Examining the Association Between Pre-existing Sleep Disturbance and Postoperative Delirium
Conditions: Delirium
Sponsor: Massachusetts General Hospital

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Examining the Association Between Pre-existing Sleep Disturbance and Postoperative Delirium 
 
NCT: 03498560 
11/5/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Examining the Association Between Pre-existing Sleep Disturbance and Postoperative Delirium 
 
Principal Investigator: Oluwaseun Johnson-Akeju, M.D., M.M.Sc 
Co-Principal Investigator: Jason Qu, M.D. 
 
1. BACKGROUND AND SIGNIFICANCE 
Post-operative delirium (POD), commonly encountered after surgery,1 is an acute brain dysfunction 
characterized by disturbances in attention, awareness, and cognition not explained by a preexisting 
neurocognitive disorder.1 2 2 Although the increased mortality rates ascribed to delirium remain debatable, 
delirium remains a leading cause of preventable morbidity in hospitalized elderly patients. It is also associated 
with prolonged hospitalization, prolonged institutionalization, and long-term cognitive deficits. The total 
healthcare cost attributable to delirium is estimated between $143 and $152 billion annually. Thus, principled 
strategies to pre-emptively identify and target patients at risk for delirium may result in significantly improved 
peri-operative outcomes. 
 
Sleep is a naturally occurring state of decreased arousal that is crucial for normal immune and cognitive 
function.3 Basic science and clinical studies suggest sleep disturbance as a modifiable risk factor for post-
operative delirium (POD). Sleep deprivation, which is associated with increased pro-inflammatory cytokine levels 
including interleukin-6,4-6 precedes the onset of delirium in some patients.7 8A recent investigation linking brain 
activity of microglia, astrocytes, interleukin-6 and delirium in humans,9 suggests a mechanistic link between sleep 
deprivation, brain inflammation and delirium. Further, conditions associated with delirium are characterized by 
activation of the inflammatory cascade with acute release of inflammatory mediators.10-24 Increasing age is a 
significant risk factor for the development of delirium. Notably, aging is associated with activated brain glia cells.25 
26 Following a systemic challenge such as critical illness, these activated glia have been suggested to facilitate 
an exaggerated neuroinflammatory state that predisposes to delirium.25-28 Thus, as systemic inflammation may 
be involved in the pathophysiology of delirium, sleep disturbance may constitute a modifiable risk factor for POD. 
However, structured studies are necessary to make clear the extent to which this association exists and is 
modifiable. 
 
Systematic Literature Search 
We conducted a systematic search into the association between sleep disturbance and POD. The search 
included patients across a range of surgical specialties. The aim of the search was to capture studies that 
assessed a history of sleep disturbance and POD. Published literature were searched using strategies devised 
by a librarian using a combination of standardized terms and keywords, and were implemented in Pubmed, 
Embase, CINAHL, Web of Science and Cochrane from inception until May 31st, 2017. We identified 1,238 
citations (328 studies in the MEDLINE database (PubMed), 939 in EMBASE, 86 in CINAHL, 266 in Web of 
Science and 76 in the Cochrane Library Database), and included 12 unique studies enrolling 1,878 patients. The 
studies were methodologically diverse with respect to metrics that were used to diagnose sleep disturbance and 
POD. 
 
Search Methodology Summary 
All studies were reported between 2001 and 2015. They included seven prospective cohort studies29-35 
and five retrospective studies.36-40 Nine studies had a sample size greater than or equal to 60.30 31 33-35 37-40 The 
largest study was a retrospective cohort study involving 432 patients, 40 while the smallest was a prospective 
cohort study with 40 patients.29 Four studies specified obstructive sleep apnea as the type of sleep disorder 
evaluated.30 32 33 37 However, the other studies did not explicitly specify the type of sleep disorder that was 
evaluated.29 31 35 36 38-41 Eight studies assessed pre-operative sleep disorder,29 30 32 33 36-38 41 three studies assessed 
sleep disorder immediately post-surgery but before the onset of delirium,35 39 40 and one study assessed sleep 
disorder occurring after the onset of delirium.31 Five studies evaluated orthopedic surgeries,30 34 36 37 39 four studies 
evaluated cardiac surgeries29 31 33 35 and others evaluated thoracic and non-cardiac surgeries.32 38 40 Eight studies 
utilized the Confusion Assessment Method (CAM), a standardized evidence-based tool, 20, 21 to diagnose 
delirium;29 30 32-35 38 39 two studies used the Diagnosis and Statistical Manual of Mental Disorders (DSM-IV);31 40 
and two studies utilized patient chart records and information obtained from caregivers to diagnose delirium.36 37 
We excluded cross-sectional studies, case reports and studies not reported in English language.  

