Postoperative But Not Preoperative Depression Is Associated With Cognitive Impairment After Cardiac Surgery

Exploratory Analysis of Data From a Randomized Trial

Choy Lewis; Mehmet E. Dokucu; Charles H. Brown; Lauren Balmert; Nina Srdanovic; Ashwin Shaan Madhan; Sahej Singh Samra; John Csernansky; Jordan Grafman; Charles W. Hogue


BMC Anesthesiol. 2022;22(157) 

In This Article


This study is an exploratory analysis of data collected from a prospective randomized clinical investigation of 460 patients evaluating whether targeting mean arterial pressure during cardiopulmonary bypass to be above the lower limit of cerebral autoregulation improves neurological outcomes compared with usual care.[16] The results of that study have been reported in accordance with guidelines of Consolidated Standards of Reporting Trials. The parent study was approved by the Institutional Review Boards of The Johns Hopkins Medical Institutions, Baltimore, MD and Northwestern University, Chicago, IL. Patients provided written informed consent to participate in the study.


Patients aged ≥ 55 years with planned CABG with or without cardiac valve surgery, valve surgery, or ascending aortic surgery were eligible for enrollment in the parent trial if they were at risk for neurological complications based on history of stroke, and/or carotid bruit, and/or hypertension, and/or diabetes Patients were excluded if there was a contraindication to MRI; if the estimated glomerular filtration rate was ≤ 60 mL/min or they were on current renal dialysis; if they were receiving emergency surgery; inability to attend outpatient visits; or if they had visual impairment or if they were unable to speak and read English. The patients were enrolled between October 2, 2009 and January 10, 2019 at The Johns Hopkins Hospital, Baltimore, MD and Northwestern Memorial Hospital, Chicago, IL. The study was approved by the Institutional Review Board Committees of The Johns Hopkins Medical Institutes (Baltimore, MD) and Northwestern University Feinberg School of Medicine (Chicago, IL). Written informed consent was obtained from all patients.

Intraoperative Management

The patients received a benzodiazepine, propofol, fentanyl, isoflurane, and a skeletal muscle relaxant for anesthesia. Cerebral blood flow autoregulation monitoring was performed after anesthesia induction using transcranial Doppler (Compumedics DWL, El Paso, TX) method as we have described.[16,17] Non-pulsatile cardiopulmonary bypass was conducted using a membrane oxygenator, flow of 2.0 to 2.4 L/min/m2, and using β-stat pH management. Arterial pH and PaCO2 were maintained within a normal range by continuous in-line monitoring calibrated with arterial blood gases. Patients were randomized after anesthesia induction to have their mean arterial blood pressure targets during cardiopulmonary bypass to be above the lower limit of autoregulation or based on usual institutional practice.[16] Blood pressure was raised with phenylephrine (100 mcg) and by reducing isoflurane concentrations to 0.7% after first ensuring target CPB flow. Patients and assessors were blinded to randomization group.

Neuropsychological and Neurological Evaluations

Neuropsychological testing was performed one to two days before surgery.[16,18] This testing was repeated one month (four to six weeks) after surgery during the patient's postoperative clinic visit with their surgeon. The cognitive testing battery evaluated domains reported to be adversely affected by cardiac surgery.[19] The battery consisted of the Rey Auditory Verbal Learning Test; Rey Complex Figure Test; Symbol Digit Modalities Test; Trail Making A and B; Controlled Oral Word Association Test; and the Grooved Pegboard Test as we have previously described.[16,18,20] The tests were grouped into the following cognitive domains: attention (Rey Auditory Verbal Learning Test I correct); memory (Rey Auditory Verbal Learning Test V correct, Rey Auditory Verbal Learning Test IX correct); visuoconstruction (Rey Complex Figure Test copy trial score); verbal fluency (Controlled Oral Word Association Test letters F, A, S); processing speed (Symbol Digit Modalities Test correct, Trail Making Test A); executive function (Trail Making Test B); and fine motor speed (Grooved Pegboard, dominant and non-dominant hand).[14,18] The Beck Depression Inventory was administered to assess depressive symptoms at each testing session.[21] This test is a 21-item questionnaire that assesses self-reported symptoms including such items as self-dislike, suicidal ideation, insomnia, and sadness. The score for each item ranges from 0–3 that are then summarized on a scale ranging from 0 to 63. Scores of 14–19, 20–28, 29–63 are considered to represent mild, moderate, and severe depression, respectively. A cut-off of > 13 was used as a dichotomous definition of depression. The patients were assessed at the same testing periods with the SF-36 short form of the RAND Medical Outcomes Study (MOS) health-related quality of life questionnaire.[22] This questionnaire is a multi-item scale that measures 8 health-related concepts: physical function, social function, physical role, emotional role, mental health, energy, pain, and general health perceptions. Anxiety was assessed using the Beck State-Trait Anxiety Inventory that assesses self-reported ratings of anxiety on a four-point Likert scale.[23] This inventory rates two types of anxiety: state anxiety or anxiety related to an event; and trait anxiety, or anxiety as a personal characteristic.

The patients were evaluated by their physicians and nurses daily for any acute mental status changes including abnormalities in arousal, memory, or cognition. A diagnosis of clinical delirium was entered into the medical record using International Classification of Diseases-10th Revision (Codes F05 or G93.40) criteria.


The primary outcomes were changes in cognitive function, defined as changes in Z-scores on each of the seven domains from baseline to one month postoperative time points. Secondary outcomes included the raw postoperative cognitive domain Z-scores, a composite postoperative neurocognitive dysfunction end-point, quality of life measurements, anxiety, and clinical complications (delirium, stroke, atrial fibrillation, intra-aortic balloon insertion, dialysis, multisystem organ failure, duration of ICU admission, duration of hospitalization, and death).[20] Postoperative neurocognitive dysfunction was defined by a clinically meaningful decline in cognitive function based on a change in composite Z-score, comprising all individual cognitive tests. Specifically, individual Z-scores were combined into a global Z-score at each time-point calculated from the average of the individual cognitive tests. These were then re-normalized using the mean and standard deviation of the tests at baseline.[20] Timed tests were multiplied by '-1' so that higher scores represented better performance. Prior studies have suggested that a decline in composite Z scores from baseline of 0.3 to 0.5 to be clinically important.[20,24] A difference between pre- and post-test > 0.3 was considered as postoperative neurocognitive dysfunction.[20]

Primary Exposure

The primary exposure was depressive symptomatology defined as a Beck Depression Inventory score > 13.