invasive mechanical ventilation

See: summary of findings for the main comparison (Summary of findings for the main comparison).

All nine trials presented data suitable for inclusion in this meta-analysis. First we present our primary analysis comprising the duration of mechanical ventilation and lengths of ICU and hospital stay, and doses of medication using log transformation to account for considerable skew in the data.

We present subgroup analyses of:

  1. use of a sedation protocol;

  2. use of weaning protocols or spontaneous breathing trials; and

  3. use of medications that have minimal risk of bioaccumulation.

Our secondary analysis comprised sensitivity analyses of the total duration of mechanical ventilation, lengths of ICU and hospital stay with the unlogged data. We did not conduct a sensitivity analysis of log-transformed data excluding trials assessed as high risk of bias for the primary outcome; none of the nine trials were scored as at high risk of bias. 

Total duration of mechanical ventilation

Total duration of mechanical ventilation was available for nine trials (n = 1282 patients). The pooled result indicated no difference in the total duration of mechanical ventilation (mean log days -0.14, 95% CI –0.30 to 0.02, P = 0.08). This corresponded to a 13% reduction in the geometric mean (95% CI 26% reduction to 2% increase). There was moderate heterogeneity (I² = 61%). There was no difference in the duration of mechanical ventilation according to the sedation strategy used in the control arm: sedation protocol, mean log days -0.07, 95% CI -0.28 to 0.13, P = 0.48; 7% reduction in the geometric mean, 95% CI 24% reduction to 14% increase, I² = 43%; usual care, mean log days -0.21, 95% CI -0.47 to 0.04, P = 0.10; 19% reduction in geometric mean, 95% CI 37% reduction to 4% increase, I² = 70%. Subgroup analyses according to method of extubation readiness assessment showed: no difference in the duration of mechanical ventilation with standardized spontaneous breathing trials (mean log days -0.09, 95% CI -0.27 to 0.09, P = 0.33; 9% reduction in the geometric mean, 95% CI 24% reduction to 11% increase, I² = 52%) or usual care (mean log days -0.22, 95% CI -0.54 to 0.10, P = 0.17; 20% reduction in the geometric mean, 95% CI 42% reduction to 11% increase, I² = 72%). Subgroup analysis according to type of sedative agent used found no difference in the duration of ventilation for drugs with minimal bioaccumulation (mean log days -0.16, 95% CI -0.39 to 0.08, P = 0.19; 15% reduction in the geometric mean 95% CI 32% reduction to 8% increase, I² = 72%) (Analysis 1.2; Analysis 1.3; Analysis 1.4; Figure 4).

Figure 4.

Forest plot of comparison: 1 Total duration of mechanical ventilation, outcome: 1.1 Duration of mechanical ventilation (log days).

We attempted to explain potential sources of heterogeneity by examining the following variables post hoc: country of study origin; year study published. We did not conduct the analysis based on year of publication as all trials but one (Kress 2000) were published after 2002. We chose this time as in 2002 the Society of Critical Care Medicine published clinical practice guidelines that endorsed the use of DSI and the use of other minimal sedation practices such as the use of a sedation protocol and thus may have altered mainstream sedation practices. Most trials were conducted in North America. Pooled analysis of these five studies (de Wit 2008; Girard 2008; Kress 2000; Mehta 2008; Mehta 2012) demonstrated a reduction in the duration of ventilation (mean log days -0.23, 95% CI -0.40 to -0.05, P = 0.01; equivalent to a 21% reduction in the geometric mean 95% CI 5% to 33% reduction, I² = 56%). However, pooled analysis of four studies conducted outside of North America (Anifantaki 2009; Nassar 2014; Weisbrodt 2011; Yilmaz 2010) demonstrated no difference in the duration of mechanical ventilation (mean log days -0.02, 95% CI -0.33 to 0.29, P = 0.91; 2% reduction in the geometric mean, 95% CI 28% reduction to 34% increase, I² = 61%) (Analysis 1.5; Figure 5).

Figure 5.

Forest plot of comparison: 1 Total duration of mechanical ventilation, outcome: 1.5 Duration of mechanical ventilation by country of origin (log days).

Mortality

Seven trials (Anifantaki 2009; de Wit 2008; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011; Yilmaz 2010) reported ICU mortality, one trial reported 28-day mortality, and one trial reported hospital mortality. No trial reported 60 or 90-day mortality. Pooled data demonstrated no difference in overall mortality (RR 0.88, 95% CI 0.75 to 1.05, P = 0.15, I² = 0%) between the DSI and control groups. Pooled data for ICU mortality similarly demonstrated no difference (RR 0.96, 95% CI 0.77 to 1.21, P = 0.75, I² = 0%). There was no difference in hospital mortality (RR 0.76, 95% CI 0.50 to 1.15, P = 0.19) or 28-day mortality (RR 0.82, 95% CI 0.59 to 1.12, P = 0.21) (Analysis 2.1).

Length of stay – ICU and hospital

Length of ICU stay was reported in all nine studies. Pooled data identified no difference in ICU stay (mean log days -0.10, 95% CI -0.22 to 0.03, P = 0.13; 10% reduction in geometric mean, 95% CI 20% reduction to 3% increase, I² = 45%). Eight trials (Anifantaki 2009; de Wit 2008; Girard 2008; Kress 2000; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011) reported hospital length of stay with no difference in duration between DSI and non-DSI groups (mean log days -0.06, 95% CI -0.20 to 0.08, P = 0.44; 6% reduction in the geometric mean, 95% CI 18% reduction to 8% increase, I² = 39%) (Analysis 3.1; Analysis 3.2).

Time to first extubation

No trial reported time to first extubation.

Adverse events

Accidental removal of the endotracheal tube (ETT) was reported in six trials (Anifantaki 2009; Girard 2008; Kress 2000; Mehta 2008; Mehta 2012; Nassar 2014) with no difference found between study groups (RR 1.07, 95% CI 0.55 to 2.12, P = 0.84, I² = 31%). Tracheostomy rates, reported in six trials (Girard 2008; Kress 2000; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011), were lower in the DSI group (RR 0.73, 95% CI 0.57 to 0.92, P = 0.009, I² = 0%). Four trials (Kress 2000; Mehta 2008; Mehta 2012; Nassar 2014) reported on removal of catheters; there was no difference in the rate of removal of catheters or devices (RR 1.48, 95% CI 0.76 to 2.90, P = 0.25, I² = 0%). New onset delirium was reported in three trials (Girard 2008; Mehta 2012; Nassar 2014) (RR 1.02, 95% CI 0.91 to 1.13, P = 0.78, I² = 0%). We did not pool new cardiac adverse events as data were reported in only two trials (Mehta 2008; Mehta 2012) (Analysis 4.1; Analysis 5.1; Analysis 6.1; Analysis 7.1).

Total sedation doses

Mean total drug doses for various sedatives and analgesics were available from eight trials: seven trials had benzodiazepine dose data (Anifantaki 2009; de Wit 2008; Kress 2000; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011) available as midazolam equivalents and one trial presented lorazepam equivalents (Girard 2008). For this trial we converted lorazepam equivalents to midazolam equivalents (conversions 0.5 mg lorazepam = 1 mg midazolam). Three trials had morphine data available (Anifantaki 2009; Mehta 2008; Weisbrodt 2011), six trials (de Wit 2008; Girard 2008; Mehta 2008; Mehta 2012; Nassar 2014; Weisbrodt 2011) had fentanyl data,and six trials (Anifantaki 2009; de Wit 2008; Girard 2008; Kress 2000; Nassar 2014; Weisbrodt 2011) had propofol data. There was no difference in drug dose for midazolam (mean log dose (mg) 0.00, 95% CI -0.68 to 0.69, P = 1.00), equivalent to a 0% difference (95% CI 49% reduction to 99% increase in the geometric mean, I² = 91%); morphine (mean log dose (mg) -0.18, 95% CI -0.70 to 0.33, P = 0.48), a 16% reduction (95% CI 50% reduction to 39% increase in the geometric mean, I² = 0%); fentanyl (mean log dose (µg) -0.15, 95% CI -0.69 to 0.39, P = 0.54), a 14% reduction (95% CI 50% reduction to 48% increase in the geometric mean, I² = 86%); or propofol (mean log dose (mg) 0.29, 95% CI -0.21 to 0.80, P = 0.26), a 34% increase (95% CI 19% reduction to 125% increase in the geometric mean, I² = 80%) (Analysis 8.1; Analysis 8.2; Analysis 8.3; Analysis 8.4).

Quality of life

Quality of life was reported for three trials (Girard 2008; Kress 2000; Mehta 2012) but in separate subsequent publications (Jackson 2010; Kress 2003; Rose 2013). Each reported on quality of life using the Short Form-36 (SF-36). All three trials reported the individual scores for the physical and mental health domains of SF-36; only one trial reported total score (Rose 2013). There was no difference in the physical or mental health domains comparing the DSI and control groups: physical domain MD of score of -0.92 (95% CI 2.16 reduction to 0.33 increase, P = 0.15, I² = 0%); mental domain MD of score of 1.08 (95% CI 2.55 reduction to 4.71 increase, P = 0.56, I² = 56%) (Analysis 9.1; Analysis 9.2).

Sensitivity analyses using unlogged data

We conducted this analysis to explore the effects of DSI prior to log-transforming the data. For eight trials we obtained means and standard deviations from the corresponding authors, for the remaining trial the mean and standard deviation were taken from the published manuscript (Yilmaz 2010). Pooled results for the duration of mechanical ventilation showed no difference (mean -1.04 days, 95% CI -4.17 to 2.09, P = 0.51) with substantial heterogeneity present (I² = 91%). Pooled results for lengths of ICU and hospital stay showed no difference (ICU mean -0.85 days, 95% CI -2.42 to 0.72, P = 0.29, I² = 36%; hospital mean -0.46 days, 95% CI 4.00 reduction to 3.09 increase, P = 0.80, I² = 36%) (Analysis 10.1; Analysis 10.2; Analysis 10.3).

Sensitivity analyses excluding studies with high risk of bias

No trial included in the analysis met the definition of high risk of bias (two or more domains scored as high risk of bias) so further analysis was not required.

Funnel plots

Funnel plots did not show asymmetry and thus publication bias is not likely to be present, however the power is low with only nine studies (Figure 6).

Figure 6.

Funnel plot of comparison: 1 Total duration of mechanical ventilation, outcome: 1.1 Duration of mechanical ventilation (log days).

Discussion

Summary of main results

See: Summary of findings for the main comparison (Summary of findings for the main comparison).

We identified nine RCTs that included 1282 patients as eligible for our analysis. The primary outcome, total duration of mechanical ventilation, was reported in all nine trials. Pooled analysis using both log-transformed (due to skewed data) and unlogged data showed that DSI did not reduce the total duration of mechanical ventilation compared to sedation strategies that did not include DSI. We advise that caution should be taken when interpreting and applying the findings as there was moderate and statistically significant heterogeneity among the studies. As well, the overall effect of treatment is always < 1 and the upper limit of the CI is only marginally higher than the no-effect line. Thus we believe these results should be considered unstable given the statistical and clinical heterogeneity identified in the included trials. Subgroup analyses according to the sedation titration method in the control group, standardized assessment of extubation readiness, and use of drugs with limited bioaccumulation did not demonstrate a difference in the duration of ventilation. Yet we did find a reduction in the duration of mechanical ventilation when trials conducted outside of North America were excluded. There was no difference in ICU and hospital lengths of stay, mortality, adverse events rates, drug consumption, or quality of life with DSI compared to other sedation strategies. We did show a reduction of tracheostomy rates in favour of DSI.

Overall completeness and applicability of evidence

We believe there were sufficient trials to address our study objectives. Our meta-analysis is based upon nine trials that administered DSI in a similar fashion to primarily medical or mixed ICU populations. However, results for the one primary and most secondary outcomes demonstrated moderate heterogeneity. Surveys of perceived clinical practice report variable adoption of sedation strategies that are endorsed by practice guidelines, with substantial international variation (Bertolini 2001; Mattia 2006; Mehta 2009; Payen 2007; Varney Gill 2012; Woien 2012). Likely contextual factors within study ICUs or related to country of origin that influence 'usual care' sedation and weaning practices account for differences in the duration of mechanical ventilation. As such we did find a reduction in the duration of mechanical ventilation when trials conducted outside of North America were excluded.

Where available, we extracted from each trial the potential differences in usual care practices including nurse to patient ratio, hierarchy of decision making, choice of method used to titrate study medications, management of agitation once the patient awakened (for example, types of medication used, use of physical restraints), differences in mechanical ventilation practices including determining and initiating readiness to wean, ventilatory parameters used for weaning, timing of sedative interruption, and compliance with the intervention to help explain heterogeneity. As with any intervention it is important to consider exposure to the study intervention and as such we had planned a subgroup analysis based on compliance with DSI. There was insufficient information to conduct this analysis.