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Pooled Analysis Summary 
  
A total of 1,199 patients and 244 cases of 
delirium were analyzed. We found that the pooled 
odds ratio for the association between sleep 
disturbance and POD was 5.24 (95% CI: 3.61 to 
7.60, p <0.001; I2=0.0%, p=0.76). The pooled odds 
ratio for the association between pre-delirium sleep 
disturbance and POD of 5.24 (95% CI: 3.61 to 7.60, 
p <0.001; I2=0.0%, p=0.76; Fig 2b) was statistically 
significant. 
The 
odds 
ratio 
associated 
with 
obstructive sleep apnea and unspecified types of 
sleep disorder were 4.75 (95% CI: 2.65 to 8.54, p 
<0.001; I2=0.0%, p=0.85), and 5.60 (95% CI: 3.46 to 
9.07, p <0.001; I2=0.0%, p=0.41), respectively. We 
conducted a sensitivity analysis using risk ratios 
obtained from the prospective studies, 29 30 32-34 42 and 
found that the pooled risk ratio for the association 
between sleep disturbance and POD of 2.90 (95% 
CI: 2.28 to 3.69, p <0.001; I2=0.0%, p=0.89; Fig 5) 
was significant.  
 
Evans et al., in a pilot prospective study that used EEG recordings to objectively study predictors of POD, 
found that diminished sleep time and increased sleep latency on POD 1 is associated with increased incidence 
and severity of delirium.43 Sleep disturbance is a hallmark feature of the postoperative period,44-48 and results 
from this study do not resolve whether pre-existing sleep disturbance is associated with an increased incidence 
of POD.  Other studies that have evaluated the association between sleep disorder and delirium have utilized 
measures such as wrist actigraphy or the Pittsburgh Sleep Quality Index (PSQI) to evaluate sleep disturbance. 
Unfortunately, the use of actigraphy or the PSQI in isolation do not provide accurate details on sleep quality or 
microstructure dynamics of sleep such as slow-delta oscillations, sleep spindles, K-complexes or REM alpha 
oscillations. These dynamics, which may aid the pre-emptive identification of patients that are prone to 
developing POD, can be obtained using a portable sleep polysomnography (PSG) device.  
 
Therefore, we aim to study the association between preoperative sleep disturbance and POD. Our central 
hypothesis is that preexisting sleep dysfunction will correlate with incidence of POD. To enable assessment of 
objective sleep quality metrics, our cohort will be comprised of patients admitted to the hospital prior to surgical 
procedures. We will perform cognitive and delirium assessments, polysomnography and blood sample collection 
peri-operatively. Additionally, previous research has demonstrated a clear link between infection and sleep 
apnea. Thus, we will track subjects’ postoperative infection rates in order to assess the generalizability of this 
outcome to sleep disturbance overall.  At the conclusion of this study, we will have expanded our knowledge of 
the pathophysiology of POD. 
 
2. SPECIFIC AIMS 
The specific aims of this study are: 
 
AIM 1: To use PSG and a validated sleep questionnaire to characterize sleep quality in POD patients 
Hypothesis 1.1. POD will be associated with significantly decreased pre-operative total sleep time 
Hypothesis 1.2. POD will be associated with a pre-existing history of sleep disruption as measured by the 
Pittsburgh Sleep Quality Assessment (PSQI) 
 
AIM 2: To use serum profiling to understand the association between POD and circadian disruption 
Hypothesis 2.1. POD will be associated with decreased am mRNA transcript levels of clock genes (Bmal1, Clock, 
Per1 and Per2).  
 
 
Figure 1. Pooled analysis of studies with crude odds ratio 

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3. Subject Selection  
Primary inclusion criteria for patients: 1) age ≥ 60; 2) inpatient and scheduled for surgical procedure at MGH.  
Primary exclusion criteria for patients: 1) blindness, deafness or the inability to speak English; 2) inability to 
provide informed consent. 
Primary objective drop for patients: 1) post-operative intubation >24 hours. 
 
