Review question/objective
The objective of this review is to identify the effectiveness of haloperidol prophylaxis in critically ill patients with a high risk for delirium.
More specifically, the questions are:
- Is the prophylactic use of haloperidol effective in preventing delirium?
- Is the prophylactic use of haloperidol effective in reducing unplanned/accidental removal of tubes/lines and catheters?
- Is the prophylactic use of haloperidol effective in reducing the duration of mechanical ventilation and incidence of re-intubation?
- Is the prophylactic use of haloperidol effective in reducing ICU and hospital length-of-stay and re-admissions?
Background
Delirium is a common clinical syndrome characterized by inattention and acute cognitive dysfunction1-4, as well as by fluctuating mental status and disorganized thinking.5 Over the years, several terms have emerged to describe delirium as "acute confusional state", "acute brain syndrome", "acute cerebral insufficiency" and "toxic-metabolic encephalopathy". However, the term delirium has evolved to describe a transient, reversible syndrome that is acute and fluctuating, and which occurs in the setting of a medical condition.2,6
Delirium may result from diverse pathophysiological mechanisms, including derangement of several neurotransmitter systems within the brain, which are not fully understood. Current widely postulated theory concludes that delirium is caused by cholinergic deficiency with an excess of dopamine.6,7 However gamma-aminobutyric acid (GABA) and glutamate have both also been implicated in the development of delirium. Glutamate is metabolized into GABA, which is an inhibitory neurotransmitter. Hypnotic or sedative drug withdrawal may cause the level of GABA to drop, which in turn may cause delirium.8
In hospital settings, the prevalence of delirium has been estimated at anywhere between 10% and 30% in general medical patients and upwards of 80% in patients who are admitted to an intensive care unit (ICU).9,10 Therefore, and given the high prevalence of delirium in the ICU population, it should not be surprising that a large percentage of psychiatric consults arise from this setting.10
It should be noted that delirium in ICUs is associated with prolonged ICU and hospital length-of-stay, prolonged duration of mechanical ventilation, unplanned removal of tubes and catheters, and increased morbidity and mortality.1,4,5,9,11 For this reason, the Society of Critical Care Medicine recommends routine assessment in the ICU for the presence of delirium.12
Therefore, preventive treatment for delirium may be beneficial, and several antipsychotics (such as haloperidol) have been studied for the prophylactic treatment in ICUs.5,11 Some studies suggest that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects.11,13
More recently, there have been studies that evaluated the efficacy of second generation (atypical) antipsychotic medications in ICU patients for the prevention of delirium (as quetiapine, olanzapine and ziprasidone).14 As pharmacological treatment and prevention for delirium traditionally includes haloperidol, second-generation antipsychotics have emerged as an alternative for the prevention of delirium. However the evidence for use of antipsychotics in the ICU is weak, hence evidence on haloperidol as a prophylactic agent against delirium needs to be analyzed before antipsychotics can be used routinely.1,4,5,9,11,14
The main mechanisms of action of haloperidol are thought to be antagonism at cortical dopamine (D2) receptors, nigrostriatal pathway D2 blockade, and disinhibition of acetylcholine with acetylcholine increase.7,13 In this context, the use of haloperidol also includes a reduction in the need for psychotropic sedative and analgesic drugs in ventilated patients, and potentially beneficial immunomodulatory effects.7,13
In fact, according to the existing guidelines, haloperidol is recommended as the drug of choice for the treatment of ICU delirium despite a lack of placebo-controlled clinical trials.12
A preliminary search of the JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Database of Systematic Reviews, Prospero, CINAHL and Medline revealed that there are currently no systematic reviews (neither published nor in progress) on the use haloperidol prophylaxis in critically ill patients with a high risk for delirium.
Therefore, it is necessary to examine the decision to use haloperidol prophylaxis in critically ill patients with a high risk for delirium, which involves an intense critical analysis based on scientific evidence.
Inclusion criteria
Types of participants
This review will consider studies that include patients with a predicted high risk for delirium, aged 18 years or over, and in hospital settings (intensive care units only).
Exclusion criteria: patients with a history of concurrent antipsychotic medication use.
Types of intervention(s)/phenomena of interest
This review will consider studies that assess the effectiveness of haloperidol prophylaxis in adult patients in a critical care unit in preventing delirium.
Comparator
This review will consider studies that compare:
- Adult patients in an intensive care unit who are given prophylactic haloperidol versus not given for the prevention of delirium.
- Adult patients in an intensive care unit who are given prophylactic haloperidol versus other prophylactic atypical antipsychotic medications.
Types of outcomes
This review will consider studies that include the following outcome measures:
1) Primary outcome (delirium incidence proportion):
Delirium will be assessed through validated instruments which may include, but will not be limited to: Cognitive Test for Delirium, Abbreviated Cognitive Test for Delirium, Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Intensive Care Delirium Screening Checklist, Neelon and Champagne Confusion Scale, Delirium Detection Score and the Nursing Delirium Screening Scale.
2) Secondary outcome:
Duration of mechanical ventilation, incidence of re-intubation, incidence of unplanned/accidental removal of tubes/lines and catheters, ICU and hospital length-of-stay, re-admissions for both settings.
Types of studies
This review will consider both experimental and epidemiological study designs, including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies for inclusion.
Search strategy
The search strategy aims to find both published and unpublished studies. A three-step search strategy will be used in this review. An initial limited search of MEDLINE and CINAHL will be undertaken, followed by an analysis of text words in the titles and abstracts, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in Portuguese, English and Spanish will be considered for inclusion in this review. Studies published between 1967 (date of approval by the US Food and Drug Administration-FDA15) and 2015 will be considered for inclusion in this review. Studies in another language or date of publication will be excluded.
The databases to be searched include:
MedicLatina
CINAHL Complete
MEDLINE Complete
EMBASE
Cochrane Central Register of Controlled Trials
Scielo - Scientific Electronic Library Online
The search for unpublished studies will include:
ProQuest - Nursing and Allied Health Source Dissertations
Banco de teses da CAPES (http://www.capes.gov.br)
RCAAP - Repositorio Cientifico de Acesso Aberto de Portugal.
Initial keywords to be used will be:
Delirium
Haloperidol
Prophylaxis
Critical car*
Intensive car*
Adult*
Assessment of methodological quality
Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.
Data extraction
Data will be extracted from papers included in the review independently by two reviewers, using the standardized data extraction tool from the JBI-MAStARI (Appendix II). Data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. For missing information or to clarify unclear data, the authors of primary studies will be contacted. Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.
Data synthesis
Quantitative data will, where possible, be pooled in statistical meta-analysis using the JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for dichotomous data) and their 95% confidence intervals will be calculated for outcome analysis. Heterogeneity will be statistically assessed using the standard Chi-square and also explored using subgroup analyses based on different study designs and different unplanned removals of tubes/lines and catheters and different interventions (as haloperidol in terms of dosage and timing of administration). Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation.
Conflicts of interest
The authors have no conflict of interest to declare.
References