The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study

Ammu T. Susheela; Senthil Packiasabapathy; Doris-Vanessa Gasangwa; Melissa Patxot; Jason O’Neal; Edward Marcantonio; Balachundhar Subramaniam

doi:10.12688/f1000research.12552.1

Home Browse The use of dexmedetomidine and intravenous acetaminophen for the prevention...

ALL Metrics

Views

Downloads

Get PDF

Get XML

Export

▬

✚

Research Article

Clinical trial

The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study

[version 1; peer review: 1 approved, 1 approved with reservations]

Ammu T. Susheela ¹, Senthil Packiasabapathy¹, Doris-Vanessa Gasangwa¹, [...] Melissa Patxot¹, Jason O’Neal², Edward Marcantonio³, Balachundhar Subramaniam¹

Ammu T. Susheela ¹, Senthil Packiasabapathy¹, [...] Doris-Vanessa Gasangwa¹, Melissa Patxot¹, Jason O’Neal², Edward Marcantonio³, Balachundhar Subramaniam¹

PUBLISHED 16 Oct 2017

Author details Author details

¹ Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215-5400, USA
² Department of Anesthesiology, Vanderbilt University Medical Center, 1215 21st Ave. S., Suite 5160 MCE NT, Nashville, Tennessee, 37232, USA
³ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215-5400, USA

Ammu T. Susheela
Roles: Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Senthil Packiasabapathy
Roles: Validation, Writing – Review & Editing

Doris-Vanessa Gasangwa
Roles: Resources, Validation, Writing – Review & Editing

Melissa Patxot
Roles: Resources, Validation, Writing – Review & Editing

Jason O’Neal
Roles: Conceptualization, Investigation, Methodology, Supervision

Edward Marcantonio
Roles: Conceptualization, Investigation, Methodology, Supervision

Balachundhar Subramaniam
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Delirium is associated with many negative health outcomes. Postoperative sedation and opioid administration may contribute to delirium. We hypothesize that the use of dexmedetomidine and Intravenous acetaminophen (IVA) may lead to reduced opioid consumption and decreased incidence of postoperative delirium. This pilot study aims to assess feasibility of using dexmedetomidine and IVA in cardiac surgical patients, and obtain effect size estimates for incidence and duration of delirium.
Methods: A total of 12 adult patients >60 years of age undergoing cardiac surgery were recruited for the study after IRB approval and randomized into 4 groups: Propofol only (P), Propofol with IVA (P+A), Dexmedetomidine only (D), Dexmedetomidine with IVA (D+A). Preoperative baseline cognition and postoperative delirium was assessed daily until discharge. The feasibility was assessed by the number of patients who successfully completed the study.
Results: All patients completed the study protocol successfully. The total incidence of delirium in the study population was 42% (5/12): 67% (2/3) in the group P, and 67% (2/3) in the group D, 33% (1/3) in D+A group and 0%(0/3) P+A group. The incidence of delirium was 17% (1/6) in the group receiving IVA compared to 67% (4/6) that did not receive IVA. The mean duration of delirium was 0-1 days. One patient expired after surgery, unrelated to the study protocol. One patient in the D group experienced hypotension with systolic blood pressure <90 mm of Hg.
Conclusions: The feasibility of performing a large-scale project is ascertained by the study. Patients receiving IVA had lower incidence of delirium compared to patients not receiving IVA which suggests that IVA may have a role in reducing the incidence of delirium. A prospective randomized, placebo-controlled trial will be the next step in investigating the role of dexmedetomidine and IVA in reducing the incidence of delirium.

Keywords

delirium, dexmedetomidine, acetaminophen, cardiac surgery, coronary artery bypass grafting (CABG), propofol, cognitive assessments

Corresponding author: Ammu T. Susheela

Competing interests: The authors declare that they have no competing interests of conflicts of interest.

Grant information: Balahundhar Subramaniam is supported by the National Institutes of Health Research Project Grant GM 098406.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2017 Susheela AT et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

How to cite: Susheela AT, Packiasabapathy S, Gasangwa DV et al. The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2017, 6:1842 (https://doi.org/10.12688/f1000research.12552.1) First published: 16 Oct 2017, 6:1842 (https://doi.org/10.12688/f1000research.12552.1) Latest published: 21 Dec 2017, 6:1842 (https://doi.org/10.12688/f1000research.12552.2)

Introduction

Delirium is defined as a change in mental status, characterized by acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness^1,2. Delirium increases the risk of mortality, readmissions, and accelerated cognitive decline^2–6. Around 158 billion dollars of national healthcare cost is attributable to delirium⁷. The incidence of delirium in cardiac surgery is 11–46%². Delirium is preventable in 30–40% of the cases². Some of the modifiable risk factors for delirium include the choice of analgesic and sedatives⁸.

Currently used sedatives, like midazolam, act via GABA receptors and release deliriogenic mediators⁹. Dexmedetomidine is an alpha 2 adrenergic agonist, with no interaction with GABA receptors.

A recent study by Li et al. in 285 elderly cardiac surgical patients evaluated dexmedetomidine versus propofol and showed no difference in the incidence of delirium¹⁰. A major limitation of this study is that Confusion Assessment Method (CAM) and CAM- ICU are limited assessments and may miss delirium. There are other tools that could help assess cognitive assessment more efficiently. A meta-analysis suggested that the use of dexmedetomidine for sedation in cardiac surgery patients may reduce the incidence of delirium⁹. The first study in the meta-analysis was a retrospective study by Corbett SM et al. that does not mention how delirium was assessed in individual hospitals¹¹. The second study by Shehabi Y et al. was not powered adequately and used CAM-ICU for assessing delirium both in intubated and extubated patients which have reduced sensitivity for delirium in verbal patients and could have underestimated the incidence of delirium¹². The third study was a small study by Maldonado JR et al. of only 118 patients recruited and only 90 patients finally analyzed, with 28 randomized patients excluded for protocol violations which introduce a significant selection bias¹³. It also showed a 94% reduction in the incidence of delirium and this effect size is almost implausibly large and has not been seen in other studies. The final study by Dasta JF et al. was not designed to identify patients with delirium with any specific tools such as CAM and thus could have gross underestimated delirium incidence¹⁴.

The use of IV acetaminophen (IVA) has been shown in multiple studies to reduce the amount of opioids consumed by patients undergoing surgeries^4,15. IVA has never been studied in the context of cardiac surgery and delirium prevention. So, we hypothesized that the use of dexmedetomidine and acetaminophen would provide adequate analgesia, leading to a decreased opioid consumption and decreased incidence of delirium.

Methods

Purpose

This is a pilot trial which ran from 13^th November 2013 to 9^th April 2015 to assess the feasibility of using IV dexmedetomidine and acetaminophen in the cardiac surgical intensive care unit. The study also aimed to obtain effect size estimates for primary study outcomes which will help power an ongoing large scale randomized trial (NCT02546765, registered on 13^th January 2015).

Study design

This is a single-centered, double-blinded, prospective, randomized controlled pilot trial.

Study population

Patients who are 60 years of age or older who were undergoing coronary artery bypass grafting (CABG), and/or valve surgery were included in the study. Exclusion criteria were preoperative left ventricular ejection fraction < 30%, emergent and percutaneous procedures, aortic surgeries, preexisting cognitive impairment, recent seizures, patients on medications for cognitive decline, serum creatinine > 2 mg%, liver dysfunction, known history of alcohol or drug abuse, and hypersensitivity to any of the study drugs. (Figure 1)

Figure 1. Consort diagram.

Randomization

Fourteen patients were recruited (the initial 2 patients to help train the investigators in the use of cognitive assessments). The remaining twelve patients were randomized into the following 4 groups, containing 3 patients each (1:1:1:1 allocation). (Table 1)

Table 1. Table 1 provides all different groups in the study.

