• Users Online: 4717
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe News Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 40-44

Pharmacologic prevention of delirium after cardiac surgery: Current best available evidence


Department of Cardiac Surgery, Harefield Hospital, London, England

Date of Submission11-May-2020
Date of Acceptance04-Jun-2020
Date of Web Publication13-Jul-2020

Correspondence Address:
Dr. Shahzad G Raja
Department of Cardiac Surgery, Harefield Hospital, London
England
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hm.hm_9_20

Rights and Permissions
  Abstract 

Delirium is a familiar neuropsychological syndrome confronted after cardiac surgery associated with a significant morbidity and mortality. Although several therapeutic options including dexamethasone, rivastigmine, risperidone, ketamine, dexmedetomidine, propofol, and clonidine have been used for delirium prevention, there is still lack of certainty regarding the most effective drug. In the current era of evidence-based medicine, the systematic review (with homogeneity) of randomized controlled trials is regarded as the most precise tool for determining the benefit of a therapeutic intervention. This review article aims to assess the current best available evidence to determine the most effective pharmacologic agent for prevention of delirium post cardiac surgery.

Keywords: Cardiac surgery, delirium, dexmedetomidine, dexamethasone, pharmacologic intervention, rivastigmine, statin


How to cite this article:
Soni MK, Raja SG. Pharmacologic prevention of delirium after cardiac surgery: Current best available evidence. Heart Mind 2020;4:40-4

How to cite this URL:
Soni MK, Raja SG. Pharmacologic prevention of delirium after cardiac surgery: Current best available evidence. Heart Mind [serial online] 2020 [cited 2022 May 17];4:40-4. Available from: http://www.heartmindjournal.org/text.asp?2020/4/2/40/289695


  Introduction Top


Delirium is a neuropsychological syndrome characterized by an acute onset of a fluctuating disturbance in attention; environmental awareness; and cognition and/or perception.[1] It is a common occurrence after general anesthesia and surgery.[2] It is reported to affect up to 47% of patients undergoing cardiac surgery and is more prevalent in elderly patients.[3] A complex interplay of neurotransmitters, pro-inflammatory markers, physiologic stressors, metabolic disorders, and electrolyte imbalances is central to the pathophysiology of delirium.[4] Delirium is associated with enhanced mortality and morbidity, loss of independence, long-term deterioration in cognitive function and dementia, prolonged hospital stay, institutionalization, and enhanced resource utilization.[5]

A variety of pharmacologic agents such as dexmedetomidine, propofol, midazolam, lorazepam, sevoflurane, morphine, dexamethasone, ketamine, and statins have been utilized for the prevention and treatment of delirium post cardiac surgery.[6] These drugs with disparate pharmacologic characteristics have contrasting advantages and disadvantages in clinical practice. However, despite the reported benefits of these pharmacologic agents there is no agreement regarding the most effective pharmacologic agent for preventing delirium after cardiac surgery.

In the current era of evidence-based medicine, a rational and comprehensive strategy to assess clinically pertinent research encompasses a variety of evidence ranging from randomized controlled trials (RCTs), nonrandomized observational studies to experimental data and evaluates the information's content for its reliability, comprehensibility, and precision.[7] In the present era of evidence-based medicine, the systematic review (with homogeneity) of RCTs is regarded as the most effective tool for establishing the benefit of a therapeutic intervention.[8] This review article aims to analyze the current best available evidence to determine the most effective pharmacologic agent for the prevention of delirium post cardiac surgery.


  Methods Top


Search methodology

English scientific literature was reviewed primarily by searching MEDLINE from 1966 to July 2019 using PubMed interface. Four key words used in the search included Medical Subject Headings (MeSH) search terms “drug therapy”, “confusion,” “delirium,” and “cardiac surgical procedures” The “similar articles” function was utilized to widen the search and all abstracts, studies, and citations scanned were evaluated. The reference lists of articles retrieved through these searches were also screened for relevant articles. Furthermore, EMBASE, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Science Citation Index, Current Contents, and International Network of Agencies for Health Technology Assessment databases were explored from the date of their establishment to the last week of July 2019.

The search was done in phases so as to attain the search strategy with a high sensitivity (meaning that it has the greatest probability of retrieving all pertinent publications). Related search terms were linked using the Boolean operator “OR” to obtain all abstracts that included information about a certain search term. These distinctive terms were then linked using the Boolean operator “AND” to recover publications that included information on all the search terms. This is a familiar strategy for undertaking sensitive searches and has been explained thoroughly in the British Medical Journal.[9]

Inclusion and exclusion criteria

All systematic reviews and meta-analyses of blinded and un-blinded RCTs that investigated the pharmacological prevention of postoperative delirium after cardiac surgery only were included, with language restricted to English. Patients were adults (at least 18 years of age) and received drugs in the perioperative phase. Systematic reviews and meta-analyses of RCTs recruiting patients undergoing surgery other than cardiac surgery were excluded.

