Postoperative delirium and intraop benzodiazepine

Summary of systemic review and metaanalysis on effect of intraop benzodiazepine and postop delirium

1. Perioperative Benzodiazepines and Intraop Awareness and Postop Delirium

2. Background Benzodiazepines (BDZ) are commonly used perioperatively as premedication or part of an anaesthetic Association of BDZ use with delirium has led to recommendations to avoid BDZ in those at risk for postoperative delirium. Lack of clarity on periop BDZ use and postop cognitive dysfunction Aim to assess the safety and efficacy of periop BDZ use Primary outcome : intraop awareness, postop delirium, mortality Secondary outcome : ICU and hospital length of stay (LOS)

3. Methodology Inclusion criteria Studies on adult patients undergoing inpatient surgery RCT or prospective observational study The interventional group received any BZD by any route and the comparator group did not 844 studies in peer-reviewed journals assessed for eligibility 43 studies included in meta-analysis 34 RCTs 9 observational studies

4. RCT Characteristics Surgery type No. of RCT Obstetric surgery 9 Cardiac surgery 5 Non-cardiac surgery 20 BDZ timing No. of RCT Preop 11 Intraop 17 Postop 4 BDZ type No. of RCT Midazolam 25 Diazepam 3 Lorazepam 1 Multiple BDZs 5 Route of administration No. of RCT IV bolus 18 IV infusion 4 More than 1 route 8 IM route 1

5. RCT Characteristics Comparison to other drugs No. of RCT Dexmedetomidine 7 Propofol 4 Comparators in multiple arms 6 Multiple agents in one comparator arm 3 No comparator 6 Saline placebo 4 Thiopental 2 Fentanyl 1 Ketamine 1 Lavender extract 1

6. Results – BDZ and Postop delirium Periop benzodiazepine does not modify the risk of postop delirium Pooled estimate (8 RCTs, n = 1352) for association of periop BZD and postop delirium = RR 1.43 (95% CI 0.90-2.27, I 2 =72%; P=0.13) Very low quality evidence Only 5 out of 8 RCTs used DSM-IV or CAM for assessment of delirium Subgroup analysis on BZD vs dexmedetomidine Patients who received BZD at 80% greater risk of delirium compared to dexmedetomidine group (RR 1.83 CI 1.24-2.72, I 2 =13%, P=0.002) No difference for BDZ use and delirium risk between older (>75 yr ) and younger patients (<75 yr )

7. Results – BDZ and Intraop awareness Periop benzodiazepine use has a modest effect on reducing the incidence of intraop awareness Pooled estimate (15 RCTs, n=2245) showed BZD decreased intraop awareness (RR 0.26, 95% CI 0.12-0.58; I 2 =35%; P=0.001) Very low quality evidence Only 2 RCTs used the Brice questionnaire for assessment of awareness; 13 RCTs used observations or non-standard questionnaires.

8. Results – BZD on Mortality and LOS Benzodiazepine and mortality Only 1 RCT reported on mortality Unclear association between periop BZD use and risk of death (RR 0.90, 95% CI 0.20-3.1, P=0.80) Very low quality evidence Benzodiazepine and LOS Total 18 RCTs BZD has no impact on hospital and ICU LOS Very low quality evidence

9. Strengths 1. Comprehensive literature search from 5 database. 2. Pooled estimates are analysed separately for RCTs and observational studies to maintain consistency in quality of evidence 3. Risk of bias for each included study was assessed.

10. Limitations Only a small percentage of studies contributed to usable data and meta-analysis. Only a few studies used acceptable tools to assess outcomes. 5 out of 8 RCTs used DSM-IV or CAM for assessment of delirium 2 out of 15 RCTs used the Brice questionnaire for assessment of awareness Emergence delirium and postoperative delirium were analyzed as one outcome measure. Highly heterogenous studies with huge variability in the type, route of administration and regimes of BZD use

11. Take Home Message Periop benzodiazepine does not increase the incidence of postoperative delirium and might reduce the risk of intraoperative awareness [Very-low-quality evidence] In the absence of clear evidence, current recommendations for best practice on periop benzodiazepine use are speculative . High quality research is required

12. Post-operative Delirium in Adult Patients Update of the ESAIC evidence- and consensus-based guidelines 2023

13. Post-operative delirium (POD) POD has significant impact on a patient’s post-op recovery and can be distressing to patient’s family and/or caregivers POD occurs as a result of interactions between patient, surgical and anaesthesia factors Aim of the guidelines were to summarise evidence regarding recommendations for prevention and/or treatment of patients with POD

14. Post-operative delirium (POD) Update to the guidelines published in 2017 Literature search current up to 28 Feb 2022

15. Search strategy

16. Search strategy Exclusion criteria: case reports/series, publications not in English, studies in patients <18Y, non-surgical patients, studies without clear definition of POD, studies examining POD as a composite outcome