Quality of the evidence

We advise that caution should be taken when interpreting and applying our findings. The quality of the evidence for the outcomes was moderate and indicated imprecision in the effect estimates as the overall results only marginally crossed the no-effect line. The results are based upon a small number of studies that were heterogeneous in terms of methods, the patients studied, and clinical management.

Potential biases in the review process

We believe we completed an all-inclusive literature search to identify all relevant trials. Our search strategy was developed with a senior librarian who has extensive systematic review experience. As well, our search included review of reference lists of literature, abstracts from conference proceedings, and trial databases relevant to our topic. We believe we have minimized the potential for introduction of bias in the review process as we adhered to all procedures outlined by The Cochrane Collaboration.

Agreements and disagreements with other studies or reviews

We identified one systematic review investigating the effect of DSI on duration of mechanical ventilation (Augustes 2011). The review included five RCTs identified from the CENTRAL, MEDLINE, and EMBASE databases, searched from 1966 to April 2010. The pooled data for 699 patients indicated no difference in the duration of mechanical ventilation, length of ICU or hospital stay, mortality, or number of adverse events with DSI compared to sedation strategies that did not include DSI. Our review expanded the number of databases, searched to February 2014, and identified nine eligible trials with a total of 1282 patients that had similar findings.

Authors' conclusions

Implications for practice

Oversedation has been associated with a number of negative clinical outcomes and as such sedation titration strategies that aim to reduce drug exposure are now endorsed by various clinical societies (Barr 2013; Martin 2010; Mattia 2006). The recent Clinical Practice Guidelines from the Society of Critical Care Medicine for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit recommend either DSI or titration to achieve minimal sedation be routinely used in mechanically ventilated adults unless clinically contraindicated (Barr 2013). Our review does not provide strong evidence that DSI influences the duration of mechanical ventilation, mortality, length of stay, drug consumption, quality of life, or adverse events compared to sedation strategies that do not include DSI.

We suggest caution should be used when applying our findings due to the moderate and statistically significant heterogeneity identified, and the overall effect of treatment is always < 1 with the upper limit of the CI only marginally higher than the no-effect line. Although it is not clear why DSI did not alter patient outcomes, we postulate there was no difference because drug consumption was similar between study arms. The aim of DSI is to prevent drug accumulation, reduce overall drug exposure, and permit assessment of neurological status, patient tolerance of drug discontinuation, and readiness for extubation. Thus DSI should result in a reduction of total drug consumed and this should result in reduced duration of mechanical ventilation as seen in the first DSI trial published (Kress 2000). We note that individual trials that showed a significant reduction in duration of mechanical ventilation in favour of DSI also showed significant reduction in drug consumption (Girard 2008; Kress 2000; Yilmaz 2010) and reported 90% or greater compliance with DSI (Girard 2008; Kress 2000).

Implications for research

There are several important implications for research arising from our review. Consideration should be given to patients' medication and alcohol consumption histories as drug withdrawal states may be unmasked during DSI resulting in agitation and increased drug administration following DSI. Opioids and benzodiazepines remain the mainstay for analgesia and sedation for mechanically ventilated patients worldwide (Mehta 2009). Recent studies indicate that the type of sedative administered influences duration of mechanical ventilation and incidence of delirium and coma (Pandharipande 2007; Riker 2007) resulting in the recommendation to minimize the use of benzodiazepines in the most recent sedation guidelines (Barr 2013). We were able to explore the effect of DSI when drugs that do not result in significant bioaccumulation were permitted but were unable to evaluate the effect of DSI on drug regimens that excluded benzodiazepines.

Future research should consider strategies to blind outcome assessment and, if possible, the intervention. Clinician decision making can influence duration of mechanical ventilation and, as such, assessment of readiness for weaning and extubation should be standardized and outcomes independently assessed by a blinded clinician or researcher.

Delirium has been recently established as an independent predictor of negative outcomes including prolonged duration of mechanical ventilation and increased mortality (Ely 2001; Ely 2004). As delirium may influence clinical outcomes, is common in mechanically ventilated patients, and can be linked to the selection of specific medications such as benzodiazepines and opioids, delirium incidence should be evaluated in future trials. Future trials should explore drug utilization immediately following the DSI to determine if consumption increases in response to agitation or presence of delirium.

Acknowledgements

We would like to acknowledge Elizabeth Uleryk, Director of the Hospital Library and Archives, The Hospital for Sick Children, Toronto, Ontario, Canada for her assistance with generating our search strategies.

We would also like to thank Jane Cracknell (Managing Editor, Cochrane Anaesthesia Review Group); Nicola Petrucci (content editor, Cochrane Anaesthesia Review Group); Nathan Pace (statistical editor); Bronagh Blackwood, John P Kress and Marjolein de Wit (peer reviewers); and Janet Wale (CARG consumer editor) for their review and editorial advice.

Data and analyses

Download statistical data

Comparison 1. Total duration of mechanical ventilation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Duration of mechanical ventilation91282Mean Difference (IV, Random, 95% CI)-0.14 [-0.30, 0.02]
2 Duration of mechanical ventilation by use of a protocol91282Mean Difference (IV, Random, 95% CI)-0.14 [-0.30, 0.02]
2.1 Use of a sedation protocol5672Mean Difference (IV, Random, 95% CI)-0.07 [-0.28, 0.13]
2.2 Usual care (no sedation protocol)4610Mean Difference (IV, Random, 95% CI)-0.21 [-0.47, 0.04]
3 Duration of mechanical ventilation by strategies to facilitate weaning91282Mean Difference (IV, Random, 95% CI)-0.14 [-0.30, 0.02]
3.1 Use of weaning protocol or spontaneous breathing trials or both5957Mean Difference (IV, Random, 95% CI)-0.09 [-0.27, 0.09]
3.2 Usual care (no weaning protocol or spontaneous breathing trial)4325Mean Difference (IV, Random, 95% CI)-0.22 [-0.54, 0.10]
4 Duration of mechanical ventilation by type of drug91282Mean Difference (IV, Random, 95% CI)-0.14 [-0.30, 0.02]
4.1 Drug regimen included drug with minimal bioaccumulation6744Mean Difference (IV, Random, 95% CI)-0.16 [-0.39, 0.08]
4.2 Drug regimen did not include drug regimen with minimal bioaccumulation3538Mean Difference (IV, Random, 95% CI)-0.11 [-0.25, 0.03]
5 Duration of mechanical ventilation by country of origin91282Mean Difference (IV, Random, 95% CI)-0.14 [-0.30, 0.02]
5.1 North American studies51025Mean Difference (IV, Random, 95% CI)-0.23 [-0.40, -0.05]
5.2 Non-North American studies4257Mean Difference (IV, Random, 95% CI)-0.02 [-0.33, 0.29]
Analysis 1.1.

Comparison 1 Total duration of mechanical ventilation, Outcome 1 Duration of mechanical ventilation.

Analysis 1.2.

Comparison 1 Total duration of mechanical ventilation, Outcome 2 Duration of mechanical ventilation by use of a protocol.

Analysis 1.3.

Comparison 1 Total duration of mechanical ventilation, Outcome 3 Duration of mechanical ventilation by strategies to facilitate weaning.

Analysis 1.4.

Comparison 1 Total duration of mechanical ventilation, Outcome 4 Duration of mechanical ventilation by type of drug.

Analysis 1.5.

Comparison 1 Total duration of mechanical ventilation, Outcome 5 Duration of mechanical ventilation by country of origin.

Comparison 2. Mortality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality91278Risk Ratio (M-H, Random, 95% CI)0.88 [0.75, 1.05]
1.1 ICU mortality7815Risk Ratio (M-H, Random, 95% CI)0.96 [0.77, 1.21]
1.2 28-Day mortality1335Risk Ratio (M-H, Random, 95% CI)0.82 [0.59, 1.12]
1.3 Hospital mortality1128Risk Ratio (M-H, Random, 95% CI)0.76 [0.50, 1.15]
Analysis 2.1.

Comparison 2 Mortality, Outcome 1 Mortality.

Comparison 3. Length of stay
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ICU length of stay91282Mean Difference (IV, Random, 95% CI)-0.10 [-0.22, 0.03]
2 Hospital length of stay81232Mean Difference (IV, Random, 95% CI)-0.06 [-0.20, 0.08]
Analysis 3.1.

Comparison 3 Length of stay, Outcome 1 ICU length of stay.

Analysis 3.2.

Comparison 3 Length of stay, Outcome 2 Hospital length of stay.

Comparison 4. Adverse event - accidental removal of endotracheal tube (ETT)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 accidental removal of ETT61108Risk Ratio (M-H, Random, 95% CI)1.07 [0.55, 2.12]
Analysis 4.1.

Comparison 4 Adverse event - accidental removal of endotracheal tube (ETT), Outcome 1 accidental removal of ETT.

Comparison 5. Adverse event - accidental removal of catheters
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Accidental removal of catheters4676Risk Ratio (M-H, Random, 95% CI)1.48 [0.76, 2.90]
Analysis 5.1.

Comparison 5 Adverse event - accidental removal of catheters, Outcome 1 Accidental removal of catheters.

Comparison 6. Adverse event - tracheostomy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Tracheostomy61061Risk Ratio (M-H, Random, 95% CI)0.73 [0.57, 0.92]
Analysis 6.1.

Comparison 6 Adverse event - tracheostomy, Outcome 1 Tracheostomy.

Comparison 7. Adverse event - delirium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Delirium3818Risk Ratio (M-H, Random, 95% CI)1.02 [0.91, 1.13]
Analysis 7.1.

Comparison 7 Adverse event - delirium, Outcome 1 Delirium.

Comparison 8. Total drug doses
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Benzodiazepine (midazolam equivalents)81153Mean Difference (IV, Random, 95% CI)0.00 [-0.68, 0.69]
2 Opioid - morphine3212Mean Difference (IV, Random, 95% CI)-0.18 [-0.70, 0.33]
3 Opioid - fentanyl6995Mean Difference (IV, Random, 95% CI)-0.15 [-0.69, 0.39]
4 Propofol6634Mean Difference (IV, Random, 95% CI)0.29 [-0.21, 0.80]
Analysis 8.1.

Comparison 8 Total drug doses, Outcome 1 Benzodiazepine (midazolam equivalents).

Analysis 8.2.

Comparison 8 Total drug doses, Outcome 2 Opioid - morphine.

Analysis 8.3.

Comparison 8 Total drug doses, Outcome 3 Opioid - fentanyl.

Analysis 8.4.

Comparison 8 Total drug doses, Outcome 4 Propofol.

Comparison 9. Health-related quality of life - Short Form-36 (SF-36)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Physical Domain, 6 months or more post discharge3275Mean Difference (IV, Random, 95% CI)-0.92 [-2.16, 0.33]
2 Mental Domain, 6 months or more post discharge3275Mean Difference (IV, Random, 95% CI)1.08 [-2.55, 4.71]
Analysis 9.1.

Comparison 9 Health-related quality of life - Short Form-36 (SF-36), Outcome 1 Physical Domain, 6 months or more post discharge.

Analysis 9.2.

Comparison 9 Health-related quality of life - Short Form-36 (SF-36), Outcome 2 Mental Domain, 6 months or more post discharge.

Comparison 10. Sensitivity analysis - unlogged data
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 outcome total duration of mechanical ventilation [days]91282Mean Difference (IV, Random, 95% CI)-1.04 [-4.17, 2.09]
2 outcome ICU length of stay [days]91282Mean Difference (IV, Random, 95% CI)-0.85 [-2.42, 0.72]
3 outcome hospital length of stay [days]81154Mean Difference (IV, Random, 95% CI)-0.46 [-4.00, 3.09]
Analysis 10.1.

Comparison 10 Sensitivity analysis - unlogged data, Outcome 1 outcome total duration of mechanical ventilation [days].

Analysis 10.2.

Comparison 10 Sensitivity analysis - unlogged data, Outcome 2 outcome ICU length of stay [days].

Analysis 10.3.

Comparison 10 Sensitivity analysis - unlogged data, Outcome 3 outcome hospital length of stay [days].