Group*	Sedation	Acetaminophen
Group 1 (P)	Propofol	No
Group 2 (P+A)	Propofol	Yes
Group 3 (D)	Dexmedetomidine	No
Group 4 (D+A)	Dexmedetomidine	Yes

*All groups will receive bolus doses of IV opioids (morphine and hydromorphone) as needed for breakthrough pain. I.V. Acetaminophen will be given to group 1 and group 3 every 6 hours for 48 hours, postoperatively.

Each patient was allotted a randomization number based on which the pharmacist assigned the study medications.

Study drug administration

Peri-operative anesthetic management was administered according to standard of care. Intra-operative propofol infusion was administered at the clinician’s discretion for patients in propofol group. In the post-operative period, propofol infusion was titrated to 25–100 µg/kg/min. If the patient was randomized to dexmedetomidine group, propofol infusion was avoided inside the operating room (OR). Dexmedetomidine infusion was given after chest closure at a dose of 0.1–1.0 µg/kg/hr. The medications for sedation were continued in the post-operative period until extubation or for a minimal duration of 6 hours. For patients randomized to IVA group, IVA 1 gram was given every 6 hours for the first 48 hours postoperatively up to a total of eight doses.

Patient assessment

Cognitive assessments were conducted using standard battery used for Minimental (MMSE) and Confusion Assessment Method (CAM).

Outcomes of the study

The primary outcome measured was the proportion of patients who completed the protocol successfully, which reflects the feasibility of the study. The incidence of delirium was measured to obtain effect size estimates for future studies. Secondary outcomes included hypotension, duration of delirium, breakthrough analgesic requirements, ICU days, and length of hospital stay.

Results

The baseline characteristics of the patients were comparable in all groups. The total incidence of delirium was 42% (5/12). The incidence of delirium was 67% (2/3) with propofol and 67% (2/3) with dexmedetomidine. Dexmedetomidine+Acetaminophen group had an incidence of 33% (1/3). The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA. (Table 2) Also, the incidence of delirium was 33% (2/6) in the propofol groups as compared to 50% (3/6) in the dexmedetomidine groups. The mean duration of delirium ranged from 0 to 1 day. (Table 3) Secondary outcomes were similar between the groups. One patient expired after surgery, unrelated to the study protocol. One patient in the dexmedetomidine group experienced a significant hypotension with systolic blood pressure <90 mm of Hg.

Table 2. Table 2 provides the incidence of delirium and secondary outcomes in the groups receiving propofol, dexmedetomidine, acetaminophen, and no acetaminophen respectively.

	Propofol	Dexmedetomidine	Acetaminophen	No Acetaminophen
Incidence of Delirium % (n/N)	33.3 (2/6)	50 (3/6)	16.7 (1/6)	66.7 (4/6)
Mean Delirium duration [n days]	0.5	1	0.5	1
Opioid consumption mean [SD]*	8.2 [2.02]	11.46 [4.2]	7.54 [2.15]	12.12 [4.06]
Time to extubation (mins) mean [SD]	410.67 [320.25]	439 [239.32]	499.5 [304.63]	350.17 [232.66]
Length of stay (days) mean [SD]	5.67 [0.82]	8.5 [6.5]	7.83 [6.52]	6.33 [1.97]
Adverse events	0	1	0	1
Dexmedetomidine dose mean [SD]**	N/A	0.95 [0.36]	N/A	N/A
Propofol dose mean [SD]***	43.33 [5.16]	N/A	N/A	N/A

*Opioid consumption is expressed in hydromorphone equivalent

**Mean dexmedetomidine dose is expressed as infusion rate of mcg/kg/hr

***Mean propofol dose is expressed as infusion rate of mcg/kg/min

Table 3. Table 3 provides the incidence of delirium and secondary outcomes in the 4 groups in the study namely propofol, propofol + acemaninophen, dexmedetomidine, dexmedetomidine + acetaminophen.

	Propofol	Propofol + Acetaminophen	Dexmedetomidine	Dexmedetomidine + Acetaminophen
Incidence of Delirium % (n/N)	66.6 (2/3)	0 (2/3)	66.6 (2/3)	33.3 (1/3)
Mean Delirium duration [n days]	1	0	1	1
Opioid consumption mean [SD]*	2.84 [1.95]	2.63 [2.2]	5.24 [5.3]	2.4 [2.2]
Time to extubation (mins) mean [SD]	213.67 [42.83]	607.67 [371.66]	486.67 [278.55]	391.33 [242.43]
Length of stay (days) mean [SD]	6 [0]	5.33 [1.15]	6.67 [3.06]	10.33 [9.29]
Adverse events	0	0	0	1

*Opioid consumption is expressed in hydromorphone equivalent

Dataset 1.The datasets used and/or analyzed during the current study. No statistical evaluation was done due to the small sample size.

Discussion

The use of IV dexmedetomidine and acetaminophen in the cardiac surgical patients was feasible. The study protocol was easily incorporated into patient care. All the enrolled patients completed the study protocol. There were no instances where the implementation of the study protocol was abandoned by the physicians. Sedation provided was useful. Apart from the incidence of hypotension in one patient with dexmedetomidine use, no other adverse events recorded directly related to the intervention.

No other statistical evaluation was done due to the small sample size. The overall incidence of delirium in our trial, at 42%, is close to previous reports². The incidence of delirium in patients receiving IVA was 17% compared to 67% in the other group suggesting that IVA may be beneficial in reducing the incidence of delirium following cardiac surgery. The pilot study led to a larger ongoing trial (NCT02546765).

A major limitation of our study is the small sample size, but this was a feasibility trial to study effect size for the design of future larger studies. Also, there was no blinding for the choice of sedatives used in the patients. The assessors were blinded to acetaminophen administration.

A multi-center randomized, controlled trial will be the next step in investigating the role of dexmedetomidine and IVA in reducing the incidence of delirium.

Data availability

F1000Research: Dataset 1. The datasets used and/or analyzed during the current study. No statistical evaluation was done due to the small sample size., 10.5256/f1000research.12552.d180828¹⁶

Ethics and consent

This study has been approved by the Committee on Clinical Investigations at Beth Israel Deaconess Medical Center (IRB Protocol #: 2013-P-000149). Informed consent was obtained for all subjects prior to initiation of study procedures. The study was conducted from 13^th November 2013 to 9^th April 2015.

Competing interests

The authors declare that they have no competing interests of conflicts of interest.

Grant information

Balahundhar Subramaniam is supported by the National Institutes of Health Research Project Grant GM 098406.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Faculty Opinions recommended