Data extraction and validation of the studies

The papers retrieved by the search strategy were then evaluated. The evaluation of each publication was undertaken in a methodical manner, using critical appraisal checklists. These are extensively available in various templates and assist in evaluating the publication for methodological and analytical robustness and help detect any major methodological deficiencies.[10] The following information was retrieved from each study:First author, year of publication, number of RCTs, drugs used, number of patients, and key outcomes. Finally, a conclusion was drafted based on the soundness of the studies identified, taking into account the source and the strength of the evidence using the grading system suggested by the Centre for Evidence-Based Medicine [Table 1] and [Table 2].[8]
Table 1: Levels of evidence

Click here to view
Table 2: Grades of recommendation

Click here to view



  Results Top


A total of six systematic reviews were retrieved for evaluation after screening a total of 649 citations.[11],[12],[13],[14],[15],[16] Following evaluation four systematic reviews were found to meet the inclusion criteria [Figure 1] and [Table 3].[12],[14],[15],[16] The systematic review by Liu et al.[11] included 28 noncardiac RCTs and hence was excluded. Vallabhajosyula et al. evaluated the role of statins in delirium prevention in critically ill and cardiac surgery patients.[13] All of the 6 studies included in this systematic review demonstrated appreciable heterogeneity (I2 = 73%). However, for cardiac surgery studies the heterogeneity was moderate (I2 = 55%). Satins were administered to 22 292 (7.7%) of the 289 773 patients. Out of the total study cohort, 4382 (1.5%) patients underwent cardiac surgery and statins were administered to 2321 (53.0%) patients. Delirium was experienced by 710 (3.2%) patients in the statins group compared to 3478 (1.3%) patients in the nonstatin group. Overall, no difference was noted between groups in the total cohort (P = 0.56) or those who underwent cardiac surgery (P = 0.89). This systematic review was excluded as it had a heterogeneous patient population.
Figure 1: Flow chart depicting study selection for the review

Click here to view
Table 3: Key systematic reviews

Click here to view


The systematic review by Tao et al.[12] included 14 RCTs. Nine of these trials compared a pharmacologic agent against a placebo while 4 studies used usual care as the control. The drugs evaluated in these RCTs included dexmedetomidine (n=4), dexamethasone (n = 3), risperidone (n = 2), ketamine (n = 1), rivastigmine (n = 1), clonidine (n = 1), propofol (n = 1), and methylprednisolone (n = 1). Similarly, the systematic review by Mu et al.[16] included 13 RCTs (10 prevention and 3 treatment) evaluating dexamethasone, rivastigmine, risperidone, ketamine, dexmedetomidine, propofol, clonidine, and haloperidol. One systematic review compared the effectiveness of dexmedetomidine versus propofol[14] while another compared the effectiveness of dexmedetomidine against other medications[15] in reducing delirium post cardiac surgery.

The two systematic reviews of RCTs evaluating a variety of agents revealed that prophylactic use of therapeutic agents for prevention of delirium after cardiac surgery not only diminished the risk of delirium but also its duration in the postoperative phase.[12],[16] However, due to marked clinical and statistical heterogeneity these systematic reviews failed to show outright superiority of a single agent.

Liu et al. conducted a meta-analysis of 8 RCTs comparing the impact of dexmedetomidine and propofol on delirium in patients post cardiac surgery.[14] This meta-analysis demonstrated a marked reduction in the occurrence of delirium with dexmedetomidine administration (P = 0.0002). However, it is important to mention that despite the authors' conclusion that dexmedetomidine, compared with propofol, might be a superior option for the prevention of postoperative delirium after cardiac surgery; there are several limitations of this meta-analysis. Marked heterogeneity in the selection of patients, the study period, the sedation levels, the definitions of outcomes, and the methods of assessments in these RCTs included in the meta-analysis may impact the outcome. Similarly, Geng et al., in their meta-analysis, pooled data from four studies and showed that dexmedetomidine therapy was associated with an appreciable reduction in the incidence of delirium in the postoperative phase (P = 0.0004).[15]


  Discussion Top


The evaluation of the current best available evidence suggests that pharmacologic interventions have an established role for preventing and treating delirium in adult patients after cardiac surgery (Level-1a, Grade B) with dexmedetomidine as the most effective agent (Level-1a, Grade B).

Delirium is a frequent occurrence after cardiac surgery and is associated with increased morbidity and mortality.[17] Its complex and multifactorial pathogenesis remains ill understood with no consensus on the best pharmacologic intervention to prevent and treat this disorder. A variety of drugs including cholinesterase inhibitors, antipsychotics, statins, alpha-2 receptor agonists and analgesics have been evaluated in RCTs for prevention and treatment of delirium.[18] However, these RCTs are limited by small sample sizes. In the current era of evidence-based medicine, the systematic review (with homogeneity) of RCTs is deemed the highest quality evidence for determining the benefit of a therapeutic intervention.[8]

The current best available evidence albeit with major limitations suggests that dexmedetomidine may be beneficial for preventing and treating postoperative delirium in cardiac surgical patients. Dexmedetomidine is a highly selective, shorter-acting alpha-2 receptor agonist that binds to transmembrane G protein-binding adrenoreceptors without any effect on the GABA receptor.[12] Head-to-head comparison with propofol as well as morphine based therapy showed superiority of dexmedetomidine. However, dexmedetomidine use is associated with clinically important bradycardia and hypotension.[14]