Appendices

Appendix 1. Ovid MEDLINE search strategy

(1950 to December 2012)

1. critical care/ or intensive care/ or intensive care units/ or burn units/ or coronary care units/ or respiratory care units/
2. "hypnotics and sedatives"/ or dexmedetomidine/ or diazepam/ or lorazepam/ or midazolam/ or propofol/ or exp Fentanyl/ or remifentanyl.mp. or Benzodiazepines/ or clonidine/ or ketamine/ or hydromorphone/ or morphine/ or sufentanil/ or conscious sedation/ or deep sedation/ or Tramadol/
3. ((interrup* or hold or holds or holding or vacation* or holiday* or cessation* or cease* or stop or stops or stopping or stopped or suspend* or withhold* or (target adj2 based) or (spontaneous adj2 awaken*)) adj5 sedat*).ti,ab.
4. (randomised controlled trial.pt. or randomised controlled trials as topic/ or randomised controlled trials/ or random allocation/ or double-blind method/ or single-blind method/ or (random* or (doubl* adj2 dummy) or ((Singl* or doubl* or trebl* or tripl*) adj5 (blind* or mask*)) or RCT or RCTs or (control* adj5 trial*) or multicent* or placebo* or metaanalys* or (meta adj5 analys*) or guideline.pt. or practice guideline.pt. or sham or effectiveness or efficacy or compar*).ti,ab. or Clinical Protocols/ ) and (humans/ not animals/)
5. (1 and 2 and 4) or (3 and 4)

Appendix 2. EMBASE (OvidSP) search strategy

(1980 to December 2012)

1. burn unit/ or coronary care unit/ or intensive care unit/ or intensive care/ or exp intensive care nursing/
2. exp central depressant agent/ or exp hypnotic sedative agent/ or exp narcotic agent/ or exp central depressant agent/ or exp hypnotic sedative agent/ or exp narcotic agent/ or dexmedetomidine/ or benzodiazepine derivative/ or benzodiazepine/ or diazepam/ or diazepam derivative/ or lorazepam/ or benzodiazepine derivative/ or benzodiazepine/ or diazepam/ or benzodiazepine receptor stimulating agent/ or midazolam/ or midazolam maleate/ or anesthetic agent/ or fospropofol/ or intravenous anesthetic agent/ or ketamine/ or propofol/ or narcotic analgesic agent/ or diamorphine/ or fentanyl derivative/ or hydromorphone/ or morphine/ or morphine 6 acetate/ or morphine 6 glucuronide/ or morphine sulfate/ or morphinomimetic agent/ or morphinone/ or normorphine/ or opiate/ or tramadol/ or narcotic agent/ or diamorphine/ or fentanyl derivative/ or remifentanyl.mp. or clonidine/ or sufentanil/ or sufentanil citrate/ or conscious sedation/ or deep sedation/
3. ((interrup* or hold or holds or holding or vacation* or holiday* or cessation* or cease* or stop or stops or stopping or stopped or suspend* or withhold* or (target adj2 based) or (spontaneous adj2 awaken*)) adj5 sedat*).ti,ab.
4. (randomised controlled trial/ or double blind procedure/ or single blind procedure/ or triple blind procedure/ or ct.fs. or (random* or (doubl* adj2 dummy) or ((Singl* or doubl* or trebl* or tripl*) adj5 (blind* or mask*)) or RCT or RCTs or (control* adj5 trial*) or multicent* or placebo* or metaanalys* or (meta adj5 analys*) or sham or effectiveness or efficacy or compar*).ti,ab. or practice guideline/ or clinical pathway/ or clinical protocol/ or nursing care plan/ or nursing protocol/) and (human/ not animals/)
5. (1 and 2 and 4) or (3 and 4)

Appendix 3. CINAHL (EBSCOhost) search strategy

1982 to December 2012

S1 (MH "Critical Care") OR (MH "Intensive Care Units") OR (MH "CoronaryCare Units") OR (MH "Respiratory Care Units") OR (MH "Stroke Units") OR (MH "Burn Units")
S2 (MH "Hypnotics and Sedatives") OR (MH "Diazepam") OR (MH "Lorazepam") OR (MH "Midazolam") OR (MH "Propofol") OR (MH "Triazolam") OR (MH "Fentanyl") OR (MH "Antianxiety Agents, Benzodiazepine") OR (MH "Clonidine") OR (MH "Ketamine") OR (MH "Dihydromorphinone") OR (MH "Morphine") OR (MH "Sufentanil") OR (MH "Conscious Sedation") OR (MH"Sedation") OR TX dexmedetomidine OR remifentanyl OR "deep N2 sedat*"
S3 TX ((interrup* OR awaken* OR hold$ OR vacation* OR holiday* OR cessation* OR cease* OR stop$ OR suspend* OR withhold*) and sedation) OR TX ("target N2 based") OR TX ("spontaneous N2 awaken*")
S4 (S1 AND S2) OR S3

Appendix 4. CENTRAL (The Cochrane Library)

CENTRAL, The Cochrane Library,2012, Issue 12

#1 MeSH descriptor: [Critical Care] explode all trees
#2 MeSH descriptor: [Intensive Care] explode all trees
#3 MeSH descriptor: [Intensive Care Units] explode all trees
#4 MeSH descriptor: [Burn Units] explode all trees
#5 MeSH descriptor: [Coronary Care Units] explode all trees
#6 MeSH descriptor: [Respiratory Care Units] explode all trees
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 MeSH descriptor: [Hypnotics and Sedatives] explode all trees
#9 MeSH descriptor: [Dexmedetomidine] explode all trees
#10 MeSH descriptor: [Diazepam] explode all trees
#11 MeSH descriptor: [Lorazepam] explode all trees
#12 MeSH descriptor: [midazolam] explode all trees
#13 MeSH descriptor: [propofol] explode all trees
#14 MeSH descriptor: [Fentanyl] explode all trees
#15 MeSH descriptor: [Benzodiazepines] explode all trees
#17 MeSH descriptor: [clonidine] explode all trees
#18 MeSH descriptor: [ketamine] explode all trees
#19 MeSH descriptor: [hydromorphone] explode all trees
#20 MeSH descriptor: [morphine] explode all trees
#21 MeSH descriptor: [sufentanil] explode all trees
#22 MeSH descriptor: [conscious sedation] explode all trees
#23 MeSH descriptor: [deep sedation] explode all trees
#24 MeSH descriptor: [Tramadol] explode all trees
#25 (remifentanyl or (central depressant agent*) or (narcotic agent*) or (hypnotic sedative agent*) or diazepam*or lorazepam or benzodiazepine*or midazolam* or an?esthetic*or fospropofol or etamine* or propofol or (narcotic analgesic*) or diamorphine or fentanyl* or hydromorphone or morphin* or normorphine or opiate* or tramadol or clonidine* or sufentanil*):ti,ab
#26 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25
#27 ((interrup* or hold* or vacation* or holiday* or cessation* or cease* or stop* or suspend* or withhold* or (target near based) or (spontaneous near awaken*)) near sedat*)
#28 (#7 and #26) or #27

Appendix 5. LILACS (Latin American and Caribbean Health Sciences Literature) search strategy

1986 to December 2012

("INTERRUPT" or "INTERRUPTED" or "INTERRUPTING" or "INTERRUPTION" or "INTERRUPTIONS" or "CEAS$" or "HOLD$" or or "STOP$" or or "VACATION$" or "HOLIDAY$" or "SUSPEND$" or "SUSPENSION" or "WITHHOLD$") and ("HYPNOTIC$"" OR "sedatives" OR "dexmedetomidine" OR "diazepam" OR "lorazepam" OR "midazolam" OR "propofol" OR "fentanyl" OR "remifentanyl" OR "benzodiazepine" OR "clonidine" OR "ketamine" OR "hydromorphone" OR "morphine" OR "sufentanil" OR "tramadol")

Appendix 6. Web of Science search strategy

#1 TS=((critical OR intensive OR burn OR coronary OR cardiac OR respiratory) SAME (care OR unit*))       
#2 TS=(hypnotic* OR sedat* OR dexmedetomidine OR diazepam OR lorazepam OR midazolam OR propofol OR Fentanyl OR remifentanyl OR Benzodiazepine* OR clonidine OR ketamine OR hydromorphone* OR morphine* OR sufentanil OR tramadol) OR TS=((conscious OR deep) SAME sedat*)
#3 TS=(time OR interrup* OR hold OR holds OR holding OR vacation* OR holiday* OR cessation* OR cease* OR stop OR stops OR stopping OR stopped OR suspend* OR withhold*) OR TS=(target SAME based) OR TS=(spontaneous SAME awaken*) OR TS=((physiologic or drug) SAME monitor*)  
#4 #3 OR (#2 AND #1)  
#5 TS=(random* OR RCT* OR multicent* OR placebo* OR meta?analys* OR sham OR effectiveness OR efficacy OR compar*) OR TS=(control* SAME trial*) OR TS=(doubl* SAME dummy) OR TS=((Singl* or doubl* or trebl* or tripl*) SAME (blind* or mask*))
#6 #5 AND #4   

Appendix 7. DARE - Database of Abstracts of Reviews of Effects

1. critical care/ or intensive care/ or intensive care units/ or burn units/ or coronary care units/ or respiratory care units/ or ((critical or intensive or burn or coronary or cardiac or respiratory) adj5 (care or unit*)).mp.
2. "hypnotics and sedatives"/ or dexmedetomidine/ or diazepam/ or lorazepam/ or midazolam/ or propofol/ or exp Fentanyl/ or remifentanyl.mp. or Benzodiazepines/ or clonidine/ or ketamine/ or hydromorphone/ or morphine/ or sufentanil/ or conscious sedation/ or deep sedation/ or Tramadol/ or ("hypnotics and sedatives" or dexmedetomidine or diazepam or lorazepam or midazolam or propofol or Fentanyl or remifentanyl or Benzodiazepine* or clonidine or ketamine or hydromorphone* or morphine* or sufentanil or ((conscious or deep) adj5 sedat*) or Tramadol).mp.
3. 1 and 2

Appendix 8. EBM Reviews - Health Technology Assessment

1) critical care/ or intensive care/ or intensive care units/ or burn units/ or coronary care units/ or respiratory care units/ or ((critical or intensive or burn or coronary or cardiac or respiratory) adj5 (care or unit*)).mp.
2) "hypnotics and sedatives"/ or dexmedetomidine/ or diazepam/ or lorazepam/ or midazolam/ or propofol/ or exp Fentanyl/ or remifentanyl.mp. or Benzodiazepines/ or clonidine/ or ketamine/ or hydromorphone/ or morphine/ or sufentanil/ or conscious sedation/ or deep sedation/ or Tramadol/ or ("hypnotics and sedatives" or dexmedetomidine or diazepam or lorazepam or midazolam or propofol or Fentanyl or remifentanyl or Benzodiazepine* or clonidine or ketamine or hydromorphone* or morphine* or sufentanil or ((conscious or deep) adj5 sedat*) or Tramadol).mp.
3) 1 and 2

Appendix 9. Study screening form

Screening Form: Daily Sedative Interruption Systematic Review

Reviewer Initials__ __Review Date _ _ /_ _ /_ _ (dd/mm/yy)
Primary Author 
Citation (journal, year, vol, pg) 
Level of ReviewTitle and Abstract Full text
STUDY SELECTION
Study TypeRCTYes   No 
PopulationStudy patients received invasive mechanical ventilationYes   No 
 Study patients received care in ICU or high-acuity unitYes   No 
 Study patients > 16 years of ageYes   No 
InterventionReceived daily sedative interruptionYes   No 
ComparisonSedation management other than DSIYes   No 
OutcomesDuration of mechanical ventilationYes   No 
Decision  INCLUDE   EXCLUDE
Primary reason for exclusion  Study type
   Population
   Intervention
   Comparison group
   Outcomes

Appendix 10. Data extraction form

Data extraction form

Reviewer Initials 
Review Date (dd/mm/yy) 
Study ID 
Primary Author (last, first initial) 
Citation (journal, year, vol, pg) 
Confirm study eligibility

Yes

No (if No, please complete screening tool)

Study type

Simple RCT

Cluster RCT

Factorial RCT

General notes

Participants

Participant inclusion criteria: (please list):

INTERVENTION: N = CONTROL: N =

Age

mean (SD)

med (IQR)

 

Age,

mean (SD)

med (IQR)

 
% male n (%) % male n (%) 

Severity of illness

Name measure (e.g. Sofa)

 

Severity of illness

Name measure e.g.Sofa)

 

mean (SD)

med (IQR)

 

mean (SD)

med (IQR)

 
Setting

Mixed ICU

Medical ICU

Surgical ICU

Other (describe)

 

Academic hospital

Non-teaching hospital

Not reported

 

Closed ICU structure

Open ICU structure

Not reported

Name country study conducted 
Nursing staffing for vent patients:

1:1

1:2

1:3

Not reported

INTERVENTION GROUP

Describe method of DSI (verbatim) 
Name all Rx interrupted: 
Frequency of assessment of level of sedation. Please specify: q ____ h 
Delirium screening: 
Method (specify) 
Criteria for cessation of DSI: 
targeted to sedation score/GCSfixed duration
targeted to clinician assessmentother
Method of re-initiating Rx:

__ 50% of previous dose

__ > 50% of previous dose

Duration of mech vent prior to randomization mean (SD) med (IQR) 
Duration of mech vent prior to 1st DSI mean (SD) med (IQR) 
Was compliance with DSI reported?Yes
specify rate of compliance and how measuredNo

CONTROL GROUP

Describe method of sedation used for control group (verbatim)

Frequency of assessment of level of sedation. Please specify: q ____ h

 
Delirium screening:Yes
Method (specify)No
Protocol 
Guideline 
Usual care 
sedation scoring tool 
Describe ventilation weaning strategies:

Usual

weaning protocol, no SBT

weaning protocol includes SBT

SBT only

Name all Rx used: 
Duration of mech vent prior to randomization mean (SD) med (IQR) 
Use of DSI in control group (cross-over)n (%)

OUTCOMES

Please record unit of measurement for ALL outcomes (days/hours)

INTERVENTION  CONTROL 
Intubation to successful extubation Intubation to successful extubation 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 
Successful extubation/discontinuation of mechanical ventilation defined as no requirement for reintubation at (tick interval that applies):

24 hours

48 hours

72 hours

96 hours

7 days

Successful extubation/discontinuation of mechanical ventilation defined as no requirement for reintubation at (tick interval that applies):

24 hours

48 hours

72 hours

96 hours

7 days

Intubation to first extubation Intubation to first extubation 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 
ICU length of stay ICU length of stay 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 
Hospital length of stay Hospital length of stay 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 

n

mean (SD)

Median (IQR)

Mean diff (95% CI, P value)

 

Mortality n/N (%)

ICU

28/30 day

60 day

90 day

Hospital

 

Mortality n/N (%)

ICU

28/30 day

60 day

90 day

Hospital

 
Self extubation, n (%) Self extubation, n (%) 
Catheter removal, n (%) Catheter removal, n (%) 
Cardiac events, n (%) Cardiac events, n (%) 
New onset delirium, n (%)not recordedNew onset delirium, n (%)not recorded
HrQOL (measure) HrQOL (measure) 
Mean (SD) median (IQR) Mean (SD) median (IQR) 

Total drug dose

Drug name

Mean (SD) median (IQR

Total drug dose

Drug name

Mean (SD) median (IQR)
Key Conclusions made by authors PERSONAL COMMUNICATIONList any personal communication with authors & corresponding dates. Domain
Description (verbatim) JudgmentRandom sequence generation 

Yes

No

Unclear

Allocation concealment 

Yes

No

Unclear

Blinding (participants, personnel, outcome) 

Yes

No

Unclear

Incomplete outcome dataIntubation to successful extubation

Not measured

Yes

No

Unclear

Intubation to first extubation

Not measured

Yes

No

Unclear

ICU length of stay

Not measured

Yes

No

Unclear

Hospital length of stay

Not measured

Yes

No

Unclear

Mortality n/N (%)

Not measured

Yes

No

Unclear

Self extubation

Not measured

Yes

No

Unclear

Catheter removal

Not measured

Yes

No

Unclear

Cardiac events

Not measured

Yes

No

Unclear

HRQOL

Not measured

Yes

No

Unclear

Selective outcome reporting

Yes

No

Unclear

Other sources of bias 

Yes

No

Unclear

  

What's new

DateEventDescription
5 December 2014AmendedThe previously unpublished included study Nassar 2012 has now been published. The citation has been updated to reflect this change (Nassar 2014), however, all data had been obtained from the author at the time of this review's original publication, and so the results remain unchanged.

Contributions of authors

Conceiving the review: Lisa Burry (LB), Louise Rose (LR)

Designing the review: LB, LR, SM

Co-ordinating the review: LB

Undertaking manual searches: LB, LR

Screening search results: LB, LR

Organizing retrieval of papers: LB, LR

Screening retrieved papers against inclusion criteria: LB, LR

Appraising quality of papers: SM, Iain McCullagh (IM), LB

Abstracting data from papers: SM, IM

Writing to authors of papers for additional information: SM, LB

Providing additional data about papers: SM, LB

Obtaining and screening data on unpublished studies: LB

Data management for the review: LB

Entering data into Review Manager (RevMan 5.2): LB

RevMan statistical data: LB, Dean Ferguson (DF)

Other statistical analysis not using RevMan: DF, LB

Entry of data: LB

Interpretation of data: all

Statistical inferences: DF

Writing the review: LB, LR, SM

Providing guidance on the review: DF, NF, IM

Securing funding for the review: LB

Performing previous work that was the foundation of the present study: N/A

Guarantor for the review (one author): LB

Person responsible for reading and checking review before submission: LB

Declarations of interest

Three authors (Sangeeta Mehta, Lisa Burry, and Dean Fergusson) completed the largest multi-centre RCT included in this review (Mehta 2012). Two authors (Sangeeta Mehta, Lisa Burry) published a pilot study that also met the inclusion criteria (Mehta 2008).

Iain J McCullagh, Niall Ferguson, and Louise Rose: none known

Sources of support

Internal sources

  • none, Other.

    none

  • Department of Pharmacy, Mount Sinai Hospital, Canada.

External sources

  • Canadian Society of Hospital Pharmacists, Canada.

    Clinical Pharmacist Research Award ($3500CDN)

Differences between protocol and review

  1. In the protocol (Burry 2011a) we stated that the pooled estimates of the difference in means would be calculated using either the fixed-effect model (FEM) or the random-effects model (REM) depending on the degree of heterogeneity. To be more conservative we used the random-effects model for all analyses.

  2. We expanded the list of adverse events in our secondary outcomes to include tracheostomy rates and delirium as these were reported in newer trials. We believe these are valuable clinical endpoints that needed to be included in the protocol.

Notes

December 5th 2014; review amended

The previously unpublished included study (Nassar 2012) has now been published (Nassar 2014). However, all data had been obtained from the author at the time of this review's original publication in July 2014 (Burry 2014), and so the results of this amended review remain unchanged.

The following changes have been made to the published review:

Selective reporting (reporting bias) and other potential sources of bias

Previously we considered Nassar 2012 to be at unclear risk for both types of biases because the study was not yet published, and we obtained study details via personal communication with the study's author. Nassar 2014 is now published and judged to be at low risk for both types of biases.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anifantaki 2009

Methods

RCT

Single medical-surgical ICU, university hospital, in Greece

Compares a nursing-implemented protocol of daily interruption of sedative infusions to sedation as directed by the ICU team

Participants

Included: all mechanically ventilated patients receiving continuous infusion of sedatives 48 hours after ICU admission

Excluded: 1) pregnancy, 2) transfer to ICU after resuscitation following cardiac arrest, 3) initiation of sedative infusion in another hospital

Control group (n = 48): mean age 56.1 ± 21.1; female n (%) 13 (27.1%); Apache II mean 18.9 ± 8.1

Intervention group (n = 49): mean age 52.1 ± 21.3; female n (%) 14 (28.6%); Apache II mean 17.4 ± 6.8

Interventions

Control group (usual care):

  • The usual practice for the administration of sedation is continuous intravenous infusion to achieve a 3 to 5 score on the Ramsay sedation scale unless the patient needed deeper sedation (such as neurosurgery, acute respiratory distress syndrome)

  • The physician made the decisions about sedation in accordance with the ICU policy

Intervention group (daily interruption):

  • After a patient was recruited to the study, a research nurse stopped the sedative infusion in the intervention group

  • If symptoms of excitation, inconvenience, haemodynamic instability or respiratory distress or signs of neurological deterioration (e.g. increasing intracranial pressure) were observed, they were reported to the physician, and the sedative and analgesic infusion was started at half the previous rate and titrated to the desired level of sedation. During the interruption, remifentanil was not stopped but was instead tapered to a rate of 0.05 - 0.25 mg/hour

  • When a muscle-relaxant drug was being administered, this was restarted after discontinuation

  • Interruption was not attempted if one of the following conditions was present: severe haemodynamic instability, intracranial pressure > 18 mmHg, suspected or diagnosed deteriorated cerebral oedema or haemorrhage and positive end-expiratory pressure (PEEP) > 15 cmH20

Drug therapy used:

  • Standard regimen in the study unit was propofol with remifentanil. Propofol was substituted by midazolam if hypertriglyceridaemia or metabolic acidosis occurred

  • If a patient requires a deep sedation level, midazolam was added

  • Fentanyl is usually used only for bolus doses

Sedation assessment:

  • Ramsay scale target 3-5 was the usual practice, unless the patient needed deeper sedation (e.g. neurosurgery, acute respiratory distress syndrome)

  • Frequency of assessment not specified

Mechanical ventilation weaning strategies:

  • Not described

Outcomes
  1. Duration of mechanical ventilation

  2. Lenght of ICU stay

  3. Length of hospital stay

  4. Mortality (overall)

  5. Drug exposure

Notes
  • Compliance: interruption attempts were made in 75.5% of days in the intervention group; 46.5% in the control group

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients were assigned to the intervention or the control group with a randomization computer program stratified by disease severity using APACHE II score and the existence of brain damage as the criteria. Groups appear well balanced in terms of Apache II, gender and age
Allocation concealment (selection bias)Unclear riskNot reported; unable to obtain from authors
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot done
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported. Probably not done. But objective outcome assessed
Incomplete outcome data (attrition bias)
All outcomes
Low riskAccounted for all patients
Selective reporting (reporting bias)Low riskAll outcomes stated in the methods are presented in the results
Other biasLow risk

Appears to be free of other sources of bias

Sample size calculation was presented in the methods

de Wit 2008

Methods

RCT

Single, closed medical ICU within a university hospital; United States

Compares daily interruption of sedation to nursing-implemented sedation protocol

Participants

Included: Adults 18 years or older receiving invasive mechanical ventilation

Excluded: 1) neuromuscular blockaded, 2) severe chronic neurocognitive dysfunction requiring assistance with most activities of daily living, 3) transfer from another ICU, 4) tracheostomy at the time of study enrolment, 5) inability to obtain consent before the time point when sedation was to be interrupted

Control group (n =38): mean age (95% CI) = 51 (46.8, 55.8) ; female n (%) = 20 (52.6%); SOFA median = 9 (7.6, 10.3); Apache II median = 24 (21.6, 27.4)

Intervention group (n = 36): mean age (95% CI) = 52 (47.4,56.5); female n (%) = 19 (52.8%); SOFA median = 10 (8.2, 10.9); Apache II median = 26 (22.9, 28.8)

Interventions

Control group:

  • Sedation in all patients was managed according to the algorithm up to the time of randomization

  • The algorithm was developed locally by the medical ICU team of physicians, nurses and pharmacist and was based on the algorithm developed by Brook et al. The algorithm's goals were to maximize the use of boluses, minimize the duration of continuous intravenous infusion of sedation, and treat pain with opioids. It includes daily attempts to decrease sedation dosages

  • Nursing staff underwent a two-month introductory period in the use of the algorithm

  • After educational training, the algorithm underwent an one-month run-in period prior to study initiation

Intervention group:

  • Sedation in all patients was managed according to the algorithm up to the time of randomization. Patients randomly assigned to the intervention group were not managed with the algorithm once enrolled, and all sedation management was left to the discretion of the ICU team. However, clinicians were instructed to target a RASS score of -2 to -3 unless the ICU team felt that a different sedation depth was necessary. Clinicians titrated sedatives and opioids throughout the day when study investigators were not present

  • Daily interruption was performed as outlined by Kress et al. Forty-eight hours after initiation of mechanical ventilation, all sedatives and opioids administered as either continuous infusions or bolus infusions were discontinued until the patient was awake or agitated. Sedation was typically interrupted in the morning, but timing was based on practicalities such as daily rounds, procedures, and travel outside the ICU

  • Patients were observed continuously by a study investigator during sedative and opioid interruption. Clinicians involved in the care of study patients did not initiate sedation interruption, nor were they involved in the decision to resume sedation

  • Awake was defined as being able to perform at least three of the following four commands: a) open eyes, b) visually track the investigator, c) stick out tongue, and d) squeeze hand

  • Agitation was defined a priori as a RASS score > 0. Study investigators decided if and when to rescue sedation

  • Once the patient was awake, agitated, or developed vital sign changes, sedation was resumed at 50% of the previous dosage

  • After the third study patient assigned to the intervention group experienced a study-related adverse event, the protocol was amended because of safety concerns. The protocol was amended to resume sedation if any of the following vital sign changes occurred: tachypnoea of > 35 breaths/minute for > 5 minutes, arterial oxygen saturation < 90%, heart rate > 140 beats/minute or sustained change > 20% in either direction, or systolic blood pressure > 180 mmHg or < 90 mmHg. These changes were based on a study evaluating the efficacy of SBTs