References

1. Bellelli G, Morandi A, Di Santo SG, et al.: “Delirium Day”: a nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool. BMC Med. 2016; 14(1): 106. PubMed Abstract | Publisher Full Text | Free Full Text
2. Inouye SK, Westendorp RG, Saczynski JS: Delirium in elderly people. Lancet. 2014; 383(9920): 911–922. PubMed Abstract | Publisher Full Text | Free Full Text
3. Inouye SK: Delirium in older persons. N Engl J Med. 2006; 354(11): 1157–1165. PubMed Abstract | Publisher Full Text
4. O'Neal JB: The utility of intravenous acetaminophen in the perioperative period. Front Public Health. 2013; 1: 25. PubMed Abstract | Publisher Full Text | Free Full Text
5. Saczynski JS, Marcantonio ER, Quach L, et al.: Cognitive trajectories after postoperative delirium. N Engl J Med. 2012; 367(1): 30–39. PubMed Abstract | Publisher Full Text | Free Full Text
6. Cui V, Tedeschi CM, Kronzer VL, et al.: Protocol for an observational study of delirium in the post-anaesthesia care unit (PACU) as a potential predictor of subsequent postoperative delirium. BMJ Open. 2017; 7(7): e016402. PubMed Abstract | Publisher Full Text | Free Full Text
7. Leslie DL, Marcantonio ER, Zhang Y, et al.: One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008; 168(1): 27–32. PubMed Abstract | Publisher Full Text | Free Full Text
8. Rudolph JL, Jones RN, Levkoff SE, et al.: Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation. 2009; 119(2): 229–36. PubMed Abstract | Publisher Full Text | Free Full Text
9. Lin YY, He B, Chen J, et al.: Can dexmedetomidine be a safe and efficacious sedative agent in post-cardiac surgery patients? a meta-analysis. Crit Care. 2012; 16(5): R169. PubMed Abstract | Publisher Full Text | Free Full Text
10. Li X, Yang J, Nie XL, et al.: Impact of dexmedetomidine on the incidence of delirium in elderly patients after cardiac surgery: A randomized controlled trial. PLoS One. 2017; 12(2): e0170757. PubMed Abstract | Publisher Full Text | Free Full Text
11. Corbett SM, Rebuck JA, Greene CM, et al.: Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation. Crit Care Med. 2005; 33(5): 940–5. PubMed Abstract | Publisher Full Text
12. Shehabi Y, Grant P, Wolfenden H, et al.: Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Anesthesiology. 2009; 111(5): 1075–84. PubMed Abstract | Publisher Full Text
13. Maldonado JR, Wysong A, van der Starre PJ, et al.: Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009; 50(3): 206–17. PubMed Abstract | Publisher Full Text
14. Dasta JF, Jacobi J, Sesti AM, et al.: Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis. Pharmacotherapy. 2006; 26(6): 798–805. PubMed Abstract | Publisher Full Text
15. Macario A, Royal MA: A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Pain Pract. 2011; 11(3): 290–296. PubMed Abstract | Publisher Full Text
16. Susheela AT, Packiasabapathy S, Gasangwa DV, et al.: Dataset 1 in: The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study. F1000Research. 2017. Data Source

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 16 Oct 2017

Author details Author details

Ammu T. Susheela
Roles: Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Senthil Packiasabapathy
Roles: Validation, Writing – Review & Editing

Doris-Vanessa Gasangwa
Roles: Resources, Validation, Writing – Review & Editing

Melissa Patxot
Roles: Resources, Validation, Writing – Review & Editing

Jason O’Neal
Roles: Conceptualization, Investigation, Methodology, Supervision

Edward Marcantonio
Roles: Conceptualization, Investigation, Methodology, Supervision

Balachundhar Subramaniam
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – Review & Editing

Competing interests

The authors declare that they have no competing interests of conflicts of interest.

Grant information

Balahundhar Subramaniam is supported by the National Institutes of Health Research Project Grant GM 098406.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

Revised

Published: 21 Dec 2017, 6:1842

https://doi.org/10.12688/f1000research.12552.2

version 1

Published: 16 Oct 2017, 6:1842

https://doi.org/10.12688/f1000research.12552.1

© 2017 Susheela AT et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Download

Export To

metrics

	Views	Downloads
F1000Research	-	-
PubMed Central Data from PMC are received and updated monthly.	-	-

Citations

SEE MORE DETAILS

CITE

how to cite this article

Susheela AT, Packiasabapathy S, Gasangwa DV et al. The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study [version 1; peer review: 1 approved, 1 approved with reservations] F1000Research 2017, 6:1842 (https://doi.org/10.12688/f1000research.12552.1)

NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

track

receive updates on this article

Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?

Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 1

VERSION 1

PUBLISHED 16 Oct 2017

Views

Reviewer Report 27 Nov 2017

Michael Simon Avidan, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.13591.r27502

This is an interesting and important feasibility study, which seeks to determine whether it is possible to conduct a (large) study evaluating various combinations of sedation/analgesia post cardiac surgery, with the intention of preventing postoperative delirium. In general, with a very small feasibility study, the investigators demonstrate that conducting such a study might be possible. However this study has important constraints.

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.
The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.
Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.
I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.
More efficient tools might not necessarily be more sensitive.
I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.
From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.
The reasons for the exclusion criteria are not clear.
With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).
The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Not applicable
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

No

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 14 Dec 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

14 Dec 2017

Author Response
Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.
1. The investigators state, “The mean
... Continue reading
Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.Thank you. Yes. We reported the mean duration as a range.

The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.Thank you. We agree that only the feasibility of performing a project is ascertained.

Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.Thank you. We agree this is a pre-pilot study indeed. It was a feasibility project and we certainly do not want to overinterpret. Thus, we wrote “IVA may be beneficial in reducing the incidence of delirium following cardiac surgery. ” Since this is a feasibility study we agree that a larger study is needed to draw a concrete conclusion.

I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.Thank you. Agreed.

More efficient tools might not necessarily be more sensitive.Thank you. Agreed.

I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.Thank you. We planned this pilot study as a means to assess the feasibility of performing a large-scale project. However, there is no other preexisting data to power the next larger trial. Since this pilot study showed a 66% reduction in the incidence of delirium, for the power calculation, a 50% reduction in the delirium incidence was used. Each group needed 56 patients (alpha=0.05 and 1-Beta=0.80).

From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.Thank you. A multicenter trial is definitely required to answer with precision. However, it will be a major leap to go from a pilot study to a multicenter trial. Thus, we chose to do the second step of testing in a larger sample size with what is known so far. Depending on what this study shows, the obvious next step will be a larger multicenter trial.

The reasons for the exclusion criteria are not clear.Thank you. We chose a homogenous set of patients to determine the drug efficacy. We wanted to avoid patients who might not get extubated in a reasonable amount of time (hence the EF, aortic surgery exclusion, etc). As we chose to give Q6H IV acetaminophen, we wanted to avoid any clinical situation that can potentially set up patients for drug toxicity etc. Preexisting cognitive dysfunction, etc. could muddle the picture in a 120 patient study. In a larger multicenter trial if and when launched, the heterogeneity can be accounted for and thus need not necessarily be an exclusion criteria.

With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).Thank you. Yes, these interactions will be analyzed in the ongoing trial

The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).Thank you for the caution. We agree with all the comments.
Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.Thank you. Yes. We reported the mean duration as a range.

The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.Thank you. We agree that only the feasibility of performing a project is ascertained.

Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.Thank you. We agree this is a pre-pilot study indeed. It was a feasibility project and we certainly do not want to overinterpret. Thus, we wrote “IVA may be beneficial in reducing the incidence of delirium following cardiac surgery. ” Since this is a feasibility study we agree that a larger study is needed to draw a concrete conclusion.

I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.Thank you. Agreed.

More efficient tools might not necessarily be more sensitive.Thank you. Agreed.

I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.Thank you. We planned this pilot study as a means to assess the feasibility of performing a large-scale project. However, there is no other preexisting data to power the next larger trial. Since this pilot study showed a 66% reduction in the incidence of delirium, for the power calculation, a 50% reduction in the delirium incidence was used. Each group needed 56 patients (alpha=0.05 and 1-Beta=0.80).

From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.Thank you. A multicenter trial is definitely required to answer with precision. However, it will be a major leap to go from a pilot study to a multicenter trial. Thus, we chose to do the second step of testing in a larger sample size with what is known so far. Depending on what this study shows, the obvious next step will be a larger multicenter trial.

The reasons for the exclusion criteria are not clear.Thank you. We chose a homogenous set of patients to determine the drug efficacy. We wanted to avoid patients who might not get extubated in a reasonable amount of time (hence the EF, aortic surgery exclusion, etc). As we chose to give Q6H IV acetaminophen, we wanted to avoid any clinical situation that can potentially set up patients for drug toxicity etc. Preexisting cognitive dysfunction, etc. could muddle the picture in a 120 patient study. In a larger multicenter trial if and when launched, the heterogeneity can be accounted for and thus need not necessarily be an exclusion criteria.

With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).Thank you. Yes, these interactions will be analyzed in the ongoing trial

The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).Thank you for the caution. We agree with all the comments.
Competing Interests: The authors report no competing interests. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 14 Dec 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

14 Dec 2017

Author Response
Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.
1. The investigators state, “The mean
... Continue reading
Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.Thank you. Yes. We reported the mean duration as a range.

The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.Thank you. We agree that only the feasibility of performing a project is ascertained.

Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.Thank you. We agree this is a pre-pilot study indeed. It was a feasibility project and we certainly do not want to overinterpret. Thus, we wrote “IVA may be beneficial in reducing the incidence of delirium following cardiac surgery. ” Since this is a feasibility study we agree that a larger study is needed to draw a concrete conclusion.

I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.Thank you. Agreed.

More efficient tools might not necessarily be more sensitive.Thank you. Agreed.

I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.Thank you. We planned this pilot study as a means to assess the feasibility of performing a large-scale project. However, there is no other preexisting data to power the next larger trial. Since this pilot study showed a 66% reduction in the incidence of delirium, for the power calculation, a 50% reduction in the delirium incidence was used. Each group needed 56 patients (alpha=0.05 and 1-Beta=0.80).

From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.Thank you. A multicenter trial is definitely required to answer with precision. However, it will be a major leap to go from a pilot study to a multicenter trial. Thus, we chose to do the second step of testing in a larger sample size with what is known so far. Depending on what this study shows, the obvious next step will be a larger multicenter trial.

The reasons for the exclusion criteria are not clear.Thank you. We chose a homogenous set of patients to determine the drug efficacy. We wanted to avoid patients who might not get extubated in a reasonable amount of time (hence the EF, aortic surgery exclusion, etc). As we chose to give Q6H IV acetaminophen, we wanted to avoid any clinical situation that can potentially set up patients for drug toxicity etc. Preexisting cognitive dysfunction, etc. could muddle the picture in a 120 patient study. In a larger multicenter trial if and when launched, the heterogeneity can be accounted for and thus need not necessarily be an exclusion criteria.

With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).Thank you. Yes, these interactions will be analyzed in the ongoing trial

The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).Thank you for the caution. We agree with all the comments.
Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.Thank you. Yes. We reported the mean duration as a range.

The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.Thank you. We agree that only the feasibility of performing a project is ascertained.

Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.Thank you. We agree this is a pre-pilot study indeed. It was a feasibility project and we certainly do not want to overinterpret. Thus, we wrote “IVA may be beneficial in reducing the incidence of delirium following cardiac surgery. ” Since this is a feasibility study we agree that a larger study is needed to draw a concrete conclusion.

I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.Thank you. Agreed.

More efficient tools might not necessarily be more sensitive.Thank you. Agreed.

I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.Thank you. We planned this pilot study as a means to assess the feasibility of performing a large-scale project. However, there is no other preexisting data to power the next larger trial. Since this pilot study showed a 66% reduction in the incidence of delirium, for the power calculation, a 50% reduction in the delirium incidence was used. Each group needed 56 patients (alpha=0.05 and 1-Beta=0.80).

From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.Thank you. A multicenter trial is definitely required to answer with precision. However, it will be a major leap to go from a pilot study to a multicenter trial. Thus, we chose to do the second step of testing in a larger sample size with what is known so far. Depending on what this study shows, the obvious next step will be a larger multicenter trial.

The reasons for the exclusion criteria are not clear.Thank you. We chose a homogenous set of patients to determine the drug efficacy. We wanted to avoid patients who might not get extubated in a reasonable amount of time (hence the EF, aortic surgery exclusion, etc). As we chose to give Q6H IV acetaminophen, we wanted to avoid any clinical situation that can potentially set up patients for drug toxicity etc. Preexisting cognitive dysfunction, etc. could muddle the picture in a 120 patient study. In a larger multicenter trial if and when launched, the heterogeneity can be accounted for and thus need not necessarily be an exclusion criteria.

With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).Thank you. Yes, these interactions will be analyzed in the ongoing trial

The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).Thank you for the caution. We agree with all the comments.
Competing Interests: The authors report no competing interests. Close
Report a concern

Views

Reviewer Report 09 Nov 2017

Nicolai Goettel, Department of Anesthesia, University of Basel, Basel, Switzerland

Approved

https://doi.org/10.5256/f1000research.13591.r27423

In this single center randomized controlled trial (RCT), Susheela and coworkers investigate the use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in elderly patients undergoing cardiac surgery. This pilot study primarily aimed to assess the feasibility of a larger RCT with identical interventions.

As a pilot project, the study is methodically sound. Overall, the manuscript is well-written and pleasant to read. The authors applied CONSORT criteria which is a definite plus.

Postoperative delirium has specific features that may be related to surgery (and anesthesia) and has a probable neuroinflammatory component. I therefore do not agree with your statement that 30-40% of delirium cases could be prevented, at least not in your sample of patients undergoing cardiac surgery. So far, multicomponent interventions to prevent delirium have only been proven efficacious in a general population of elderly hospitalized patients.¹

Please also discuss the opioid-sparing effects of intraoperative dexmedetomidine. Next to the missing interaction with GABA receptors, this might be an additional mechanism for delirium prevention when using dexmedetomidine.

Please discuss the reasons to exclude patients with preexisting cognitive impairment from your study. Preoperative cognitive impairment was found to be one of the most important risk factors for postoperative delirium (odds ratio ranged from 6.3 (95% CI 2.9 to 13.7) up to 11.5 (95% CI 6.1 to 20.1)).²By excluding these patients (also in the follow-up RCT), you likely decrease the number of patients affected by the primary outcome measure (postoperative delirium) in your study. It would be interesting to investigate the effects of dexmedetomidine and intravenous acetaminophen in these high-risk patients.

I find it difficult to blind the intravenous administration of propofol and dexmedetomidine. At best, you may try to conceal the study drug from patient, surgeon, ICU caregivers, and investigators by using opaque syringes and lines. Was study drug administration really double-blind?

Was there any kind of standardization in anesthesiologic management? If yes, state drugs and dosage.

At what frequency did you assess patients for postoperative delirium in the ICU/on the ward? Who assessed the patients?

I wish the investigators of this pilot project the best of luck with the larger ongoing trial!

References

Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340: 669–76.
National Institute for Health and Care Excellence. NCGC National Clinical Guideline Centre. Delirium: diagnosis, prevention and management. http://www.nice.org.uk/guidance/cg103/evidence/full-guideline-134653069.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Author Response 10 Nov 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

10 Nov 2017

Author Response

Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the ... Continue reading Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the recommendations.

We thank you for the review.

Response

In this single-center randomized controlled trial (RCT), Susheela and coworkers investigate the use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in elderly patients undergoing cardiac surgery. This pilot study primarily aimed to assess the feasibility of a larger RCT with identical interventions.

As a pilot project, the study is methodically sound. Overall, the manuscript is well-written and pleasant to read. The authors applied CONSORT criteria which is a definite plus.

Thank you

Postoperative delirium has specific features that may be related to surgery (and anesthesia) and has a probable neuroinflammatory component. I, therefore, do not agree with your statement that 30-40% of delirium cases could be prevented, at least not in your sample of patients undergoing cardiac surgery. So far, multicomponent interventions to prevent delirium have only been proven efficacious in a general population of elderly hospitalized patients.1

Thank you. These estimates are from the pilot study result. The ongoing study will inform us better about the effect size.

Please also discuss the opioid-sparing effects of intraoperative dexmedetomidine. Next, to the missing interaction with GABA receptors, this might be an additional mechanism for delirium prevention when using dexmedetomidine.

Thank you. Agreed. It is possible that dexmedetomidine can reduce the analgesic requirements. The ongoing study will inform us of this effect size as well due to the crossover design.

Please discuss the reasons to exclude patients with preexisting cognitive impairment from your study. Preoperative cognitive impairment was found to be one of the most important risk factors for postoperative delirium (odds ratio ranged from 6.3 (95% CI 2.9 to 13.7) up to 11.5 (95% CI 6.1 to 20.1)).2 By excluding these patients (also in the follow-up RCT), you likely decrease the number of patients affected by the primary outcome measure (postoperative delirium) in your study. It would be interesting to investigate the effects of dexmedetomidine and intravenous acetaminophen in these high-risk patients.

Thank you. As this is the first study of this size, we would like to get a homogenous group examined first and definitely the next step is to do the patients with preexisting cognitive dysfunction.