4. Subject Enrollment 
Recruitment: This study will be performed at the Massachusetts General Hospital in Boston, MA. We will enroll 
100 male and female patients into the study. Cardiac surgical patients and orthopedic trauma patients represent 
the primary surgical patients that are admitted to the hospital prior to their surgical procedures. Thus, we will 
screen cardiac and orthopedic surgical schedules to identify potential eligible subjects. We will engage members 
of the patient’s clinical care team to ask the patient if he/she is willing to have a study team member approach 
him/her to discuss a research study. This initial care patient contact will be performed by cardiac or orthopedic 
clinical staff (M.D., P.A, N.P, R.N), cardiac or orthopedic anesthesia care providers (M.D., C.R.N.A, S.R.N.A), or 
hospital geriatric clinicians (M.D., P.A, or N.P). Study team members will only approach patients that are 
interested in learning more about the study. They will explain the details of the study and provide a flyer 
summarizing study procedures to the patient. Formal written consent will be obtained prior to any study related 
procedures. 
 
Retention: All subjects who provide written consent but later decline participation in the study will not be subject 
to any study-related follow-up. 
 
Remuneration: There will be no monetary remuneration for this study. 
 
Procedure for informed consent: Members of the patient’s clinical care team will briefly introduce the study to 
the patient. Study team members will only approach patients that are interested in learning more about the study. 
Study team members will explain the details of study and provide a flyer summarizing study procedures to the 
patient. If the study team member is a non-physician (i.e. clinical research coordinator), he/she will explicitly offer 
the patient an opportunity to speak to physician investigators. The study team member will review and discuss 
the details of the research study with the patient using the informed consent document as a guide. The discussion 
will include all the required elements of informed consent. A formal written consent will be obtained only after all 
questions and concerns have been addressed. 
Treatment Assignment and Randomization: Not applicable. 
 
5. Study Design 
Pre-operative Visit: We will obtain a written consent prior to conducting the Long-CAM, PSQI, Patient Health 
Questionnaire (PHQ-9), Trust in Physician Scale (TPS) and the abbreviated Montreal cognitive assessment. 
Next, we will place a portable PSG device at approximately 7 pm to record neurophysiological data using the 
Compumedics Portable PSG monitoring device. Due to clinical care concerns, patient acuity, patient 
unavailability and several other unforeseen factors, PSG may not be placed on all study subjects. A minimum of 
the following electrodes will be placed for sleep staging: Two central channels (C3 and C4), two electrooculogram 
channels to capture lateral eye movements, and two reference channels over the left and right mastoids.  
 
Post-operative Day 0: PSG electrodes will be removed at approximately 6am. Additionally, we will obtain 
approximately 13ml of blood to be processed into mRNA to understand the association between peri-operative 
circadian cycle disruption of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and POD. The PI will 
ensure that appropriate privacy and de-identification procedures are in place for the collection and storage of 
blood. All MGH ORs are equipped with a four-channel frontal EEG device (Sedline, Masimo, Irvine, CA). Thus, 
we will collect intraoperative routine EEG data that is recorded as part of routine anesthetic management. Due 
to clinical care concerns, patient acuity, Sedline electrode unavailability and several other unforeseen factors, 
blood and Sedline EEG data may not be obtained on all study subjects.    
 
Post-operative Days 1-3: On post-operative day 1, we will obtain approximately 13ml of blood as a post-surgical 
measure of mRNA levels to understand the association between peri-operative circadian cycle disruption of four 

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circadian clock genes (Bmal1, Clock, Per1 and Per2) and POD. Delirium assessments may be conducted twice 
daily (AM and PM with at least 6 hours between tests) beginning on postoperative day 1 using the Long 
Confusion Assessment Method (CAM).49 50 PHQ-9 will be assessed on POD 3 only. Subjects who elect to 
withdraw from the study during their hospital stay will be re-approached by the study team within 8-24 hours of 
study withdrawal. The study team member will elicit the reason for study discontinuation and confirm the 
withdrawal decision. This visit serves to ensure that the withdrawal decision was made during an informed and 
non-delirious cognitive state. In the event that a subject finds it difficult to complete an assessment (i.e. pain, 
clinical intervention), only the long-CAM domains necessary to dispel the presence of delirium will be assessed 
(i.e. acute onset, inattention, disorganized thinking and altered level of consciousness). Subjects who cannot 
complete this shortened assessment will be re-approached several hours later. Long-CAM assessments for 
subjects who are reintubated for clinical care or for further surgical management will be considered missing data. 
 
Post-operative Day 30: PHQ-9 and the Pain Interference 8a (PROMIS SF v1.0) questionnaires will be 
administered over the phone. Subjects’ infection rates will also be tracked postoperatively. 
 