  • RASS score was recorded at the time sedation was interrupted and again when sedation was resumed

Drug therapy used: morphine or fentanyl for pain, midazolam or lorazepam for agitation

Sedation assessment: Richmond agitation-sedation scale (RASS) target of -2 to -3 unless otherwise specified by the ICU team. Frequency of assessment not specified

Mechanical ventilation weaning strategies:

  • Mechanical ventilation weaning was standardized in both groups through the use of daily SBTs

Outcomes
  1. Total duration of mechanical ventilation, days

  2. Time to successful extubation from mechanical ventilation, days

  3. ICU length of stay, days

  4. Hospital length of stay, days

  5. 28-day ventilator-free survival

  6. ICU mortality

  7. Hospital mortality

  8. Drug exposure

Notes
  • Study stopped early by Data Safety Monitoring Board because of signal of harm to the daily interruption group in terms of the primary endpoint - longer duration of mechanical ventilation. Also noted slower improvement in SOFA scores, longer ICU and hospital length of stay

  • Concerns raised that DSI may be potentially harmful for some patient populations such as those with alcohol or substance abuse issues

  • Reverse cross-over: all patients received sedation algorithm for 48 hours at which point it was stopped in the daily interruption group and continued in the control group

  • Compliance: 79 episodes of DSI occurred in 38 patients

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer randomization (information provided by author)
Allocation concealment (selection bias)Low riskNot stated in manuscript. Concealed, opaque envelop (information provided by author)
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot possible. Study investigators observed the patient during the interruption and decided if and when to resume sedation
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported. Probably not done. But objective outcome assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Enrolment and attrition data presented

High rate of data censoring (for death on mechanical ventilation, withdrew from the study, required reintubation within 72 hours of extubation, or underwent tracheostomy). Patients in the intervention group were significantly more likely to have censored observations and were more likely to withdraw from the study

ITT analysis was not performed

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow risk

Power calculation presented in the methods

Study stopped early by Data Safety Monitoring Board because of signal of harm to the daily interruption group in terms of the primary endpoint - mortality and longer duration of mechanical ventilation. There is potential of misleading estimates of treatment effects but the trial had clearly stated methods how to handle termination and interim analysis

Girard 2008

Methods

Multi-centre RCT

Four closed ICU in tertiary-care hospital; United States

Compares paired sedation and ventilator weaning protocol with usual sedation care with daily ventilator weaning protocol

Participants

Included: Age 18 years or older, requiring mechanical ventilation for > 12 hours, including patients receiving full ventilatory support or those in whom support was being weaned

Excluded: 1) admission after cardiac arrest, 2) continuous mechanical ventilation for > 2 weeks, 3) moribund state (i.e. death was perceived to be imminent), 4) withdrawal of life support planned, 5) profound neurological deficits (e.g. large stroke or severe dementia), 6) current enrolment in another trial)

Control group (n =168): median age (IQR) 64 (57, 75); female n (%) 83 (49.0%); SOFA median (IQR) 8 (6, 11.5) APACHE II median 26.5 (21, 31)

Intervention group (n = 167): median age (IQR) 60 (48, 71); female n (%) 77 (46.0%); SOFA median (IQR) 9 (6, 11) APACHE II median 26 (21, 33)

Interventions

Control group (usual care including spontaneous breathing trial):

  • According to each study centre intensive care units usual practice of care, physicians and nurses managed all patients with patient-targeted sedation, titrating sedative and analgesic doses to maintain the level of arousal and comfort deemed clinically appropriate for each patient. Each intensive care unit used a validated sedation scale to monitor depth of sedation

  • Beginning the morning after enrolment, intensive care unit nurses and respiratory therapists or study personnel managed patients according to the study protocols

  • Patients in the control group were not prevented from undergoing spontaneous awakening trial (SAT) if the managing clinician felt that they were indicated

Intervention group (spontaneous awakening trial (SAT) plus spontaneous breathing trial):

  • In accordance with the SAT protocol, patients in the intervention group were assessed every morning with an SAT safety screen. Patients passed the screen unless they were receiving a sedative infusion for active seizures or alcohol withdrawal, were receiving escalating sedative doses due to ongoing agitation, were receiving neuromuscular blockers, had evidence of active myocardial ischaemia in the previous 24 hours, or had evidence of increased intracranial pressure

  • Patients who failed the screen were reassessed the following morning

  • Patients who passed the screen underwent an SAT with all sedatives and analgesics used for sedation were interrupted. Analgesics needed for active pain were continued. Patients were monitored by intensive care staff or study personnel for up to 4 hours. patients passed the SAT if they opened their eyes to verbal stimuli or tolerated sedative interruption for 4 hours or more without exhibiting failure criteria

  • Patients failed the SAT if they developed sustained anxiety, agitation, or pain, a respiratory rate of >35 breaths/min for 5 minutes or longer, an Sp02 < 88% for 5 minutes or longer, an acute cardiac dysrhythmia, or two or more signs of respiratory distress, including tachycardia, bradycardia, use of accessory muscles, abdominal paradox, diaphoresis, or marked dyspnoea. When patients failed an SAT, intensive care staff restarted sedatives at half the previous dose and then titrated the medications to achieve patient comfort. patients who passed the SAT were immediately managed with the SBT protocol

Drug therapy used:

  • Opiates (expressed in fentanyl equivalents), benzodiazepines (expressed in lorazepam equivalents), or propofol

Sedation assessment:

  • Trained study personnel did neurological assessments every day with two well-validated instruments: level of arousal with the Richmond agitation-sedation scale (RASS) and delirium was diagnosed with the confusion assessment method for the intensive care unit (CAM-ICU)

Mechanical ventilation weaning strategies:

  • Patients in the control group were assessed every morning with an spontaneous breathing trial (SBT) safety screen. Patients passed the screen if they had adequate oxygenation (Sp02>88% on FiO2< 50% and a positive end-expiratory pressure (PEEP) < 8 cm H20, any spontaneous inspiratory effort in a 5-min period, no agitation, no evidence of myocardial ischaemia in the previous 24 hours, no significant use of vasopressors or inotropes (dopamine or dobutamine >5 mcg/kg/min, norepinephrine > 2 mcg/min, or vasopressin or milrinone at any dose), and no evidence of increased intracranial pressure. Patients who failed the screen were reassessed the following morning

  • Patients who passed underwent an SBT: ventilatory support was removed, and the patient was allowed to breathe through either a T-tube circuit or a ventilatory circuit with continuous positive airway pressure of 5 cm H20 or pressure support ventilation of less than 7 cm H20. No change was made in FiO2 or PEEP during the SBT

  • Patients failed the SBT if they developed a respiratory rate of more than 35 or less than 8 breaths per minutes for 5 minutes or longer, hypoxaemia (Sp02 <88% for > 5 minutes), abrupt changes in mental status, an acute cardiac arrhythmia, or two or more signs of respiratory distress, including tachycardia (>130 beats/minute), bradycardia (<60 beats/min), use of accessory muscles, abdominal paradox, diaphoresis, or marked dyspnoea. Patients who failed the SBT were ventilated immediately with the ventilator settings used before the trial. Patients passed the SBT if they did not develop any failure criteria during a 120 minute trial. If the SBT was successful, the patients' physicians were notified verbally. Study personnel did not participate in decisions to extubate patients

Outcomes
  1. Ventilator-free days (from study day 1 to 28)

  2. Time to discharge, days

  3. Time to discharge, days

  4. 28-day mortality

  5. 1-year mortality

  6. Tracheostomy

  7. Re-intubation

  8. Self-extubation

  9. Duration of coma

  10. Duration of delirium

  11. Drug exposure

  12. HrQOL (SF-36) reported in subsequent publication (Jackson 2010)

Notes
  • One patient withdrawn by surrogate decision maker before data collection started

  • Median time from admission to enrolment (days): 2.2 (1.1 to 3.9) days intervention group versus 2.2 (1.1 to 3.9) days control group

  • Compliance: Intervention group n (%): 150 (90%) SAT; sedatives held before any SBT 150 (90%); underwent an SBT 136 (81%) versus control group n(%): 0 (0%) SAT; sedatives held before any SBT 52 (31%); underwent an SBT 146 (87%)

  • Patients in the intervention group were more awake on the first day they passed an SBT safety screen

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Patients were randomly assigned in a 1:1 manner to management with paired SAT and SBT protocols or usual care (including patient-targeted sedation and an SBT protocol

A computer-generated, permuted-block randomization scheme was stratified according to study centre by a Vanderbilt biostatistician.

Groups appear well balanced in terms of Apache II, gender and age

Allocation concealment (selection bias)Low riskEach assignment was designated on a tri-folded piece of paper enclosed in a consecutively numbered, sealed, opaque envelope. After informed consent was obtained, before data were collected, the appropriate envelope was opened by local study personnel
Blinding of participants and personnel (performance bias)
All outcomes
High risk

Blinding not possible

Trained study personnel did neurological assessments every day with two well-validated instruments: level of arousal with Richmond agitation-sedation scale (RASS) and delirium with confusion assessment method for the ICU (CAM-ICU)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Objective outcome

Study personnel did not participate in decisions to extubate patients

Beginning the morning after enrolment, intensive care nurses and respiratory therapists or study personnel managed patients according to the study protocols

Incomplete outcome data (attrition bias)
All outcomes
Low risk

All patients screened and enrolled accounted for in the results

Complete follow-up with patients were followed up from enrolment until death or discharge, and survivors were followed up for vital status until 1 year after enrolment using the hospitals' electronic record systems, telephone calls, in-person visits, and a commercial version of the Social Security Death Master File

Selective reporting (reporting bias)Low riskAll outcomes described in the methods were reported in the results
Other biasLow risk

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication

An independent biostatistician re-analysed the final data-set and verified all of the results

Kress 2000

Methods

RCT

Single, open, medical ICU in tertiary-care hospital; United States

Compares daily interruption of sedative infusions in mechanical ventilated critically ill patients to no daily interruption of sedative infusions. Within each group, the patients were then randomly assigned to receive either midazolam or propofol

Participants

Included: patients who were intubated and receiving mechanical ventilation and who were deemed by the intensive care unit team to require sedation by continuous intravenous infusion. Included among these patients were all those who showed agitation or discomfort after recovering from the effects of the drugs used to facilitate endotracheal intubation (e.g., thiopental or etomidate)

Excluded: 1) pregnancy; 2) transfer from an outside institution where sedatives had already been administered; 3) admission after resuscitation from cardiac arrest

Control group (n = 60): median age (IQR) 61 (40,74); female n (%) 34 (56.7%); APACHE II median 22 (16,25)

Intervention group (n = 68): median age (IQR) 57 (42,71); female n (%) 34 (50.0%); APACHE II median 20 (15,25)

Interventions

Control group:

  • The patients in the control group were monitored each day by research staff, and the total daily doses of sedative drugs infused were recorded. The adjustment of the dosages of sedative drugs in the control group was left to the discretion of the ICU team

  • Apart from daily interruption and resumption of sedative-drug infusions in the intervention group, all other decisions regarding patient care were made by the ICU team

Intervention group:

  • An investigator not directly involved in the patients' care interrupted the infusion of midazolam or propofol and the infusion of morphine simultaneously on a daily basis until the patients were awake and could follow instructions or until they became uncomfortable or agitated and were deemed to require the resumption of sedation

  • If the patient was receiving a paralytic drug, the sedative infusion was not interrupted

  • A research nurse who was not directly involved in the patients' care evaluated the patients each day throughout the period when infusions were stopped until the patients were either awake or uncomfortable and in need of resumed sedation. The research nurse immediately contacted a study physician when a patient awakened, at which time the study physician examined the patient and decided whether to resume the infusions

  • For the patients in the intervention group who were receiving paralytic drugs, the sedative infusions were stopped daily, after administration of the paralytic drug had been stopped in a manner identical to that for patients in the intervention group who were not receiving paralytic drugs

  • A patient was considered "awake" if he or she was able to perform at least three of the following four actions, which could be assessed objectively: open eyes in response to a voice, use the eyes to follow the investigator on request, squeeze a hand on request, and stick out the tongue on request

  • Patients were considered to have been awake on any given day if they had been awake at any time during that day

  • The sedative infusions were started again after the patient was awake or, if agitation prevented successful waking, at half (50%) the previous rates and were adjusted according to the need for sedation

Drug therapy used:

  • Morphine for analgesia, sedation with either midazolam or propofol

Sedation assessment:

  • Ramsay scale target 3-4, frequency not reported

  • Non-validated pain scale (1 = extreme pain, 2 = severe pain, 3 = moderate pain, 4=slight pain, 5 = no pain), frequency not reported

Mechanical ventilation weaning strategies:

