Delirium is defined as an acute alteration in consciousness, attention, cognition and perception that fluctuates in nature.1-7 Although reversible, the duration and severity of the delirium episode may lead to poor patient outcomes for up to one year following the episode, placing a financial burden on the healthcare system.1-6,8-11 The increased risk of cognitive impairment following delirium may manifest in problems with memory, attention, reasoning and processing speed.2-6,8-10 This can range in severity from minor impairment to features of severe dementia, with 35% dying within six months of hospital discharge.12-14 Delirium has known negative impacts on quality of life, patient safety (accidental self-harms, falls, physical restraints) and on family members’ satisfaction with care.2-5 For the healthcare system, increased costs are incurred with increased bed occupancy, length of hospital stay, treatment, rehabilitation and staffing.11-13
Delirium can occur at any age and in any setting, however patients admitted for treatment in intensive care units (ICU) are at the greatest risk.1 In Australia, the incidence of delirium in ICU has been reported at 37% (unstandardized assessment method) and 21% (standardized assessment method).1 In a multicenter Australian and New Zealand study, the incidence was determined to be 45% (standardized assessment).15 However, in a review of international healthcare literature, the incidence of delirium in adult ICU patients ranged from 22% to 90%, depending on the medical diagnosis and assessment method used.16,17 Postoperative delirium is a serious problem with incidence estimated to affect 10% to 40% of patients undergoing general surgery and 50% to 90% of patients undergoing cardiac surgery.4,18-21
Early recognition, increased screening and early intervention have been shown to improve patient outcomes.17,22 The gold standard for delirium diagnosis is an interview conducted by a trained clinician (psychiatrist) using Diagnostic and Statistical Manual of Mental Disorders (i.e. DSM-IV) criteria.17,22-24 However, feasibility issues of this approach in the clinical setting make it impractical.22 Arguably, critical care nurses are ideally placed to screen and recognize delirium early.17,22,23 A number of delirium assessment tools have been developed to assist nurses in screening and assessment.25 The Society of Critical Care Medicine Pain, Agitation and Delirium guideline advocates frequent monitoring, at least once per shift (every eight to 12 hours) using a valid assessment tool.17,18,22,26,27 Five assessment tools have been reviewed by the Society of Critical Care Medicine: the Confusion Assessment Method for ICU (CAM-ICU), Intensive Care Delirium Screening Checklist (ICDSC), Cognitive Test for Delirium, Delirium Detection Score and Nursing Delirium Screening Scale.26 The CAM-ICU and ICDSC are both used for identifying delirium in both mechanically ventilated and self-ventilating patients and have been validated in research studies.26 Studies conducted to compare assessment tools have revealed that the CAM-ICU may be highly sensitive while the ICDSC may have greater specificity.3,11,13,28 However, more recent studies suggest that the two assessment tools perform differently in different populations and settings and that specificity is sometimes better for the CAM-ICU than the ICDSC.13,29 The consensus among experts is that both instruments are excellent screening tools and either will provide better assessment than other instruments or an unstructured clinical assessment.13,29
There are significant predisposing and precipitating risk factors associated with delirium.4,19 Among the predisposing risk factors, there is strong evidence for advanced age, previous psychiatric conditions, cerebrovascular disease, pre-existing cognitive impairment, hypertension, diabetes and emergency surgery.4,19 The type of surgery, blood product transfusion, hypothermia, insufficient renal perfusion, hypoxia, hypoxemia, prolonged mechanical ventilation and postoperative atrial fibrillation are significant precipitating risk factors.4,19 Additionally, iatrogenic or environmental factors may contribute to the development of delirium.4,23 The ICU environment is often noisy, with patients admitted into windowless, single occupancy rooms.30 These factors have been found to disrupt patient sleep-wake cycles, placing them at greater risk of delirium.30,31
Postoperative cardiac surgery patients are a cohort that are at increased risk of developing postoperative delirium associated with specific preoperative, intraoperative and postoperative factors.9 Preoperative risk factors include advanced age, hypertension, pulmonary hypertension, decreased ejection fraction, atrial fibrillation, diabetes, impaired renal perfusion, vascular disease, and drug and alcohol use.9 Intraoperatively, open heart surgery is typically performed either with (on-pump) or without (off-pump) the use of cardiopulmonary bypass (CBP).9,19,32,33 Cardiopulmonary bypass is accompanied with hypothermia, hypoxia or hypoxemia resulting in a systemic inflammatory response and hemodynamic instability, leading to patients requiring extended anesthetic time and blood product transfusions.9 Studies have suggested that on-pump cardiac surgery is showing increased incidences of delirium in patients than in those who undergo off-pump.32,33 The postoperative risk factors include prolonged mechanical ventilation associated with the continuous infusion of sedative medications, opioids for pain management, atrial fibrillation, hypotension, sleep disruption, cardiogenic shock and sepsis.9