17. POD – Basic Science Reasonable evidence that neuroinflammation contributes to acute deficits resembling delirium Some evidence that precedex has some anti-inflammatory properties Further research is needed on impact of NSAIDs on delirium

18. POD – Risk factors Recommend to evaluate for: Older age ASA >2 Charlson Comorbidity Index >2 MMSE <25 Quality of evidence: moderate Strength of recommendation: strong

19. POD – Use of drugs Comparing precedex vs non-dexmedetomidine/placebo, precedex was associated with a lower incidence of POD in non-cardiac surgery (OR 0.55, CI 0.43 to 0.7) Comparing precedex with other drugs, precedex was associated with a reduction in POD in both cardiac and non-cardiac surgery Precedex was associated with bradycardia and hypotension

20. POD – Use of drugs Use of neuroleptics (haloperidol), sleep medications (melatonin), cholinesterase inhibitors (physostigmine) and ketamine did not reduce the incidence of POD

21. POD – Use of drugs Workgroup does not suggest the use of any particular drug as prophylaxis to reduce the risk of POD Precedex is not suggested as prophylaxis in view of haemodynamic effects and weak evidence supporting its benefits Quality of evidence: low Strength of recommendation: weak

22. POD – Type of anaesthesia Comparing propofol vs sevoflurane, days of POD per person were higher in the propofol group (0.5±0.8 vs 0.3±0.5) No evidence that RA has a lower incidence of POD as compared to GA

23. POD – Type of anaesthesia Workgroup does not recommend any specific type of surgery or type of anaesthesia to reduce the incidence of POD Quality of evidence: low Strength of recommendation: weak

24. POD – Type of anaesthesia Workgroup does not recommend using any specific biomarkers to identify patients at risk of POD Quality of evidence: low Strength of recommendation: weak

25. POD – Preventive measures Workgroup recommends pre-operative anaesthesia consult in older adults, including screening for risk factors and performing optimisation as appropriate Quality of evidence: low Strength of recommendation: strong

26. POD – Preventive measures Workgroup recommends that results of pre-operative screening be shared with the team and documented in the records Quality of evidence: low Strength of recommendation: strong

27. POD – Preventive measures Workgroup recommends multicomponent non-pharmacological interventions ( eg staff education, protocols, systematic screening) in all patients at risk of POD Quality of evidence: moderate Strength of recommendation: strong

28. POD – Preventive measures Other risk factors that should be evaluated for include: Frailty Sensory impairment Malnutrition Polypharmacy Anaemia

29. POD – Preventive measures Measures that can be adopted to minimise the risk of POD include: Reorientation measures Sleeping aids Early mobilisation Early catheter removal Early nutrition commencement These measures should be personalised to the patient and their risk factors

30. POD – Neuromonitoring Workgroup recommends use of index-based EEG monitoring depth of anaesthesia guidance to decrease the risk of POD Quality of evidence: low Strength of recommendation: weak

31. POD – Neuromonitoring Workgroup recommends use of multi-parameter EEG monitoring (burst suppression, DSA) during anaesthesia to reduce the risk of POD Quality of evidence: low Strength of recommendation: weak

32. POD – Management Workgroup recommends the use of antipsychotics as a short-term therapy in the lowest-possible dose if non-pharmacological measures fail Quality of evidence: very low Strength of recommendation: weak

33. POD – Management Workgroup recommends against the use of BZDs for the treatment of delirium in post-operative patients. Precedex is recommended for the treatment of POD in cardiac surgery. Quality of evidence: very low Strength of recommendation: weak

34. POD – Management Symptom Suggested pharmacological therapy Psychosis/hallucinations Neuroleptics ( eg haloperidol, risperidone, olanzapine) Pain Opioid-based analgesia Day-night rhythm disorders Melatonin

35. POD – Management Symptom Suggested pharmacological therapy Anxiety Short-acting BZDs Agitation Alpha-2 agonists (in ICU), short-acting drugs ( eg propofol)

36. POD – Management Workgroup unable to make recommendations for the use of melatonin (severe bias), gabapentinoids , rosuvastatin or morphine (insufficient data) to treat POD

37. Strengths Rigorous application of POD definition to included studies Thorough literature search, including all post-anaesthesia/-surgical patients

38. Limitations Non-English studies excluded Only one database searched Studies were rather heterogenous

39. Take home messages Despite further research, there is no significant change in recommendations for prevention and treatment of POD Minimizing the incidence of POD requires a multidisciplinary effort to tackle various aspects of a patient’s care, often starting well before planned surgery Neuromonitoring plays an important role in reducing the risk of POD Management of POD comprises non-pharmacological and pharmacological options

40. Thank you