  • Not reported

Outcomes
  1. Intubation to successful extubation, days

  2. ICU length of stay, days

  3. Hospital length of stay, days

  4. Hospital mortality

  5. Adverse events

  6. Endotracheal tube removal

  7. Catheter removal

  8. Diagnostic tests

  9. Reintubations

  10. Tracheostomy

  11. Discharged home

  12. Drug exposure

  13. Complications and HrQOL (SF-36) reported in subsequent publications (Kress 2003)

Notes
  • Compliance with interruption was 100% (excluding when managed with chemical paralysis or goals of care had change to comfort care measures only)

  • Crossover (18/60 patients in the control group had infusions stopped temporarily on days other than the final day of administration, and the percentage of days on which the drugs were stopped ranged from 0-54%

  • A total of 150 patients were enrolled in the study; 75 to each group. Seven in the intervention group and 15 in the control group were excluded because either the endotracheal tube was removed or they died on the first or second day in the ICU

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Random assignment were generated by computer

Groups appear well balanced in terms of Apache II, gender and age

Allocation concealment (selection bias)Low riskConcealed in sealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Patients' assignment to the study groups were known only to the study investigators

The study investigator not directly involved in the patients' care interrupted the infusion of sedation on a daily basis until the patient was awake and could follow instructions or until they became uncomfortable or agitated and were deemed to require the resumption of sedation. The research nurse not who was not directly involved in the patients's care evaluated the patients each day when infusions were stopped. This nurse immediately contact a study physician when a patient awakened

The investigators commented in the limitations of the paper that they cannot be certain that the clinicians involved in patient care were completely unaware of the study-group assignments. They attempted to minimize this problem by not disclosing the end points of the study to the clinicians

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Objective outcome

Apart from daily interruption and resumption of sedative infusions in the intervention group, all other decisions regarding patient care were made by the ICU team

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Data were analysed on an ITT basis

Patients who died during the first or second day in the ICU and those from whom the endotracheal tube was successfully removed during the first or second day, before the sedative infusion could be interrupted, were not included in the analysis. All patients were followed until discharge from the hospital

Selective reporting (reporting bias)Low riskAll pre-specified outcomes reported
Other biasLow risk

Appears to be free of other sources of bias

Sample size calculation not presented

Mehta 2008

Methods

Multi-centre RCT

Three academic, closed, medical-surgical ICUs; Canada

A pilot trial to evaluate safety and feasibility compares nursing-directed sedation protocol with daily awakening to nursing-directed sedation protocol alone

Participants

Included: Age 18 years or older, anticipated duration of mechanical ventilation > 48 hours, the ICU team has decided to initiate continuous infusions of sedatives and/or analgesics

Excluded: 1) receiving neuromuscular blockade agents, 2) allergy to any of the study medications, 3) known alcohol, sedative, analgesic abuse, 4) psychiatric illness, 5) acute or chronic neurologic dysfunction (e.g. cerebrovascular accident, dementia), 6) admission after cardiac arrest, 7) lack of commitment to life support, 8) anticipated death within 48 hours, 9) any condition for which 6-month mortality was estimated to be > 50%, 10) non-English speaking, and 11) sedative infusion for > 24 hours at another institution prior to transfer

Control group (n = 33): median age (IQR) 57.9 (42.6, 67.0); female n (%) 13 (39.0%); Apache II mean (SD) 27.7 (± 8.4); medical ICU n (%) 30(91.0%)

Intervention group (n = 32): median age (IQR) 61.4 (52.4,75.5); female n (%) 19 (59%); Apache II mean (SD) 26.6 (± 8.4); medical ICU n (%) 29 (94.0%)

Interventions

Control group (RN directed protocol):

  • All patients, control group and intervention group, had sedation and analgesia managed using the nurse-implemented protocol, in which midazolam was administered for sedation and morphine for analgesia. Fentanyl could be substituted for morphine in patients with severe renal dysfunction (creatinine clearance < 10 mL/min) or morphine allergy

  • The bedside nurse used the sedation agitation scale (SAS) to assess level of sedation hourly and titrated sedative-analgesic agents to the lowest level necessary to maintain a SAS score of 3 to 4

  • When an increase in medication was indicated based on the SAS score, the bedside nurse decided whether an increase in analgesic, sedative, or both was required. When reductions in sedative and analgesic doses were required to maintain the SAS score in the desired range (i.e., SAS score was 1 or 2), the nurse alternated reductions in analgesic and sedative agents. Midazolam and morphine were reduced in 1-2 mg decrements, and fentanyl was reduced in 12.5-25 mcg decrements at 15-30 minute intervals. once the dosage of midazolam or morphine was < 3 mg/hr, 0.5 mg decrements could be used. If the patient had a SAS score of 1 to 2, yet showed signs of agitation or distress, the nurse could use boluses as needed, recording the reason for the boluses. If at any time the patient became extremely agitated (e.g., SAS score 7), sedative therapy could deviate from the protocol. Intermittent doses of sedatives or analgesics were used for procedures as needed

  • Patients randomized to the control group had sedatives-analgesics managed according to the protocol but did not have these infusions interrupted daily unless deemed necessary on clinical grounds by the attending physician. Infusions were terminated when the patient was oversedated (e.g., SAS 1 or 2) while receiving doses of 0.5 -1 mg/hr of midazolam or morphine (or fentanyl 12.5-25 µg/hr)

Intervention group (Daily Interruption):

  • Patients allocated to the intervention group (DSI) had continuous infusions of sedatives and analgesics discontinued daily @ 0900H for the assessment of ongoing sedative requirements. "Awakeness" was assessed by the attending physician, investigator, or the research coordinator. Patients were considered awake if the SAS score was 4 to 7 and the patient could perform at least three of the following tasks on request: 1) open their eyes; 2) use their eyes to follow the evaluator; 3) squeeze a hand; and 4) wiggle their toes. Once the patient was awake, the attending physician or fellow assessed the patient's ongoing sedative-analgesic needs. If the patient was deemed to require ongoing continuous infusion, both sedative and analgesic infusions were restarted at 50% of the previous infusion rate

  • The infusions interrupted were midazolam, morphine/fentanyl

  • Criteria for cessation of DSI: If, at any time, the patient because agitated (e.g. SAS score 6 or 7) or exhibited signs of discomfort/pain before the physician's assessment, the infusions were resumed by the nurse at half the infusion rate before awakening and again titrated to achieve a SAS score 3 to 4. Signs of discomfort included: respiratory rate > 35 breaths/min, SpO2 <90%, heart rate > 140 beats/min ( or a change of 20% in either direction), systolic blood pressure > 180 mmHg, or increased anxiety and diaphoresis

Mechanical ventilation weaning strategies were standardized in both groups:

  • Patients were weaned from the ventilator at the discretion of the clinical team; however, only pressure support with positive end-expiratory pressure (PEEP) could be used for weaning. To standardize the assessment of a patient's readiness to wean, respiratory therapists assessed patients daily for the following criteria: awake, adequate cough with suctioning, PaO2 <60 mmHg, SpO2 < 90%, FiO2 <0.4, PEEP < 10 cm H20, respiratory rate < 35 breaths/min, minute ventilation < 15 L/min, no inotrope or vasopressor infusions (exception of dopamine < 3 mcg/kg/min), mean arterial pressure > 60 mmHg, and no evidence of acute myocardial ischaemia (i.e., chest pain, consistent electrocardiogram findings, elevated biomarkers, or new arrhythmia). If all eight criteria were met, the attending physician was notified and a 1-hour trial of unassisted breathing (UBT) was initiated. During the UBT, ventilatory support was withdrawn and the patient breathed spontaneously at the previous FiO2, a: 1) t-tube, 2) tracheostomy mask, or 3) ventilator circuit using flow triggering and continuous positive airway pressure of 5 cm H20. The UBT could be terminated if the patient developed any of the following signs of failure for > 5 minutes: respiratory rate > 35 breaths/min, SpO2 < 90%, heart rate >140 beats/min, or a change in heart rate of 20% in either direction, systolic blood pressure < 90 or > 180 mmHg, or increased anxiety and diaphoresis. A UBT was successful if the patient could breathe without mechanical assistance for 1 hour. If the patient passed the UFBT, the attending physician was notified and the patient was extubated. If the patient failed the UBT, he or she was returned to the previous ventilator settings. The screen and UBT were repeated daily until the patient passed and could be extubated. If the patient required reintubation within 48 hours, sedation was resumed according to the originally assigned sedation group

Drugs used:

  • Morphine or fentanyl and midazolam or lorazepam

  • Propofol was not permitted

Sedation assessment:

  • SAS target 3-4, frequency not reported

Outcomes
  1. Ventilator days

  2. ICU length of stay

  3. Hospital length of stay

  4. ICU mortality

  5. Hospital mortality

  6. Tracheostomy

  7. Self-extubation

  8. Catheter removal

  9. Cardiac events

  10. Drug exposure

NotesPilot trial therefore not powered to detect difference in clinical outcomes (rather designed to guide large RCT)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Randomised.

Groups appear well balanced in terms of Apache II, gender and age

Allocation concealment (selection bias)Low riskCentralized, concealed
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAssessment of outcomes not blinded but objective outcome measured
Incomplete outcome data (attrition bias)
All outcomes
Low risk

No missing outcome data. Recruitment and attrition data presented. Analysis performed using ITT principle

Patients who died before extubation before 30 days were censored at the time of death. Patients for whom the decision was made to withdraw life support were censored at the time that the decision was made

Selective reporting (reporting bias)Low riskAll outcomes stated in the methods were presented in the results
Other biasLow riskAppears to be free of other sources of bias. Smple size calculation not presented

Mehta 2012

Methods

Multi-centre RCT

Sixteen closed ICUs in tertiary-care hospitals in Canada and the United States

Compares paired use of nurse-directed sedation protocol and daily interruption with nurse-directed sedation protocol

Participants

Included: Critically ill adults expected to require mechanical ventilation for at least 48 hours after enrolment, ICU team had decided to initiate continuous sedative and/or opioid infusions

Excluded: 1) admitted following cardiac arrest; 2) traumatic brain injury; 3) use of neuromuscular blocking agents; 4) enrolled in a confounding trial; 5) previously enrolled in the current trial; 6) lack of commitment to maximal therapy

Control group (n =209): median age (IQR) 60 (49,70); female n (%) 92 (44.0%); APACHE II median 23.0 (19,29)

Intervention group (n = 214): median age (IQR) 57 (46,70); female n (%) 93 (43.5%); APACHE II median 24.0 (18,28)

Interventions

Control group:

  • Beside nurses titrated opioid and sedative infusions according to a protocol that prioritized pain assessment. Nurses used the SAS or RASS to assess sedation needs hourly, and titrated infusions to maintain a comfortable yet rousable state (SAS 3 to 4 or RASS -3 to 0). When the sedation score directed an increase in medication, the bedside nurse judged whether to increase the opioid and/or benzodiazepine infusions. When patients were over-sedated, nurses alternated reducing the opioid and the benzodiazepine infusions. Midazolam, lorazepam, and morphine were reduced in 1-2 decrements, fentanyl in 12.5-25 mcg decrements, and hydromorphone in 0.1-0.5 mg decrements, at 15-30 minute intervals. If dosages of midazolam, lorazepam or morphine were < 3 mg/hr, 0.5 mg decrements could be used. If SAS was 1 to 2 (RASS -4 to -5), yet the patient showed signs of agitation or distress, bolus doses of opioid or benzodiazepine were administered as needed

  • When patients were extremely agitated (SAS 7 or RASS +3 to +4), nurses could deviate from this protocol. For both groups, infusions were discontinued when a patient was over-sedated (SAS 1 to 2 or RASS-4 to -5 while receiving 0.5 - 1 mg/hr of midazolam, lorazepam or morphine (or fentanyl 12.5-25 mcg/hr). Intermittent dosing was used for procedures as needed

  • Patients were managed off protocol during periods of neuromuscular blockade, high frequency oscillation, or palliative care

Intervention group:

  • Beside nurses titrated analgesic and sedative infusions according to a protocol that prioritized pain assessment. Nurses used the SAS or RASS to assess sedation needs hourly, and titrated infusions to maintain, ideally, a comfortable yet arousable state (equivalent to SAS 3 to 4 or RASS -3 to 0). When the sedation score directed an increase in medication, the bedside nurse judged whether to increase the opioid and/or benzodiazepine infusions. When patients were over-sedated, nurses alternated the reducing the opioid and the benzodiazepine infusions. Midazolam, lorazepam, and morphine were reduced in 1-2 decrements, fentanyl in 12.5-25 mcg decrements, and hydromorphone in 0.1-0.5 mg decrements, at 15-30 minute intervals. If dosages of midazolam, lorazepam or morphine were < 3 mg/hr, 0.5 mg decrements could be used. If SAS ws 1 to 2 (RASS -4 to -5), yet the patient showed signs of agitation or distress, bolus doses of opioid or benzodiazepine were administered as needed.When patients were extremely agitated (SAS 7 or RASS +3 to +4), nurses could deviate from this protocol. For both groups, infusions were discontinued when a patient was over-sedated (SAS 1 to 2 or RASS-4 to -5) while receiving 0.5-1 mg/hr of midazolam, lorazepam or morphine (or fentanyl 12.5 - 25 mcg/hr). Intermittent dosing was used for procedures as needed. Patients were managed off protocol during periods of neuromuscular blockade, high frequency oscillation, or palliative care

  • The bedside nurse interrupted opioid and benzodiazepine infusions daily and assessed for wakefulness, defined as SAS 4-7 or RASS (-1 to +4) and the ability to perform at least 3 of the following requests: 1) eye opening; 2) tracking of evaluator or care giver; 3) hand squeezing; and 4) toe moving. If the bedside nurse and a physician agreed that infusions were no longer required, oral or bolus intravenous therapy were used at the clinical team's discretion

  • Alternatively, if it was judged that ongoing benzodiazepine and/or opioid infusions were required, the nurse resumed the infusion(s) at 50% of the prior dose, and titrated to achieve the target level of light sedation

  • If a patient became agitated (SAS 6-7 or RASS +2 to +4) or exhibited signs of discomfort (respiratory rate > 35 breaths/minute, SpO2 < 90%, heart rate > 140 beats/minute, or a change in heart rate of 20% in either direction, systolic blood pressure > 180 mmHg or increased anxiety and diaphoresis) prior to the physician's assessment, nurses promptly resumed infusions at 50% of the prior rate and titrated to achieve the target level of sedation.