I find it difficult to blind the intravenous administration of propofol and dexmedetomidine. At best, you may try to conceal the study drug from patient, surgeon, ICU caregivers, and investigators by using opaque syringes and lines. Was study drug administration really double-blind?

Thank you. We only double-blinded the Acetaminophen arms.

Was there any kind of standardization in anesthesiologic management? If yes, state drugs and dosage.

Cardiac surgery is the most protocolized intraoperative setting. Patients were induced with 500mcg of IV fentanyl, 50-100mg of Propofol, and endotracheal intubation was facilitated with 1mg/kg intravenous rocuronium. Anesthesia was maintained with isoflurane (0.6-1.0 MAC) in 100% oxygen with intermittent fentanyl up to a maximum of additional 500 mcg of fentanyl and intermittent rocuronium. All patients were taken intubated to the ICU

At what frequency did you assess patients for postoperative delirium in the ICU/on the ward? Who assessed the patients?

Assistants trained from Edward Marcantonio’s lab (with initial half a day training session, witnessing the assessments for a few patients and also calibration with gold standard assessor). Postoperative delirium was assessed by a trained study team member with the help of cognitive assessments such as MMSE, CAM-ICU, and CAM starting from the day after the surgery. If cognitive assessments are negative for 3 consecutive days (i.e days 5, 6 & 7), assessments were completed every other day until the date of discharge.

I wish the investigators of this pilot project the best of luck with the larger ongoing trial!

Thank you
Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the recommendations.

We thank you for the review.

Response

In this single-center randomized controlled trial (RCT), Susheela and coworkers investigate the use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in elderly patients undergoing cardiac surgery. This pilot study primarily aimed to assess the feasibility of a larger RCT with identical interventions.

As a pilot project, the study is methodically sound. Overall, the manuscript is well-written and pleasant to read. The authors applied CONSORT criteria which is a definite plus.

Thank you

Postoperative delirium has specific features that may be related to surgery (and anesthesia) and has a probable neuroinflammatory component. I, therefore, do not agree with your statement that 30-40% of delirium cases could be prevented, at least not in your sample of patients undergoing cardiac surgery. So far, multicomponent interventions to prevent delirium have only been proven efficacious in a general population of elderly hospitalized patients.1

Thank you. These estimates are from the pilot study result. The ongoing study will inform us better about the effect size.

Please also discuss the opioid-sparing effects of intraoperative dexmedetomidine. Next, to the missing interaction with GABA receptors, this might be an additional mechanism for delirium prevention when using dexmedetomidine.

Thank you. Agreed. It is possible that dexmedetomidine can reduce the analgesic requirements. The ongoing study will inform us of this effect size as well due to the crossover design.

Please discuss the reasons to exclude patients with preexisting cognitive impairment from your study. Preoperative cognitive impairment was found to be one of the most important risk factors for postoperative delirium (odds ratio ranged from 6.3 (95% CI 2.9 to 13.7) up to 11.5 (95% CI 6.1 to 20.1)).2 By excluding these patients (also in the follow-up RCT), you likely decrease the number of patients affected by the primary outcome measure (postoperative delirium) in your study. It would be interesting to investigate the effects of dexmedetomidine and intravenous acetaminophen in these high-risk patients.

Thank you. As this is the first study of this size, we would like to get a homogenous group examined first and definitely the next step is to do the patients with preexisting cognitive dysfunction.

I find it difficult to blind the intravenous administration of propofol and dexmedetomidine. At best, you may try to conceal the study drug from patient, surgeon, ICU caregivers, and investigators by using opaque syringes and lines. Was study drug administration really double-blind?

Thank you. We only double-blinded the Acetaminophen arms.

Was there any kind of standardization in anesthesiologic management? If yes, state drugs and dosage.

Cardiac surgery is the most protocolized intraoperative setting. Patients were induced with 500mcg of IV fentanyl, 50-100mg of Propofol, and endotracheal intubation was facilitated with 1mg/kg intravenous rocuronium. Anesthesia was maintained with isoflurane (0.6-1.0 MAC) in 100% oxygen with intermittent fentanyl up to a maximum of additional 500 mcg of fentanyl and intermittent rocuronium. All patients were taken intubated to the ICU

At what frequency did you assess patients for postoperative delirium in the ICU/on the ward? Who assessed the patients?

Assistants trained from Edward Marcantonio’s lab (with initial half a day training session, witnessing the assessments for a few patients and also calibration with gold standard assessor). Postoperative delirium was assessed by a trained study team member with the help of cognitive assessments such as MMSE, CAM-ICU, and CAM starting from the day after the surgery. If cognitive assessments are negative for 3 consecutive days (i.e days 5, 6 & 7), assessments were completed every other day until the date of discharge.

I wish the investigators of this pilot project the best of luck with the larger ongoing trial!

Thank you
Competing Interests: The authors report no competing interests. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 10 Nov 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

10 Nov 2017

Author Response

Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the ... Continue reading Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the recommendations.

We thank you for the review.

Response

In this single-center randomized controlled trial (RCT), Susheela and coworkers investigate the use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in elderly patients undergoing cardiac surgery. This pilot study primarily aimed to assess the feasibility of a larger RCT with identical interventions.

As a pilot project, the study is methodically sound. Overall, the manuscript is well-written and pleasant to read. The authors applied CONSORT criteria which is a definite plus.

Thank you

Postoperative delirium has specific features that may be related to surgery (and anesthesia) and has a probable neuroinflammatory component. I, therefore, do not agree with your statement that 30-40% of delirium cases could be prevented, at least not in your sample of patients undergoing cardiac surgery. So far, multicomponent interventions to prevent delirium have only been proven efficacious in a general population of elderly hospitalized patients.1

Thank you. These estimates are from the pilot study result. The ongoing study will inform us better about the effect size.

Please also discuss the opioid-sparing effects of intraoperative dexmedetomidine. Next, to the missing interaction with GABA receptors, this might be an additional mechanism for delirium prevention when using dexmedetomidine.

Thank you. Agreed. It is possible that dexmedetomidine can reduce the analgesic requirements. The ongoing study will inform us of this effect size as well due to the crossover design.

Please discuss the reasons to exclude patients with preexisting cognitive impairment from your study. Preoperative cognitive impairment was found to be one of the most important risk factors for postoperative delirium (odds ratio ranged from 6.3 (95% CI 2.9 to 13.7) up to 11.5 (95% CI 6.1 to 20.1)).2 By excluding these patients (also in the follow-up RCT), you likely decrease the number of patients affected by the primary outcome measure (postoperative delirium) in your study. It would be interesting to investigate the effects of dexmedetomidine and intravenous acetaminophen in these high-risk patients.

Thank you. As this is the first study of this size, we would like to get a homogenous group examined first and definitely the next step is to do the patients with preexisting cognitive dysfunction.

I find it difficult to blind the intravenous administration of propofol and dexmedetomidine. At best, you may try to conceal the study drug from patient, surgeon, ICU caregivers, and investigators by using opaque syringes and lines. Was study drug administration really double-blind?

Thank you. We only double-blinded the Acetaminophen arms.

Was there any kind of standardization in anesthesiologic management? If yes, state drugs and dosage.

Cardiac surgery is the most protocolized intraoperative setting. Patients were induced with 500mcg of IV fentanyl, 50-100mg of Propofol, and endotracheal intubation was facilitated with 1mg/kg intravenous rocuronium. Anesthesia was maintained with isoflurane (0.6-1.0 MAC) in 100% oxygen with intermittent fentanyl up to a maximum of additional 500 mcg of fentanyl and intermittent rocuronium. All patients were taken intubated to the ICU

At what frequency did you assess patients for postoperative delirium in the ICU/on the ward? Who assessed the patients?