While the exact neurophysiological mechanism and causation of delirium remain unclear, it has been suggested that imbalances in a number of neurotransmitter pathways lead to the development of delirium.24,34 Imbalances occur in the release, synthesis and degradation of gamma-aminobutyric acid (i.e. GABA), glutamate, acetylcholine, norepinephrine, dopamine and serotonin, leading to neurological dysfunction.13,24,34,35 Some studies have proposed that these pathways are further influenced by metabolic disturbances often present in critically ill patients such as sepsis, inflammation, ischemia and glucose dysfunction.35 Delirium is a complex and multifactorial process that can occur when multiple predisposing and precipitating risk factors, iatrogenic or environmental factors and metabolic disturbances converge.4,23,36 This may explain the neuropathogenesis process of delirium.4,23,36
The management of delirium primarily involves identifying and correcting any underlying cause(s) and minimizing the duration and severity of the episode to ensure safety and to restore the patient's cognitive function.13,37 Management strategies are categorized into either non-pharmacological or pharmacological interventions. Non-pharmacological strategies lean towards prevention rather than treatment while pharmacological strategies target prevention or treatment.10,38 A number of studies have investigated the effectiveness of various pharmacological interventions that include adrenergic alpha-2 agonists (e.g. dexmedetomidine, clonidine), sedatives (e.g. propofol), benzodiazepines (e.g. diazepam, midazolam) and typical and atypical antipsychotics (e.g. haloperidol, quetiapine and olanzipine) and have shown mixed results.1 Randomized control trials (RCTs) have investigated the effectiveness of dexmedetomidine in the prevention of postoperative delirium in adult patients after cardiac surgery.39-44 Prophylactic low dose dexmedetomidine (i.e. 0.1mcg/kg/hr started intraoperatively) as a continuous infusion in the treatment group resulted in significant decreases in the occurrence of delirium after surgery during the first seven days.43 Another RCT comparing dexmedetomidine with propofol sedation in reducing delirium after cardiac surgery showed that dexmedetomidine sedation reduced the incidence, delayed the onset and shortened the duration of the delirium episode.40 Other pharmacological agents were explored in a study comparing ondansetron with haloperidol for the treatment of postcardiotomy delirium, showing that both ondansetron and haloperidol had good delirium controlling effects but lacked statistically significant differences.45 Many of these primary studies evaluate the benefits of two pharmacological interventions or a placebo but exclude assessing pharmacological harms, adverse or unintended side effects.
When pharmacological interventions are used to manage delirium episodes, it is important to be aware of the effectiveness and harms associated with their use.46 According to Consolidated Standards of Reporting Trials (CONSORT) extension for harms, the preferred term is “harms” rather than “safety”.46 Although the term “safety” may be reassuring, it can be confusing or misused, often obscuring the real or potential “harms” that can lead to misleading conclusions.46,47
Identifying drug harms that minimize the duration and severity of the delirium episode is of great importance to policy makers, clinicians and patients.26,38,47,48 The safe and effective use of pharmacological agents has been associated with improved clinical outcomes, however there are currently no medications that are approved by the United States Food and Drugs Administration for the treatment of delirium.26,38 Assessing harms can be challenging as a greater importance is placed on benefits when trials are reported, as well as the impracticality of ascertaining all possible harms associated with each drug.46,47 A standardized tool for the assessment of harms exists: the McMaster Quality Assessment Scale of Harms (McHarm) explores drug related harms in quantitative studies.47 A limited number of published RCTs investigating effectiveness and harms of pharmacological interventions in the treatment of delirium following postoperative cardiac surgery exist.42,49 One RCT examined the impact of dexmedetomidine on the incidence of delirium in elderly patients after cardiac surgery and found no significant decrease in the incidence of delirium in the treatment group compared with the control group.49 However, an increase in postoperative hypotension requiring treatment was noted.49
A preliminary search of the JBI Database of Systematic Reviews and Implementation Reports, Cochrane Library, PubMed, EPISTEMONIKOS and PROSPERO found that there are existing systematic review protocols and finalized systematic reviews on the effectiveness of pharmacological interventions for the treatment of delirium in adult patients in ICUs.5,50-55 These reviews have not used the exact inclusion criteria, search strategy or critical appraisal and synthesis approaches proposed in this systematic review. Nor have they systemically examined both effectiveness and harms; these existing reviews have not examined harms systematically by using the McHarm approach. Moreover, the primary and secondary outcomes considered in the current review are more comprehensive compared to those in existing reviews. In addition, none of the existing systematic reviews performed a priori subgroup analyses on studies examining the effectiveness and harms of pharmacological interventions on delirium in patients who underwent cardiac surgery with CBP (on pump) versus cardiac surgery without CBP (off pump).