  • Daily interruption could be delayed for procedures or transports out of the ICU

  • Patients were managed off protocol during periods of neuromuscular blockade, high frequency oscillation, or palliative care

Drug therapy used:

  • morphine, fentanyl or hydromorphone (expressed in fentanyl equivalents), midazolam or lorazepam (expressed in midazolam equivalents); propofol, ketamine, and dexmedetomidine infusions were not permitted

Sedation assessment:

  • SAS or RASS every hour

  • Delirium screening with ICDSC daily

Mechanical ventilation weaning strategies:

  • Standardized in both groups

  • Patients were weaned from mechanical ventilation at the discretion of the ICU team. Each day, respiratory therapists assessed patients' readiness for a trial of unassisted breathing

  • To standardize the assessment of a patient’s extubation readiness, respiratory therapists assessed patients daily for the following criteria: awake, adequate cough with suctioning, PaO2> 60 mmHg; SpO2> 90%, FiO2< 0.4, positive end expiratory pressure < 10 cmH2O, respiratory rate < 35 breaths/minute, minute ventilation <15 L/min, no inotrope or vasopressor infusions (except dopamine < 3 mcg/kg/min), mean arterial pressure >60 mmHg, and no evidence of acute myocardial ischaemia (i.e., chest pain, consistent ECG findings, elevated biomarkers, or new arrhythmia). If all criteria were met, a 1-hour trial of unassisted breathing was initiated during which ventilatory support was withdrawn and the patient breathed spontaneously at the previous FiO2, through a t-tube circuit, a tracheostomy mask, or the ventilator circuit using continuous positive airway pressure of 5 cmH2O. The breathing trial could be terminated if any of the following signs of failure persisted for > 5 minutes: respiratory rate >35 bpm, SpO2< 90%, heart rate >140 bpm or a change in heart rate of 20% in either direction, systolic blood pressure < 90 or >180 mmHg, or increased anxiety and diaphoresis

  • A breathing trial was successful if the patient could breathe without mechanical assistance for one hour; in this case the ICU team was notified and the patient was extubated if the ICU team agreed. If the ICU team did not agree with extubation, the reason was recorded; and the screening and breathing trial were repeated the subsequent day. If the patient failed the unassisted breathing trial, the previous ventilator settings were resumed, and the screening and breathing trial were repeated daily until extubation. If the patient required reintubation within 48 hrs, sedation was resumed according to the originally assigned group. When patients passed a trial of unassisted breathing, respiratory therapists notified a physician with a view to extubation. Research staff recorded reasons for delayed extubation, and daily screening continued until extubation. If reintubation occurred within 48 hours, study sedation procedures resumed

Outcomes
  1. Intubation to successful extubation, days

  2. ICU length of stay, days

  3. Hospital length of stay

  4. ICU mortality

  5. Hospital mortality

  6. Self-extubation

  7. Catheter removal

  8. Tracheostomy

  9. Cardiac events

  10. Delirium

  11. Drug exposure

  12. HrQoL and cognitive status post discharge reported in subsequent abstract (Rose 2013)

Notes
  • Compliance with interruption was 72.2% of all eligible study days; and 74.0% of study days excluding the day of enrolment.

  • Crossover: 34 patients (16.4%) in the control group had infusions interrupted on 54 occasions, accounting for 2.3% of study days.

  • Surgical and trauma patients randomized to daily interruption had significantly shorter time to successful extubation than those randomized to protocolized sedation alone (subgroup analysis).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerized, from central methods centre
Allocation concealment (selection bias)Low riskResearch staff randomized the patient using the automated telephone randomization system, that stratified by centre using undisclosed variable block sizes
Blinding of participants and personnel (performance bias)
All outcomes
High riskNone of the participants, study personnel, clinicians, or investigators analysing the data were masked to group assignment
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Not blinded but objective outcome measured

Patients were weaned from mechanical ventilation at the discretion of the ICU team

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition and exclusions reported. ITT analysis performed
Selective reporting (reporting bias)Low riskAll a priori outcomes reported
Other biasLow risk

Appears to be free of other sources of bias

Sample size calculation stated

Nassar 2014

Methods

RCT

Single medical-surgical ICU, South America

Compares daily interruption to intermittent sedation

Participants

Inclusion Criteria:
18 years of age who required expected to require mechanical ventilation more than 24 hours

Exclusion Criteria: < 18 years of age; pregnant women

Requirement for deep levels of sedation (intracranial hypertension, status epilepticus, hypothermia post cardiac arrest, severe asthma exacerbation and severe hypoxaemic respiratory failure in which it was decided to undergo alveolar recruitment, prone position or ECMO)

Predicted survival < 6 months (e.g., metastatic cancer)

Previous cognitive impairment (e.g., advanced dementia)

Readmitted to the ICU after participating in the trial

Interventions

Control group:
Patients in the intermittent sedation group were kept without continuous infusion of sedatives if the intubation was performed in the ICU or had their infusion stopped after randomization if the patient was admitted intubated from another unit. After the patient was awake, if he/she was calm and collaborative (SAS 4), he/she was kept without infusion of sedatives. If the patient was uncomfortable or agitated (SAS ≥ 5), the physician was consulted and possible causes of discomfort were investigated and treated. Pain was treated with boluses of fentanyl (50-150 mcg). If the pain recrudesced in < 2 hr or there was a persistent pain stimulus a continuous infusion of fentanyl was started and titrated by the bedside nurse using a numeric pain scale. If agitation had no visible cause and pain was already empirically treated with fentanyl, then delirium was suspected and haloperidol was administered. If the patient was still uncomfortable or agitated, a continuous infusion of midazolam or propofol were initiated to achieve SAS 3-4

Intervention group:

The daily interruption group received sedatives aimed to a SAS target 3-4. SAS was recorded at least three times daily. Every morning, after change of shift (7AM), infusions were interrupted until patients were awake and could follow simple commands (open eyes, look at the clinician, squeeze hands, open their mouth)

The infusions were restarted at 50% of the previous dose only if the patient was agitated (SAS ≥ 5). If the patient could not follow commands after daily interruption because of agitation, the infusion was also restarted at 50% of the previous dose and titrated to SAS 3-4

Sedation assessment:

  • SAS q8h

Mechanical ventilation weaning strategies:

All patients were ventilated on pressure support mode. Pressure controlled mode was used only in cases of hypoventilation. All patients had their sedative infusions stopped when PEEP was set at 5 cmH20 and FiO2 ≥ 40%, when a spontaneous breathing trial would be performed if the patient was hemodynamically stable (MAP > 65 mmHg, no substantial use of norepinephrine or dobutamine, respiratory rate < 35 per minute, arterial partial pressure/inspired fraction of oxygen ratio > 150)

Outcomes
  1. Intubation to successful extubation (defined as no requirement for reintubation at 48 hour)

  2. Duration of ICU stay

  3. Duration of hospital stay

  4. ICU mortality

  5. Hospital mortality

  6. Self-extubation

  7. Unplanned withdrawal of catheters

  8. Delirium

  9. Drug exposure

Notes
  • Conclusions by the investigators: 1) A protocol of intermittent dose sedation and a strategy of daily interruption are not different in duration of mechanical ventilation and 2) both strategies seem to be safe in terms of complications (e.g., self-extubation, accidental removal of catheters).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generation randomization, permuted block randomization
Allocation concealment (selection bias)Low riskTri-folded piece of paper in consecutively numbered, sealed, opaque envelopes
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Objective outcome

Clinical team reasonable for the decision to extubate the patient

Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk**
Other biasLow risk**

Weisbrodt 2011

Methods

Multi-centre RCT

Two level-3, mixed medical-surgical-trauma ICUs in Australia

Pilot study to determine the feasibility of a protocol for a double-blind randomized , controlled examination of the impact of a routine, daily interruption in sedation versus standard care

Participants

Included: All patients receiving mechanical ventilation for more than 12 hours, receiving continuous infusions of fentanyl and/or midazolam, expected to require these infusions for > 48 hours

Excluded: 1) neurological or neurosurgical diagnosis at admission; 2) had taken a drug overdose; 3) could not comprehend English; or 4) had limitation to treatment, such as do not resuscitate orders

Control group (n = 24): age mean (95% CI) 69.1 (63.7-74.5), female n (%) 7 (29%), Apache II mean (95% CI) 21.4 (18.4-24.4)

Intervention group (n = 26): age mean 95%) 65.1 (58.4-71.6), female n (%) 12(46%), Apache II mean (95%) 23.4 (20.3-26.4)

Interventions

Control group:

  • Patient care was reviewed daily by a team of medical officers, lead by the intensive care staff specialist, and treatment decisions, including sedation management plans, were made in consultation with the bedside nurses. Adjustments in treatments, including continuous infusion of sedatives by bedside nurses was based on a patient's response and occurred within prescribed limits throughout the day

  • Sedation with fentanyl and/or midazolam was prescribed by the medical staff responsible for the clinical care of each patient according to the usual practice in each ICU. The use of propofol or any drug other than midazolam or fentanyl for other than extreme agitation or procedures was considered a violation of the protocol. Ad hoc interruption of continuous sedation (e.g., assessment of readiness for weaning) was permitted in both groups of patients at the discretion of the clinical medical team

  • Patient was given a replacement infusion in place of his or her prescribed sedative for a defined period each day. These infusions consisted of fentanyl and/or midazolam. Patients were not allowed to receive the blinded study drug infusion for more than 6 hours

  • According to standard of care in the participating units, sedation prescriptions were not targeted to a prespecified RASS score

  • The appropriateness of starting infusion of the study drug was assessed each morning for each patient, starting on the second morning of mechanical ventilation. The study drug was not started if the patient was scheduled for invasive procedures or investigations requiring in-hospital transport within the next 2 hours; infusion of the study drug was started after the procedure was completed

  • The Richmond agitation-sedation scale (RASS) was used to assess the level of sedation each morning of mechanical ventilation and again at the restart of the patient's prescribed sedative after cessation of the study drug

  • Before starting infusion of the study drug, the bedside nurse determined the patient's RASS score, and if the patient was sufficiently oriented and awake to interact with the instruments or otherwise communicate with the nurse, assessed by pain by using a 0 to 10 numeric rating scale, with 0 = pain free and 10 = worst pain ever experienced, and anxiety by using the Faces Anxiety Scale. Patients were exempt from infusion of the study drug that day if their pain was considered marked, they were scheduled for surgery within the study drug infusion period, or the treating clinicians deemed the infusion inappropriate because of clinical need, such as neuromuscular blockade

  • The clinical team also controlled all other aspects of patient care

Intervention group:

  • According to standard of care in the participating units, sedation prescriptions were not targeted to a prespecified RASS score

  • The patient was given a replacement infusion in place of his/her prescribed sedative for a defined period each day. These infusions consisted of physiological saline. Patients were not allowed to receive the blinded study drug for more than 6 hours

  • The Richmond agitation-sedation scale (RASS) was used to assess the level of sedation each morning of mechanical ventilation and again at the restart of the patient's prescribed sedative after cessation of the study drug