6. DATA ANALYSIS PLAN 
Hypothesis tests will be performed using a two-sided significance level (type I error) of α=0.05. Aim 1 
(Hypotheses 1 and 2) outcome will be evaluated using binominal regression models with adaptive elastic net 
penalty to examine the association between total sleep time and POD. Patient characteristics of interest (i.e. 
age, gender, baseline cognitive score, pain, depression symptom score, frailty index, Charlson comorbidity 
index) will be included into this regression model. Because missing data rarely occur entirely at random, we will 
assess associations between patient characteristics with respect to missing data. If patients with at least one 
missing outcome value are different from those with complete outcomes data, we will use multiple imputation to 
assign values to missing data risk factors and outcomes in regression modeling. Aim 2 (Hypothesis 1) Wilcoxon 
rank-sum tests with corrections for multiple comparisons will be used to assess differences for each analyte or 
transcript. In other exploratory analysis, we will assess differences in the EEG (PSG and intraoperative) 
dynamics of delirious and non-delirious patients. To assess statistical significance for the difference in EEG 
spectra at each frequency, we will compute the 99% confidence interval of the median difference between groups 
by using an empirical bootstrap approach. The null hypothesis will be rejected only if the confidence interval of 
the median difference at each frequency exceeds the significance threshold over a contiguous frequency range 
≥ 2W. We will also characterize differences in sleep microstructure dynamics (i.e. spindle power, spindle rate, 
spindle peak frequencies, slow-delta phase- spindle amplitude modulation) between groups using algorithms 
developed in-house.  
 
7. POWER ANALYSIS 
The primary objective of this trial is to detect a difference in the duration of sleep between delirious and non-
delirious patients. Assuming a delirium event rate of 15%, a type I error of 0.05, power of 0.90 and a SD of 60 
minutes, n = 13 patients with delirium and 78 patients without delirium will enable us to detect an absolute total 
sleep time difference of 60 minutes between both groups (i.e., 360 minutes versus 300 minutes). Therefore, 
anticipating a dropout rate of approximately 10%, we aim to recruit 100 subjects. 
 
8. RISK AND DISCOMFORT 
PSG risks: The risks associated with PSG electrodes are redness, irritation at placement site, unpleasant odor 
from glue, and annoyance from having electrodes attached to the body.  
Questionnaire risks: Minimal risks associated with completing questionnaires are subject fatigue and the 
possibility of minor psychological distress associated with answering sensitive questions regarding psychological 
functioning. 
Data risks: Procedures are in place to reduce the likelihood of a breach of confidentiality including the de-
identification of data and storage of data only on partners approved devices/portals. However, there is a small 
risk that people outside of this study may be exposed to information about study subjects. 
 

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9. POTENTIAL BENEFITS 
Subjects will have no direct benefit from taking part in this study. Findings from these studies will help advance 
our understanding of the neurobiology of delirium. We envision that in the future the information obtained from 
the proposed research will enhance the diagnosis and management of POD. 
 
10. MONITORING AND QUALITY ASSURANCE 
Because this study is a physiological study of sleep neurophysiology, as opposed to a clinical trial, the principal 
investigator and co-investigators will be responsible for monitoring and quality assurance of the study. In 
conjunction with the research assistants, weekly meetings will be held and documented. Current subjects in the 
study will be discussed at each meeting, and charts will be reviewed for completeness. The team will evaluate 
the progress of the study, verify that the rights and well-being of the subjects are protected, verify that the 
reported study data are accurate, complete and verifiable from source documents, and the conduct of the study 
is in compliance with the approved protocol and amendments. 
 
Serious Adverse Events:  Expedited review will occur for all events meeting the FDA definition of SAEs – i.e., 
any fatal event, immediately life-threatening event, permanently or substantially disabling event, event requiring 
or prolonging inpatient hospitalization, or any congenital anomaly. This also includes any event that a study 
investigator judges to impose a significant hazard, contraindication, side effect, or precaution.  Reporting to the 
IRB will be done within 24 hours of the SAE. 
 
Study Stopping Rules:  If at any time during the course of the study, the PIs or CO-Is judge that risk to subjects 
outweighs the potential benefits, the PI/CO-Is shall have the discretion and responsibility to recommend that the 
study be terminated.  
  
AE Reporting Guidelines: Unanticipated problems involving risks to subjects or others including adverse events 
will be reported to the PHRC in accordance with PHRC unanticipated problems including adverse events 
reporting guidelines, as well as the RDRC within 5 days. 
 
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