The population of interest is adult patients (16 years and over) treated in a cardiothoracic ICU.
Studies of participants with the following characteristics will be included:
- Adult (age ≥16 years; rationale: in some countries and healthcare systems this is the definition of an adult).
- Treated after cardiac surgery, regardless of the type of cardiac surgery (such as, but not limited to, coronary artery bypass grafting [CABG] and valvular repairs/replacements/ transcatheter aortic valve implantation [TAVI]).
- Any ethnicity.
- Any gender.
- Identified as having delirium, regardless of type of healthcare professional who did the screening or framework/diagnostic tool used (for treatment interventions).
- With or without co-existing psychiatric or neurological conditions.
This review will include studies that evaluate pharmacological interventions for the treatment of delirium in adult patients treated in intensive care after cardiac surgery. Studies reporting pharmacological interventions will be considered for inclusion, regardless of dosage, intensity or frequency of administration. The pharmacological interventions to be considered for inclusion will be:
- Atypical and typical antipsychotics such as, but not limited to, haloperidol, quetiapine and olanzapine
- Benzodiazepines such as, but not limited to, diazepam and midazolam
- Sedatives such as, but not limited to, propofol
- Alpha-agonists such as, but not limited to, dexmedetomidine and clonidine.
For the purposes of this systematic review, the term “harms” refers to all negative consequences of all pharmacological interventions such as side effects, adverse events, adverse reaction, adverse drug reaction etc., as defined in the CONSORT statement, the statement extension for harms.46
Comparators considered for this review will be any head to head comparisons between any two pharmacological interventions from the mentioned classes of drugs.
The systematic review will consider studies that include the following outcomes:
- Mortality due to all causes (ICU mortality and post discharge mortality, such as 30-day mortality).
- Total duration of delirium.
- Severity of delirium.
- Frequency of use of physical restraints.
- Patient's quality of life during ICU stay as reported by healthcare professionals or family member.
- Family members’ satisfaction with delirium management provided.
- Duration and severity of patient aggressive or violent behavior towards healthcare staff, other patients and family members or other persons in contact with patient.
- Number and severity of patient falls.
- Number and severity of patient accidental self-harm events such as, but not limited to, unintentional extubations, accidental removals of invasive lines, catheters/cannulas.
- Harms related to pharmacological interventions such as, but not limited to, adverse events and side effects.
- Harms related to “over sedation” such as prolonged time to rouse when sedative medications are ceased, to wean from mechanical ventilation and to be deemed ready for discharge from ICU.
- ICU length of stay: number of days from admission to time of discharge from ICU.
- Length of hospital stay after ICU discharge: number of days from time of discharge from ICU to time of discharge from hospital
- Total hospital length of stay: number of days from admission to time of discharge from hospital.
- Need for additional medication for management of delirium.
- Use of additional medication for management of delirium.
Types of studies
The review will include both experimental and non-experimental study designs such as RCTs, non-RCTs, quasi-experimental, before and after studies, observational, prospective and retrospective cohort studies and analytical cross-sectional studies for inclusion. We will consider for inclusion in the first instance randomized experimental studies as they provide, through randomization, less biased evaluations of effects compared to other study designs, for both effectiveness and harms.56-58 In the absence of randomized experimental studies, we will consider non-RCTs and quasi-experimental studies. In the absence of experimental and quasi-experimental studies we will consider analytical observational studies.