Assistants trained from Edward Marcantonio’s lab (with initial half a day training session, witnessing the assessments for a few patients and also calibration with gold standard assessor). Postoperative delirium was assessed by a trained study team member with the help of cognitive assessments such as MMSE, CAM-ICU, and CAM starting from the day after the surgery. If cognitive assessments are negative for 3 consecutive days (i.e days 5, 6 & 7), assessments were completed every other day until the date of discharge.

I wish the investigators of this pilot project the best of luck with the larger ongoing trial!

Thank you
Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the recommendations.

We thank you for the review.

Response

In this single-center randomized controlled trial (RCT), Susheela and coworkers investigate the use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in elderly patients undergoing cardiac surgery. This pilot study primarily aimed to assess the feasibility of a larger RCT with identical interventions.

As a pilot project, the study is methodically sound. Overall, the manuscript is well-written and pleasant to read. The authors applied CONSORT criteria which is a definite plus.

Thank you

Postoperative delirium has specific features that may be related to surgery (and anesthesia) and has a probable neuroinflammatory component. I, therefore, do not agree with your statement that 30-40% of delirium cases could be prevented, at least not in your sample of patients undergoing cardiac surgery. So far, multicomponent interventions to prevent delirium have only been proven efficacious in a general population of elderly hospitalized patients.1

Thank you. These estimates are from the pilot study result. The ongoing study will inform us better about the effect size.

Please also discuss the opioid-sparing effects of intraoperative dexmedetomidine. Next, to the missing interaction with GABA receptors, this might be an additional mechanism for delirium prevention when using dexmedetomidine.

Thank you. Agreed. It is possible that dexmedetomidine can reduce the analgesic requirements. The ongoing study will inform us of this effect size as well due to the crossover design.

Please discuss the reasons to exclude patients with preexisting cognitive impairment from your study. Preoperative cognitive impairment was found to be one of the most important risk factors for postoperative delirium (odds ratio ranged from 6.3 (95% CI 2.9 to 13.7) up to 11.5 (95% CI 6.1 to 20.1)).2 By excluding these patients (also in the follow-up RCT), you likely decrease the number of patients affected by the primary outcome measure (postoperative delirium) in your study. It would be interesting to investigate the effects of dexmedetomidine and intravenous acetaminophen in these high-risk patients.

Thank you. As this is the first study of this size, we would like to get a homogenous group examined first and definitely the next step is to do the patients with preexisting cognitive dysfunction.

I find it difficult to blind the intravenous administration of propofol and dexmedetomidine. At best, you may try to conceal the study drug from patient, surgeon, ICU caregivers, and investigators by using opaque syringes and lines. Was study drug administration really double-blind?

Thank you. We only double-blinded the Acetaminophen arms.

Was there any kind of standardization in anesthesiologic management? If yes, state drugs and dosage.

Cardiac surgery is the most protocolized intraoperative setting. Patients were induced with 500mcg of IV fentanyl, 50-100mg of Propofol, and endotracheal intubation was facilitated with 1mg/kg intravenous rocuronium. Anesthesia was maintained with isoflurane (0.6-1.0 MAC) in 100% oxygen with intermittent fentanyl up to a maximum of additional 500 mcg of fentanyl and intermittent rocuronium. All patients were taken intubated to the ICU

At what frequency did you assess patients for postoperative delirium in the ICU/on the ward? Who assessed the patients?

Assistants trained from Edward Marcantonio’s lab (with initial half a day training session, witnessing the assessments for a few patients and also calibration with gold standard assessor). Postoperative delirium was assessed by a trained study team member with the help of cognitive assessments such as MMSE, CAM-ICU, and CAM starting from the day after the surgery. If cognitive assessments are negative for 3 consecutive days (i.e days 5, 6 & 7), assessments were completed every other day until the date of discharge.

I wish the investigators of this pilot project the best of luck with the larger ongoing trial!

Thank you
Competing Interests: The authors report no competing interests. Close
Report a concern

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 16 Oct 2017

Open Peer Review

Reviewer Status

Reviewer Reports

	Invited Reviewers
	1	2	3	4
Version 2 (revision) 21 Dec 17	read	read	read	read
Version 1 16 Oct 17	read	read

Nicolai Goettel, University of Basel, Basel, Switzerland
Michael Simon Avidan, Washington University School of Medicine, Saint Louis, USA
Yahya Shyehabi, Monash University, Clayton, Australia
George Djaiani, University Health Network, University of Toronto, Toronto, Canada

Comments on this article

All Comments(0)

Add a comment

Browse by related subjects

Back to all reports

Reviewer Report

15 Views

15 Jan 2018 | for Version 2

George Djaiani, Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada

15 Views Cite this report Responses(1)

Approved

The authors report results of a pilot study looking at postoperative administration of acetaminophen in reducing the incidence of postoperative delirium (POD) after cardiac surgery in elderly patients.

I believe that the authors are asking an important question whether adequate or superior pain relief is associated with reduced POD rates after cardiac surgery.

Concerns:

It is not clear to me why this pilot study is referred to as a feasibility trial. Both dexmedetomidine and acetaminophen are used routinely in many cardiac centres. Please comment.
I would strongly advise against quoting outcome measures as percentages of patients, you have 3 patients per group, e.g., quoting 2/3 (67%) is misleading.
The authors found that DEX group received twice as much opioids compared to the other groups. It is in contrary with previous studies identifying opioid sparing effects of DEX. (e.g. Anaesthesiology 2016; 124(2): 362-8; Lancet 2016; 15;388(10054): 1893-1902), however, it could be contributed to small sample size and the DEX administration protocol. Please comment.
If I understood correctly DEX was given until extubation or for 6 hours postoperatively. Not a standard administration practice for DEX. Please comment on rational for this design.
With respect to pain relief after cardiac surgery, spinal/epidural analgesia has been associated with superior pain relief and significant opioid sparing effects, however, there are no studies that have shown a reduction in delirium rates with either of these techniques. Please comment if acetaminophen may have some intrinsic properties other than analgesia in reducing POD after cardiac surgery.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (1)

Author Response

17 Jan 2018

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.

Concerns:
It is not clear to me why this pilot study is referred to as a feasibility trial. Both dexmedetomidine and acetaminophen are used routinely in many cardiac centers. Please comment.

Thank you for your comment. The use of IV acetaminophen was more common in our CVICU. Therefore, we chose to see if nurses will be amenable to having this as a placebo-controlled trial.

I would strongly advise against quoting outcome measures as percentages of patients, you have 3 patients per group, e.g., quoting 2/3 (67%) is misleading.

Thank you. Indeed that can mislead. We have also mentioned the number of patients.

The authors found that DEX group received twice as many opioids compared to the other groups. It is in contrary to previous studies identifying opioid-sparing effects of DEX. (e.g. Anaesthesiology 2016; 124(2): 362-8; Lancet 2016; 15;388(10054): 1893-1902), however, it could be contributed to small sample size and the DEX administration protocol. Please comment.

Thank you. Agreed.

If I understood correctly DEX was given until extubation or for 6 hours postoperatively. Not a standard administration practice for DEX. Please comment on the rationale for this design.

Thank you. That is correct. In our hospital, most of the patients get sedation prior to extubation and that was usually around 4-6 hours.

With respect to pain relief after cardiac surgery, spinal/epidural analgesia has been associated with superior pain relief and significant opioid-sparing effects; however, there are no studies that have shown a reduction in delirium rates with either of these techniques. Please comment if acetaminophen may have some intrinsic properties other than analgesia in reducing POD after cardiac surgery.