Although a number of RCTs and systematic reviews have assessed the efficacy and safety of pharmacologic agents for preventing and treating delirium in adult patients post cardiac surgery there still remains a dearth of direct comparisons of the commonly used pharmacologic agents. A more sophisticated strategy to address the issue of paucity of direct comparisons will be to conduct a network meta-analysis. Network meta-analysis can contrast multiple interventions with regards to the same condition concurrently, provide both direct and indirect evidence, and allow for the assessment of relative effectiveness of treatments which have not been compared head-to-head in RCTs.[19] It is anticipated that the network meta-analysis by Wen et al.[6] will provide useful information in the near future to enable clinicians to make more well-informed decision regarding choice of pharmacologic agent for the prevention of delirium post cardiac surgery.


  Conclusion Top


The current best available evidence suggests that dexmedetomidine, a highly selective, shorter-acting alpha-2 receptor agonist, is the most effective pharmacologic agent for the prevention of delirium after cardiac surgery. However, the current best available evidence has major limitations emphasizing the need for larger RCTs with direct comparison of key pharmacologic agents as well as network meta-analysis to provide more robust evidence to resolve this important issue.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
European Delirium Association, American Delirium Society. The DSM-5 criteria, level of arousal and delirium diagnosis: Inclusiveness is safer. BMC Med 2014;12:141.  Back to cited text no. 1
    
2.
Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in older persons: Advances in diagnosis and treatment. JAMA 2017;318:1161-74.  Back to cited text no. 2
    
3.
Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014;383:911-22.  Back to cited text no. 3
    
4.
Müller A, Lachmann G, Wolf A, Mörgeli R, Weiss B, Spies C. Peri- and postoperative cognitive and consecutive functional problems of elderly patients. Curr Opin Crit Care 2016;22:406-11.  Back to cited text no. 4
    
5.
Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: A meta-analysis. JAMA 2010;304:443-51.  Back to cited text no. 5
    
6.
Wen J, Zeng H, Li Z, He G, Jin Y. Pharmacologic interventions for preventing delirium in adult patients after cardiac surgery: Protocol of a systematic review and network meta-analysis. Medicine (Baltimore) 2018;97:e13881.  Back to cited text no. 6
    
7.
Mack MJ, Duhaylongsod FG. Through the open door! Where has the ride taken us? J Thorac Cardiovasc Surg 2002;124:655-9.  Back to cited text no. 7
    
8.
Manterola C, Asenjo-Lobos C, Otzen T. Jerarquización de la evidencia: Niveles de evidencia y grados de recomendación de uso actual Hierarchy of evidence: Levels of evidence and grades of recommendation from current use. Rev Chilena Infectol 2014;31:705-18.  Back to cited text no. 8
    
9.
Greenhalgh T. How to read a paper. The Medline database. BMJ 1997;315:180-3.  Back to cited text no. 9
    
10.
Oxman AD. Checklists for review articles. BMJ 1994;309:648-51.  Back to cited text no. 10
    
11.
Liu Y, Li XJ, Liang Y, Kang Y. Pharmacological prevention of postoperative delirium: A systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med 2019;2019:9607129.  Back to cited text no. 11
    
12.
Tao R, Wang XW, Pang LJ, Cheng J, Wang YM, Gao GQ, et al. Pharmacologic prevention of postoperative delirium after on-pump cardiac surgery: A meta-analysis of randomized trials. Medicine (Baltimore) 2018;97:e12771.  Back to cited text no. 12
    
13.
Vallabhajosyula S, Kanmanthareddy A, Erwin PJ, Esterbrooks DJ, Morrow LE. Role of statins in delirium prevention in critical ill and cardiac surgery patients: A systematic review and meta-analysis. J Crit Care 2017;37:189-96.  Back to cited text no. 13
    
14.
Liu X, Xie G, Zhang K, Song S, Song F, Jin Y, et al. Dexmedetomidine vs propofol sedation reduces delirium in patients after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials. J Crit Care 2017;38:190-6.  Back to cited text no. 14
    
15.
Geng J, Qian J, Cheng H, Ji F, Liu H. The influence of perioperative dexmedetomidine on patients undergoing cardiac surgery: A meta-analysis. PLoS One 2016;11:e0152829.  Back to cited text no. 15
    
16.
Mu JL, Lee A, Joynt GM. Pharmacologic agents for the prevention and treatment of delirium in patients undergoing cardiac surgery: Systematic review and metaanalysis. Crit Care Med 2015;43:194-204.  Back to cited text no. 16
    
17.
Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr., et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753-62.  Back to cited text no. 17
    
18.
Siddiqi N, Harrison JK, Clegg A, Teale EA, Young J, Taylor J, et al. Interventions for preventing delirium in hospitalised non-ICU patients. Cochrane Database Syst Rev 2016;3:CD005563.  Back to cited text no. 18
    
19.
Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ 2013;346:f2914.  Back to cited text no. 19
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed17344    
    Printed99    
    Emailed0    
    PDF Downloaded1664    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]