The search strategy will be designed to find both published and unpublished studies. A three-step search strategy will be used. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, 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. Third, the reference list of all identified articles will be searched for additional studies. Only studies published in English will be considered for inclusion in this review. There is no time limitation for the search.
The databases to be searched will include:
- Web of Science
- Cochrane Central Register of Control Trials
The search for unpublished studies will include:
- ClinicalTrial.gov (NZ)
- Australian Clinical Trials
- National Institute of Health
- National Clearing House
- ProQuest Dissertations and Theses.
A hand search for primary studies published in relevant journals (for the last five years) will include:
- Australian Critical Care
- Journal of Cardiothoracic Surgery
- American Journal of Respiratory and Critical Care Medicine
- Intensive Care Medicine
- Critical Care Medicine.
A web search for primary studies used in relevant clinical practice guidelines will include:
- American Society of Critical Care Medicine
- American Society of Critical Care Nurses
- Australian and New Zealand Society of Critical Care Medicine.
The following initial keywords will be used: intensive care unit, ICU, delirium, altered mental state, confused state, neurocognitive manifestations, pharmacological, treatment, drug treatment, management, intensive care units, post cardiac surgery, typical antipsychotics, atypical antipsychotics, sedatives, alpha agonists, benzodiazepines, haloperidol, propofol, dexmedetomidine, clonidine, diazepam, olanzapine, haloperidol, quetiapine.
The details of the full search strategy for PUBMED, Embase, CINAHL, Web of Science, Scopus and Cochrane Central Register of Clinical Trials are provided in Appendix I.
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.52 Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. The McHarm for primary studies will also be used to appraise the quality of the studies exploring the pharmacological harms, adverse or unintended effects.43,46
Data will be extracted from papers included in the review using the standardized data extraction tool from the Joanna Briggs Institute.52 The data extracted will include specific details about the populations, interventions (e.g. type, intensity and duration), outcomes and study methods. In addition, attempts will be made to obtain missing data from the study report(s) by contacting the authors of the included studies. This review will structure the data extraction of harms information based on the guidance provided by the CONSORT statement, specifically the statement extension for harms.46 Data extraction will be carried out by one reviewer with verification by another reviewer to minimize bias and potential errors in data extraction.
Quantitative data will, where possible, be pooled in statistical meta-analysis using the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI). In addition to the head-to-head direct comparison, meta-analysis performed using JBI SUMARI, if possible and appropriate, network meta-analysis will be conducted using STATA software (Stata Corp LLC, Texas, USA) and following the STATA guidance.59,60 All results will be subject to double entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data measured on the same measurement scale) or standardized mean differences (for continuous data measured on different scales) and their 95% confidence intervals will be calculated for analysis. As the goal of synthesis is to make generalizations beyond the included studies, a random effects model will be used for meta-analysis if possible; however, if less than five studies are available for meta-analysis, the random effects model will not be used; instead the appropriateness for fixed effect model meta-analysis will be explored.61 Heterogeneity will be explored and reported using the standard Chi2 and I2 statistics. Subgroup analyses will be performed on studies including patients with co-existing psychiatric or neurological conditions versus studies including patients without such co-existing conditions. Subgroup analyses will be performed on studies in patients who have undergone cardiac surgery with cardiopulmonary bypass (on pump) versus cardiac surgery without cardiopulmonary bypass (off pump). Subgroup analyses will be performed on studies with different study design (experimental, quasi-experimental, analytical observational studies). Data on harms will be explored using descriptive statistics and if possible inferential statistics. The synthesis and presentation of harms data will be organized based on the domains explored by McHarm, the CONSORT extension for harms, and the PRISMA harms checklist.43,46,62 Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
Assessing certainty in the findings
The presentation of the results will include a Summary of Findings (SoF) by following the recommendations provided in the Handbook published by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The SoF will be generated by using GRADEPro software.
Appendix I: Search strategy
This systematic review is conducted in order to fulfil the requirements for the Master of Clinical Science degree at the Joanna Briggs Institute, The University of Adelaide, for VL. As this review is conducted for a degree, a secondary reviewer will be involved only in the verification of data extraction and in the critical appraisal of papers selected for inclusion.
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