Thank you. Nonsteroidal anti-inflammatory drugs (NSAIDs) including acetaminophen are the other agents are used in a multimodal regimen for opioid sparing pain management. NSAIDs are generally avoided after cardiac surgery, because of their deleterious effects on the gastric mucosa, kidney and increased risk of bleeding. Intravenous (IV) acetaminophen is a good alternative, with no bleeding risk associated with its use. It inhibits cyclo-oxygenase and consequently the synthesis of pro-inflammatory cytokines.[4] It also decreases the production of inflammatory agents such as histamine and leukotrienes.[5] In addition to its peripheral effects, it may also have effects on the central nervous system which contribute to its analgesic property.[6] Billings et al previously showed that perioperative administration of acetaminophen decreases lipid peroxidation during cardiopulmonary bypass. This study explores the effect of cardiopulmonary bypass and its inflammatory response leading to erythrocyte lysis, and the effect of acetaminophen in its prevention.[7] Although the context is different, the attenuation of lipid peroxidation with secondary inflammation and injury in the immediate postoperative period as seen with acetaminophen may be relevant to its effects on the central nervous system and subsequently on the incidence of delirium. The use of IV acetaminophen has been shown to decrease opioid consumption after surgeries such as hip and knee replacements, cesarean sections, and coronary artery bypass surgeries.

Reference:
1.   Djaiani G, Silverton N, Fedorko L, et al. Dexmedetomidine versus Propofol Sedation Reduces Delirium after Cardiac Surgery. Anesthesiology. 2016;124(2):362-368.
2.   Deiner S, Department of Anesthesiology ISoMaMS, New York, New York, Department of Neurosurgery ISoMaMS, New York, New York, et al. Intraoperative Infusion of Dexmedetomidine for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery: A Randomized Clinical Trial. JAMA Surgery. 2017;152(8).
3.   Su X, Meng ZT, Wu XH, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016;388(10054):1893-1902.
4.   Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12(1):46-55.
5.   O'Neal JB. The utility of intravenous acetaminophen in the perioperative period. Frontiers in public health. 2013;1:25-25.
6.   Botting RM. Mechanism of action of acetaminophen: is there a cyclooxygenase 3? Clin Infect Dis. 2000;31 Suppl 5:S202-210.
7. Billings FTt, Petracek MR, Roberts LJ, 2nd, Pretorius M. Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial. PLoS One. 2015;10(2):e01

View more View less

Competing Interests

The authors report no competing interest.

Back to all reports

Reviewer Report

21 Views

04 Jan 2018 | for Version 2

Michael Simon Avidan, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA

21 Views Cite this report Responses(1)

Approved

The investigators have addressed my concerns.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (1)

Author Response

08 Jan 2018

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

Thank you

View more View less

Competing Interests

No competing interests to disclose.

Back to all reports

Reviewer Report

35 Views

28 Dec 2017 | for Version 2

Yahya Shyehabi, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia

35 Views Cite this report Responses(0)

Not Approved

Although this study is considered a pilot trial, the small number of patients 12 divided into 4 groups is a serious flaw in methodology. The interpretation of the data is completely meaningless not even as a feasibility study.
I believe this study should not be more than a run-in phase for a proper pilot with reasonable numbers.

I do not recommend publication in F1000.
Thanks.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

No

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Critical care and anaesthesia

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

26 Views

22 Dec 2017 | for Version 2

Nicolai Goettel, Department of Anesthesia, University of Basel, Basel, Switzerland

26 Views Cite this report Responses(1)

Approved

I do not have further comments to make to this revision of the article regarding the pilot study. I wish the investigators good luck with the follow-up (single- or multicenter) trial.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (1)

Author Response

22 Dec 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

Thank you. We appreciate your comments.

View more View less

Competing Interests

No competing interests were disclosed

Back to all reports

Reviewer Report

27 Views

27 Nov 2017 | for Version 1

Michael Simon Avidan, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA

27 Views Cite this report Responses(1)

Approved With Reservations

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.
The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.
Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.
I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.
More efficient tools might not necessarily be more sensitive.
I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.
From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.
The reasons for the exclusion criteria are not clear.
With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).
The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Not applicable
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

No

Competing Interests

No competing interests were disclosed.

Respond to this report

Responses (1)

Author Response

14 Dec 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

Dear Dr. Micheal Avidan,

Thank you for reviewing the paper. We have thoroughly reviewed the comments. We are addressing below, point-by-point all the suggestions.

The investigators state, “The mean duration of delirium was 0-1 days.” This appears to be a range.Thank you. Yes. We reported the mean duration as a range.
The investigators conclude, “The feasibility of performing a large-scale project is ascertained by the study.” I would rather argue that the feasibility of performing a project is ascertained. Whether or not a large-scale project is feasible is not necessarily established.Thank you. We agree that only the feasibility of performing a project is ascertained.
Contrary to the investigators, I do not believe that a 12 patient study with four groups supports the inference “that IVA may have a role in reducing the incidence of delirium.” This is over-interpretive of very limited data.Thank you. We agree this is a pre-pilot study indeed. It was a feasibility project and we certainly do not want to overinterpret. Thus, we wrote “IVA may be beneficial in reducing the incidence of delirium following cardiac surgery. ” Since this is a feasibility study we agree that a larger study is needed to draw a concrete conclusion.
I do not agree that using the CAM is a major limitation in delirium research (as the investigators suggest that it might lack sensitivity). I do agree that this might apply to the CAM-ICU.Thank you. Agreed.
More efficient tools might not necessarily be more sensitive.Thank you. Agreed.
I am not convinced that a 12 patient pilot trial will produce sufficiently precise estimates to power a large RCT appropriately. Although the absolute difference between proportions (delirium incidence) was 50% (67% minus 17%), the 95% confidence interval for this difference is -13% to 82%. Thus, it is not clear based on this small study what value should be used (estimated difference in delirium incidence between the groups [acetaminiphen and placebo]) for the sample size calculation.Thank you. We planned this pilot study as a means to assess the feasibility of performing a large-scale project. However, there is no other preexisting data to power the next larger trial. Since this pilot study showed a 66% reduction in the incidence of delirium, for the power calculation, a 50% reduction in the delirium incidence was used. Each group needed 56 patients (alpha=0.05 and 1-Beta=0.80).
From the registration site (for NCT02546765), it appears that 120 patients will be included in the (large) trial. This number is likely to be much too small to answer the research question with sufficient precision.Thank you. A multicenter trial is definitely required to answer with precision. However, it will be a major leap to go from a pilot study to a multicenter trial. Thus, we chose to do the second step of testing in a larger sample size with what is known so far. Depending on what this study shows, the obvious next step will be a larger multicenter trial.
The reasons for the exclusion criteria are not clear.Thank you. We chose a homogenous set of patients to determine the drug efficacy. We wanted to avoid patients who might not get extubated in a reasonable amount of time (hence the EF, aortic surgery exclusion, etc). As we chose to give Q6H IV acetaminophen, we wanted to avoid any clinical situation that can potentially set up patients for drug toxicity etc. Preexisting cognitive dysfunction, etc. could muddle the picture in a 120 patient study. In a larger multicenter trial if and when launched, the heterogeneity can be accounted for and thus need not necessarily be an exclusion criteria.
With the modified factorial design, was interaction between interventions considered? Specifically, both dexmedetomidine and acetaminophen might have an impact on the outcome of interest (delirium).Thank you. Yes, these interactions will be analyzed in the ongoing trial
The (secondary) results of the study were as follows: “The Propofol+Acetaminophen group had no occurrence of delirium. Interestingly, only 17% (1/6) of the subjects who received IVA were diagnosed with delirium compared to 67% (4/6) in the group who did not receive IVA.” The investigators should be cautious about over-interpreting these findings, or using these estimates to justify sample size for a large trial. The problem with this would be that 67% is a very high incidence, and is not likely to reflect the incidence with current standard of care (i.e., propofol or dexmedetomidine sedation, without intravenous acetaminophen). Similarly, the incidence of 17% is actually likely to be pretty close to the current delirium incidence in the type of patients who were enrolled to this study (but who receive standard of care).Thank you for the caution. We agree with all the comments.

View more View less

Competing Interests

The authors report no competing interests.

