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Research Article
Clinical trial
Revised

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 2; peer review: 3 approved, 1 not approved]
PUBLISHED 21 Dec 2017
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OPEN PEER REVIEW
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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 estimate the effect size for incidence and duration of delirium.
Methods: A total of 12 adult patients >60 years of age undergoing cardiac surgery were recruited 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 completed the study.
Results: All patients completed the study 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 range of 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 (systolic blood pressure <90 mm of Hg.)
Conclusions: The feasibility of performing a  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

Revised Amendments from Version 1

The following changes, applied to the manuscript, are based on the referees' comments:

  • Emphasized that only the feasibility of the project is ascertained. We agree that a larger study is needed to draw a concrete conclusion.
  • Reasons for the exclusion criteria were mentioned.

See the authors' detailed response to the review by Nicolai Goettel
See the authors' detailed response to the review by George Djaiani
See the authors' detailed response to the review by Michael Avidan

Introduction

Delirium is defined as a change in mental status, characterized by acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness1,2. Delirium increases the risk of mortality, readmissions, and accelerated cognitive decline26. 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 CAM- ICU is limited in delirium assessments and may miss the diagnosis. 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 by Maldonado JR et al. of recruited118 patients and 90 patients were finally analyzed. 28 randomized patients were 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 surgeries4,15. 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 thus decreased incidence of delirium.

Methods

Purpose

This is a pilot trial which ran from November 2013 to November 2014 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 13th January 2015).

Study design

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

Study population

A homogenous set of patients were chosen for this feasibility study. 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. Patients who might not get extubated in a reasonable amount of time (hence the EF, aortic surgery exclusion, etc) were excluded. Since Q6H IV acetaminophen was given, any clinical situation that can potentially set up patients for drug toxicity etc. were avoided. (Figure 1)

c82ff7cd-6a0b-415e-8e77-44e90bf0396f_figure1.gif

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*SedationAcetaminophen
Group 1 (P)PropofolNo
Group 2 (P+A) PropofolYes
Group 3 (D) DexmedetomidineNo
Group 4 (D+A) DexmedetomidineYes

*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 2 and group 4 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. In the dexmedetomidine group, 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 Mini Mental (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.

PropofolDexmedetomidineAcetaminophenNo 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]
0.510.51
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 events0101
Dexmedetomidine dose
mean [SD]**
N/A0.95 [0.36]N/AN/A
Propofol dose
mean [SD]***
43.33 [5.16]N/AN/AN/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.

PropofolPropofol +
Acetaminophen
DexmedetomidineDexmedetomidine +
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]
1011
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 events0001

*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 13th November 2013 to 9th April 2015.

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Version 2
VERSION 2 PUBLISHED 16 Oct 2017
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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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.12688/f1000research.12552.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Key to Reviewer Statuses VIEW
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 2
VERSION 2
PUBLISHED 21 Dec 2017
Revised
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Reviewer Report 15 Jan 2018
George Djaiani, Department of Anesthesia and Pain Management, Toronto General Hospital,  University Health Network, University of Toronto, Toronto, ON, Canada 
Approved
VIEWS 17
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 ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Djaiani G. Reviewer Report For: 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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.5256/f1000research.14687.r29300)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • 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
    17 Jan 2018
    Author Response
    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 ... Continue reading
COMMENTS ON THIS REPORT
  • 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
    17 Jan 2018
    Author Response
    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 ... Continue reading
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22
Cite
Reviewer Report 04 Jan 2018
Michael Avidan, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA 
Approved
VIEWS 22
The investigators have ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Avidan M. Reviewer Report For: 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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.5256/f1000research.14687.r29246)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • 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
    08 Jan 2018
    Author Response
    Thank you
    Competing Interests: No competing interests to disclose.
COMMENTS ON THIS REPORT
  • 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
    08 Jan 2018
    Author Response
    Thank you
    Competing Interests: No competing interests to disclose.
Views
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Reviewer Report 28 Dec 2017
Yahya Shyehabi, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia 
Not Approved
VIEWS 42
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 ... Continue reading
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Shyehabi Y. Reviewer Report For: 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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.5256/f1000research.14687.r29299)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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28
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Reviewer Report 22 Dec 2017
Nicolai Goettel, Department of Anesthesia, University of Basel, Basel, Switzerland 
Approved
VIEWS 28
I do not have further comments to make to this revision of the article regarding ... Continue reading
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CITE
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Goettel N. Reviewer Report For: 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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.5256/f1000research.14687.r29245)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • 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
    22 Dec 2017
    Author Response
    Thank you. We appreciate your comments.
    Competing Interests: No competing interests were disclosed
COMMENTS ON THIS REPORT
  • 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
    22 Dec 2017
    Author Response
    Thank you. We appreciate your comments.
    Competing Interests: No competing interests were disclosed
Version 1
VERSION 1
PUBLISHED 16 Oct 2017
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Cite
Reviewer Report 27 Nov 2017
Michael Avidan, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA 
Approved with Reservations
VIEWS 28
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 ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Avidan M. Reviewer Report For: 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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.5256/f1000research.13591.r27502)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • 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
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
Views
30
Cite
Reviewer Report 09 Nov 2017
Nicolai Goettel, Department of Anesthesia, University of Basel, Basel, Switzerland 
Approved
VIEWS 30
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 ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Goettel N. Reviewer Report For: 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 2; peer review: 3 approved, 1 not approved]. F1000Research 2017, 6:1842 (https://doi.org/10.5256/f1000research.13591.r27423)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • 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
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

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 16 Oct 2017
Comment
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
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