  • The appropriateness of starting infusion of the study drug was assessed each morning for each patient, starting on the second morning of mechanical ventilation. The study drug was not started if the patient was scheduled for invasive procedures or investigations requiring in-hospital transport within the next 2 hours; infusion of the study drug was started after the procedure was completed.The Richmond agitation-sedation scale (RASS) was used to assess the level of sedation each morning of mechanical ventilation and again at the restart of the patient's prescribed sedative after cessation of the study drug. Before starting infusion of the study drug, the bedside nurse determined the patient's RASS score, and if the patient was sufficiently oriented and awake to interact with the instruments or otherwise communicate with the nurse, assessed by pain by using a 0 to 10 numeric rating scale, with 0 = pain free and 10 = worst pain ever experienced, and anxiety by using the Faces Anxiety Scale. Patients were exempt from infusion of the study drug that day if their pain was considered marked, they were scheduled for surgery within the study drug infusion period, or the treating clinicians deemed the infusion inappropriate because of clinical need, such as neuromuscular blockade. The clinical team also controlled all other aspects of patient care

  • The infusion of the study drug was stopped if the patient met any of the following criteria: increased levels of pain, unstable hemodynamic status, a 1-point increase in the score on the Faces Anxiety Scale, a score of +2 or more on the RASS, ventilator dyssynchrony, any procedure or event requiring an increase in sedation, and infusion of the study drug for 6 hours. As soon as infusion of the study drug was stopped for any of the criteria, infusion of the prescribed sedative was restarted. The 6-hour maximum duration was included to preserve the blinding in patients in the control group who might not have met any of the other criteria for stopping the study drug for several days. Infusion of the study drug could be decreased or stopped by the clinical team if they thought that the level of sedation should be reduced. The clinical team also controlled all other aspects of patient care

Drug therapy used: midazolam, fentanyl. The use of propofol or any drug other than midazolam or fentanyl for other than extreme agitation or procedures was considered a violation of the protocol

Mechanical ventilation weaning strategies:

  • Not specifically described. The clinical team controlled all other aspects of patient care

Outcomes
  1. Duration of mechanical ventilation, days

  2. 28-day ventilator-free survival

  3. Duration of ICU stay, days

  4. Duration of hospital stay, days

  5. ICU mortality

  6. 6-month mortality

  7. Tracheostomy

  8. Self extubations

  9. Days from mechanical ventilation start to tracheostomy

  10. Drug exposure

Notes
  • Study terminated before recruitment of 80 patients due to slow recruitment rates

  • The replacement infusions in both groups appeared identical and were labelled 'study drug'

  • Compliance:

    • N (%) of patients receiving study drug infusion = 21 (88%) in the control group versus 22 (85%) in the study group

    • Use of ad hoc drug infusions during study participation n (%) of patients = 12 (50%) control group versus 16 (62%) in the study group

    • Use of propofol as a study violation, n (%) = 4 (17%) control group versus 7 (27%). Total propofol dose, mean (CI) = 92.9 (15.8-170.0) mg control group versus 117 (10.0-224.7) mg study group

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerized randomization 1:1 with variable block sizes
Allocation concealment (selection bias)Low riskSequentially numbered, sealed, opaque envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Blinding with replacement infusion for the interruption period for all patients

A team of non-clinical senior nurses in the ICU were responsible for randomizing patients and preparing the study drug infusion bag

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskPatients, families, bedside nurses, and treating physicians had no knowledge of the treatment given. However specific blinding of outcome assessment was not applied
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition and exclusions reported. ITT analysis performed
Selective reporting (reporting bias)Low riskAll a priori outcomes reported
Other biasLow risk

Appears to be free of other bias

Pilot study so power calculation not applicable

Yilmaz 2010

Methods

Single centre, RCT

One university hospital ICU; Turkey

Compares daily interruption of sedative infusion to nursing-implemented sedation protocol

Participants

Included: mechanical ventilation requiring sedation in ICU

Excluded: under age 18 years, pregnancy, a history of allergy to the drugs used for sedation or analgesia, a disease affecting mental status (e.g. head trauma or meningitis), current receipt of a neuromuscular blocking agent, and need for mechanical ventilation < 24 hours

Control group (n = 25): age mean ± SD 50.44 ±18.89; female n(%) 9 (36.0%); Apache II mean ± SD 19.88 ± 7.51

Intervention group (n = 25): age mean ± SD 44.76± 18.04; female n(%) 10 (40%); Apache II mean ± SD 18.00 ± 5.33

Interventions

Control group (RN directed protocol):

  • A nursing-implemented sedation protocol prepared by 2 physicians and 3 nurses was applied. The protocol was copied on coloured paper and posted at each be in the ICU. The nurses in charge of the patient were responsible for monitoring the sedation level using the scoring system in the protocol and were allowed to adjust sedation according to the protocol

  • Ramsay sedation score was used for the evaluation of the sedation level. While the ideal sedation level was accepted as Ramsay 3-4, Ramsay < 3 and Ramsay > 4 were evaluated as light and deep sedation, respectively. Ramsay score was reassessed q4h. Midazolam was the first drug selected for sedation as 2-5 mg IV bolus q5min until Ramsay score = 3 then infusion of 0.03 mg/kg/hour was initiated for maintenance

  • Pain was evaluated according to the behavioral pain scale in patients in whom agitation was caused by pain. Fentanyl was given as 50 µg IV q5minutes as a bolus dose, according to pain scale. After pain scale ≤ 6 was achieved, fentanyl 50 µg/hour infusion was initiated for maintenance

Intervention group:

  • Midazolam was the first drug selected for sedation, fentanyl for pain. It is unclear if how the drugs were titrated and by what method

  • Sedatives were interrupted; not clear if opioids were interrupted

  • Daily interruption of sedative infusions without any sedation protocol was used. Whenever the physicians wanted to interrupt the sedative drugs according to patients' blood gas analyses or hemodynamic variables, they ordered cessation of the sedative drug infusions

  • Criteria for restarting infusions was not reported

Drug therapy used:

  • Midazolam, fentanyl (dosages adjusted by protocol by RN)

  • Additional sedative drugs could be used: diazepam, propofol, dexmedetomidine (dosages ordered and adjusted by physicians)

Mechanical ventilation weaning strategies:

  • Not described

Outcomes
  1. Duration of mechanical ventilation, days

  2. Duration of sedation, days

  3. Length of ICU stay

  4. Mortality

  5. Tracheostomy

  6. Reintubation

  7. Any self-extubation

  8. Mortality

  9. Catheter removal

  10. Cardiac events

  11. Drug exposure

NotesAs per the authors: In the intervention group all sedative drugs were used according to physician's specific order and the requested sedation level was achieved. On the other hand, the requested sedation level was not achieved in 32% of cases in the control group. Physicians were informed by the nurses and additional sedative agent infusions were initiated by them, and adequate sedation level was achieved.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Block randomization was accomplished using opaque and sealed envelopes, opened at the time each patient was enrolled in the study.

Method of randomization not specified

Allocation concealment (selection bias)Low riskOpaque and sealed envelopes, opened at the time each patient was enrolled in the study
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded. Probably not done
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Not blinded

Objective outcome assessed

Incomplete outcome data (attrition bias)
All outcomes
Low riskITT analysis performed
Selective reporting (reporting bias)Low riskAll a priori outcomes reported
Other biasLow risk

Appears to be free of other sources of bias

Sample size calculation not reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Amor 2007The control group also received daily sedation interruption
Anifantaki 2007Abstract of included study Anifantaki 2009
Bein 2008The trial did not include mechanically ventilated ICU patients or an interruption of intravenous sedation. This trial compared the effect of interrupted administration of sevoflurane gas before cardiopulmonary bypass with continuous sevoflurane administration and with propofol-only anaesthesia, on cardioprotection during coronary artery bypass grafting
Brook 1999This trial did not include a daily sedative interruption in either the intervention or the control group. This study compared a nurse-directed protocol to usual care
Carson 2005Abstract of Carson 2006
Carson 2006The control group also received daily sedation interruption
de Wit 2006Abstract of included study de Wit 2008
Kress 2001This study assessed the impact of choice of sedative (either midazolam or propofol) for DSI on duration of mechanical ventilation and length of stay. It is a subgroup analysis of the trial Kress 2000 already included in the review (same patients)
Oto 2011This study compares daily interruption of sedation to continuous sedation without interruption but did not include data on the primary or any of the secondary endpoints selected for this review
Ruokonen 2009The control group also received daily sedation interruption
Strom 2010The control group also received daily sedation interruption

Characteristics of studies awaiting assessment [ordered by study ID]

Binnekade 2009

Methods

Multi-centre

Patients were randomly assigned to a daily wake-up strategy, sedation guided by bispectral index, or a control group

Clinical assessment of the sedation depth (Ramsay score) was performed in all three groups

Participants

Patients expected to need sedation for > 1 day

Mixed medical-surgical population

InterventionsDetails of daily wake-up strategy, sedation guided by bispectral index, or a control group not presented in the abstract
Outcomes
  1. ICU length of stay

  2. duration of mechanical ventilation

  3. accidental removal of indwelling devices

  4. ICU readmission rate

  5. Hospital length of stay

  6. 90-day mortality

  7. Stressful events as measured by interviews at ICU exit and 3 months post discharge

Notes

Published in abstract form only

Large sample size (617 patients)

Data not available from authors

Characteristics of ongoing studies [ordered by study ID]

Chanques 2012

Trial name or titleSedation Optimisation Strategy (S.O.S.) Ventilation
MethodsRCT; single blind (subject)             
Participants

Inclusion criteria:

  • Ventilated patient in assist control mode after a surgical procedure expected to be ventilated for 12-hours or more

  • At least 1 organ dysfunction according to SOFA score

  • Non-paralyzed because of neuromuscular blocking agents

  • Body temperature > or equal 36°C

  • Age > or equal 18 years

  • Surrogate decision maker's consent

Exclusion criteria:

  • Patients without any surgical procedure (medical patients)

  • Continuous mechanical ventilation for 24-hours or longer

  • Hospitalisation in ICU for 7-days or longer

  • Severe ARDS (Acrasis study criteria, New England Journal Medicine 2011)

  • Neurological injury

  • Active toxicomania

  • Reduction or cessation of active treatment

  • Patient under tutelage

  • Pregnancy

  • No French health insurance

  • Enrollment in another study on sedation or mechanical ventilation

Interventions

Intervention group:

  • Continuous use of sedatives and analgesics (commonly called "sedation") will be stopped upon enrolment

  • Ventilator asynchrony in Volume assist Controlled Ventilation (VCV) will be treated by switching to Pressure Support Ventilation (PSV) or adjusting setting of VCV

  • Pain, anxiety and agitation will be treated by priority setting of the mechanical ventilator aimed to deliver the most comfortable ventilator support and secondly by adding analgesics and/or psychoactive drugs without inducing a coma state

  • Persistent ventilator asynchrony or persistent agitation will be treated by 6-hours continuous sedation periods

  • Extubation will be performed according to criteria defined by the national consensus on mechanical ventilation weaning, which are based on a daily spontaneous breathing trial in the absence of any sedation

 Control group (standard practices):

  • Continuous use of sedatives and analgesics (commonly called "sedation") will be daily stopped according to criteria defined by the national consensus on sedation for ICU patients. During the period before the interruption of sedation, ventilator asynchrony in VCV will be treated by increasing the depth of sedation and then the dose of opioids

  • During the period before the interruption of sedation, pain, anxiety and agitation will be treated by a priority adjustment of sedation according to the nurse driven protocol recommended by the national consensus on sedation for ICU patients. During the period after the interruption of sedation, ventilator asynchrony will be treated by switching to the PSV mode. In case of return to VCV, asynchrony will be treated by restart of sedation

  • During the period after the interruption of sedation, pain, anxiety and agitation will be treated as for the intervention group

  • Extubation will be performed according to criteria defined by the national consensus on mechanical ventilation weaning, which are based on a daily spontaneous breathing trial in the absence of any sedation

Outcomes

Primary outcome measures: Number of days without mechanical ventilation in a 28-days period

 

Secondary outcome measures:

•   Dose and duration of sedation

•   Type and duration of mechanical ventilation

•   Complications acquired in ICU

•   Length of stay in ICU and hospital

•   ICU and hospital mortality

•   Quality of life, anxiety, depression, post-traumatic stress disorder 3 and 12 months after ICU discharge

•   Incidence and duration of organ dysfunctions

Starting dateDecember 2011
Contact informationContact: Gerald GC Chanques, MD, PhD g-chanques@chu-montpellier.fr
Notes
  • Estimated completion December 2014

  • Unclear if daily interruption is being applied in both the control and the intervention groups

Ancillary