Back to all reports

Reviewer Report

30 Views

09 Nov 2017 | for Version 1

Nicolai Goettel, Department of Anesthesia, University of Basel, Basel, Switzerland

30 Views Cite this report Responses(1)

Approved

Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340: 669–76.
National Institute for Health and Care Excellence. NCGC National Clinical Guideline Centre. Delirium: diagnosis, prevention and management. http://www.nice.org.uk/guidance/cg103/evidence/full-guideline-134653069.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (1)

Author Response

10 Nov 2017

Ammu Susheela, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215-5400, USA

Dear Nicolai Goettel,

We sincerely thank you for the opportunity to address the comments of our manuscript. We have thoroughly reviewed the comments. In this letter, we address, point-by-point, all the recommendations.

We thank you for the review.

Response

In this single-center randomized controlled trial (RCT), Susheela and coworkers investigate the use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in elderly patients undergoing cardiac surgery. This pilot study primarily aimed to assess the feasibility of a larger RCT with identical interventions.

As a pilot project, the study is methodically sound. Overall, the manuscript is well-written and pleasant to read. The authors applied CONSORT criteria which is a definite plus.

Thank you

Postoperative delirium has specific features that may be related to surgery (and anesthesia) and has a probable neuroinflammatory component. I, therefore, do not agree with your statement that 30-40% of delirium cases could be prevented, at least not in your sample of patients undergoing cardiac surgery. So far, multicomponent interventions to prevent delirium have only been proven efficacious in a general population of elderly hospitalized patients.1

Thank you. These estimates are from the pilot study result. The ongoing study will inform us better about the effect size.

Please also discuss the opioid-sparing effects of intraoperative dexmedetomidine. Next, to the missing interaction with GABA receptors, this might be an additional mechanism for delirium prevention when using dexmedetomidine.

Thank you. Agreed. It is possible that dexmedetomidine can reduce the analgesic requirements. The ongoing study will inform us of this effect size as well due to the crossover design.

Please discuss the reasons to exclude patients with preexisting cognitive impairment from your study. Preoperative cognitive impairment was found to be one of the most important risk factors for postoperative delirium (odds ratio ranged from 6.3 (95% CI 2.9 to 13.7) up to 11.5 (95% CI 6.1 to 20.1)).2 By excluding these patients (also in the follow-up RCT), you likely decrease the number of patients affected by the primary outcome measure (postoperative delirium) in your study. It would be interesting to investigate the effects of dexmedetomidine and intravenous acetaminophen in these high-risk patients.

Thank you. As this is the first study of this size, we would like to get a homogenous group examined first and definitely the next step is to do the patients with preexisting cognitive dysfunction.

I find it difficult to blind the intravenous administration of propofol and dexmedetomidine. At best, you may try to conceal the study drug from patient, surgeon, ICU caregivers, and investigators by using opaque syringes and lines. Was study drug administration really double-blind?

Thank you. We only double-blinded the Acetaminophen arms.

Was there any kind of standardization in anesthesiologic management? If yes, state drugs and dosage.

Cardiac surgery is the most protocolized intraoperative setting. Patients were induced with 500mcg of IV fentanyl, 50-100mg of Propofol, and endotracheal intubation was facilitated with 1mg/kg intravenous rocuronium. Anesthesia was maintained with isoflurane (0.6-1.0 MAC) in 100% oxygen with intermittent fentanyl up to a maximum of additional 500 mcg of fentanyl and intermittent rocuronium. All patients were taken intubated to the ICU

At what frequency did you assess patients for postoperative delirium in the ICU/on the ward? Who assessed the patients?

Assistants trained from Edward Marcantonio’s lab (with initial half a day training session, witnessing the assessments for a few patients and also calibration with gold standard assessor). Postoperative delirium was assessed by a trained study team member with the help of cognitive assessments such as MMSE, CAM-ICU, and CAM starting from the day after the surgery. If cognitive assessments are negative for 3 consecutive days (i.e days 5, 6 & 7), assessments were completed every other day until the date of discharge.

I wish the investigators of this pilot project the best of luck with the larger ongoing trial!

Thank you

View more View less

Competing Interests

The authors report no competing interests.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

Click here to access the data.

Downloaded data do not display as expected? Download the data

[1] 1. Bellelli G, Morandi A, Di Santo SG, et al.: “Delirium Day”: a nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool. BMC Med. 2016; 14(1): 106. PubMed Abstract | Publisher Full Text | Free Full Text

[2] 2. Inouye SK, Westendorp RG, Saczynski JS: Delirium in elderly people. Lancet. 2014; 383(9920): 911–922. PubMed Abstract | Publisher Full Text | Free Full Text

[3] 3. Inouye SK: Delirium in older persons. N Engl J Med. 2006; 354(11): 1157–1165. PubMed Abstract | Publisher Full Text

[4] 4. O'Neal JB: The utility of intravenous acetaminophen in the perioperative period. Front Public Health. 2013; 1: 25. PubMed Abstract | Publisher Full Text | Free Full Text

[5] 5. Saczynski JS, Marcantonio ER, Quach L, et al.: Cognitive trajectories after postoperative delirium. N Engl J Med. 2012; 367(1): 30–39. PubMed Abstract | Publisher Full Text | Free Full Text

[6] 6. Cui V, Tedeschi CM, Kronzer VL, et al.: Protocol for an observational study of delirium in the post-anaesthesia care unit (PACU) as a potential predictor of subsequent postoperative delirium. BMJ Open. 2017; 7(7): e016402. PubMed Abstract | Publisher Full Text | Free Full Text

[7] 7. Leslie DL, Marcantonio ER, Zhang Y, et al.: One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008; 168(1): 27–32. PubMed Abstract | Publisher Full Text | Free Full Text

[8] 8. Rudolph JL, Jones RN, Levkoff SE, et al.: Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation. 2009; 119(2): 229–36. PubMed Abstract | Publisher Full Text | Free Full Text

[9] 9. Lin YY, He B, Chen J, et al.: Can dexmedetomidine be a safe and efficacious sedative agent in post-cardiac surgery patients? a meta-analysis. Crit Care. 2012; 16(5): R169. PubMed Abstract | Publisher Full Text | Free Full Text

[10] 10. Li X, Yang J, Nie XL, et al.: Impact of dexmedetomidine on the incidence of delirium in elderly patients after cardiac surgery: A randomized controlled trial. PLoS One. 2017; 12(2): e0170757. PubMed Abstract | Publisher Full Text | Free Full Text

[11] 11. Corbett SM, Rebuck JA, Greene CM, et al.: Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation. Crit Care Med. 2005; 33(5): 940–5. PubMed Abstract | Publisher Full Text

[12] 12. Shehabi Y, Grant P, Wolfenden H, et al.: Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Anesthesiology. 2009; 111(5): 1075–84. PubMed Abstract | Publisher Full Text

[13] 13. Maldonado JR, Wysong A, van der Starre PJ, et al.: Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009; 50(3): 206–17. PubMed Abstract | Publisher Full Text

[14] 14. Dasta JF, Jacobi J, Sesti AM, et al.: Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis. Pharmacotherapy. 2006; 26(6): 798–805. PubMed Abstract | Publisher Full Text

[15] 15. Macario A, Royal MA: A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Pain Pract. 2011; 11(3): 290–296. PubMed Abstract | Publisher Full Text

[16] 16. Susheela AT, Packiasabapathy S, Gasangwa DV, et al.: Dataset 1 in: The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study. F1000Research. 2017. Data Source

The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study

Abstract

Keywords

Introduction

Methods

Purpose

Study design

Study population

Figure 1. Consort diagram.

Randomization

Table 1. Table 1 provides all different groups in the study.

Study drug administration

Patient assessment

Outcomes of the study

Results

Table 2. Table 2 provides the incidence of delirium and secondary outcomes in the groups receiving propofol, dexmedetomidine, acetaminophen, and no acetaminophen respectively.

Table 3. Table 3 provides the incidence of delirium and secondary outcomes in the 4 groups in the study namely propofol, propofol + acemaninophen, dexmedetomidine, dexmedetomidine + acetaminophen.

Discussion

Data availability

Ethics and consent

Competing interests

Grant information

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Browse by related subjects

The problem

How to fix it

Competing Interests Policy

Stay Updated