Anesthetics to Prevent Lung Injury in Cardiac Surgery: A Randomized Controlled Trial.

OBJECTIVES: To investigate if sevoflurane based anesthesia is superior to propofol in preventing lung inflammation and preventing postoperative pulmonary complications. DESIGN: Randomized controlled trial. SETTING: Single tertiary care university hospital. PARTICIPANTS: Forty adults undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized in a 1:1 ratio to anesthetic maintenance with sevoflurane or propofol. MEASUREMENTS AND MAIN RESULTS: Blood and bronchoalveolar lavage fluid was sampled before and after bypass to measure pulmonary inflammation using a biomarker panel. The change in bronchoalveolar lavage concentration of tumor necrosis factor alpha (TNFα) was the primary outcome. Secondary outcomes included lung inflammation defined as changes in other biomarkers and postoperative pulmonary complications. There were no significant differences between groups in the change in bronchoalveolar lavage TNFα concentration (median [IQR] change, 17.24 [1.11-536.77] v 101.51 [1.47-402.84] pg/mL, sevoflurane v propofol, p = 0.31). There was a significantly lower postbypass concentration of plasma interleukin 8 (median [IQR], 53.92 [34.5-55.91] v 66.92 [53.03-94.44] pg/mL, p = 0.04) and a significantly smaller postbypass increase in the plasma receptor for advanced glycosylation end products (median [IQR], 174.59 [73.59-446.06] v 548.22 [193.15-852.39] pg/mL, p = 0.03) in the sevoflurane group compared with propofol. The incidence of postoperative pulmonary complications was 100% in both groups, with high rates of pleural effusion (17/18 [94.44%] v 19/22 [86.36%], p = 0.39) and hypoxemia (16/18 [88.88%] v 22/22 [100%], p = 0.11). CONCLUSIONS: Sevoflurane anesthesia during cardiac surgery did not consistently prevent lung inflammation or prevent postoperative pulmonary complications compared to propofol. There were significantly lower levels of 2 plasma biomarkers specific for lung injury and inflammation in the sevoflurane group.

Prevention of Early Postoperative Decline: A Randomized, Controlled Feasibility Trial of Perioperative Cognitive Training.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction (POCD) are common after cardiac surgery and contribute to an increased risk of postoperative complications, longer length of stay, and increased hospital mortality. Cognitive training (CT) may be able to durably improve cognitive reserve in areas deficient in delirium and POCD and, therefore, may potentially reduce the risk of these conditions. We sought to determine the feasibility and potential efficacy of a perioperative CT program to reduce the incidence of postoperative delirium and POCD in older cardiac surgery patients. METHODS: Randomized controlled trial at a single tertiary care center. Participants included 45 older adults age 60-90 undergoing cardiac surgery at least 10 days from enrollment. Participants were randomly assigned in a 1:1 fashion to either perioperative CT via a mobile device or a usual care control. The primary outcome of feasibility was evaluated by enrollment patterns and adherence to protocol. Secondary outcomes of postoperative delirium and POCD were assessed using the Confusion Assessment Method and the Montreal Cognitive Assessment, respectively. Patient satisfaction was assessed via a postoperative survey. RESULTS: Sixty-five percent of eligible patients were enrolled. Median (interquartile range [IQR]) adherence (as a percentage of prescribed minutes played) was 39% (20%-68%), 6% (0%-37%), and 19% (0%-56%) for the preoperative, immediate postoperative, and postdischarge periods, respectively. Median (IQR) training times were 245 (136-536), 18 (0-40), and 122 (0-281) minutes for each period, respectively. The incidence of postoperative delirium (CT group 5/20 [25%] versus control 3/20 [15%]; P = .69) and POCD (CT group 53% versus control 37%; P = .33) was not significantly different between groups for either outcome in this limited sample. CT participants reported a high level of agreement (on a scale of 0-100) with statements that the program was easy to use (median [IQR], 87 [75-97]) and enjoyable (85 [79-91]). CT participants agreed significantly more than controls that their memory (median [IQR], 75 [54-82] vs 51 [49-54]; P = .01) and thinking ability (median [IQR], 78 [64-83] vs 50 [41-68]; P = .01) improved as a result of their participation in the study. CONCLUSIONS: A CT program designed for use in the preoperative period is an attractive target for future investigations of cognitive prehabilitation in older cardiac surgery patients. Changes in the functionality of the program and enrichment techniques may improve adherence in future trials. Further investigation is necessary to determine the potential efficacy of cognitive prehabilitation to reduce the risk of postoperative delirium and POCD.

Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial.

Importance: Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative. Objective: To evaluate the effect of postoperative intravenous (IV) acetaminophen (paracetamol) vs placebo combined with IV propofol vs dexmedetomidine on postoperative delirium among older patients undergoing cardiac surgery. Design, Setting, and Participants: Randomized, placebo-controlled, factorial clinical trial among 120 patients aged 60 years or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries at a US center. Enrollment was September 2015 to April 2018, with follow-up ending in April 2019. Interventions: Patients were randomized to 1 of 4 groups receiving postoperative analgesia with IV acetaminophen or placebo every 6 hours for 48 hours and postoperative sedation with dexmedetomidine or propofol starting at chest closure and continued for up to 6 hours (acetaminophen and dexmedetomidine: n = 29; placebo and dexmedetomidine: n = 30; acetaminophen and propofol: n = 31; placebo and propofol: n = 30). Main Outcomes and Measures: The primary outcome was incidence of postoperative in-hospital delirium by the Confusion Assessment Method. Secondary outcomes included delirium duration, cognitive decline, breakthrough analgesia within the first 48 hours, and ICU and hospital length of stay. Results: Among 121 patients randomized (median age, 69 years; 19 women [15.8%]), 120 completed the trial. Patients treated with IV acetaminophen had a significant reduction in delirium (10% vs 28% placebo; difference, -18% [95% CI, -32% to -5%]; P = .01; HR, 2.8 [95% CI, 1.1-7.8]). Patients receiving dexmedetomidine vs propofol had no significant difference in delirium (17% vs 21%; difference, -4% [95% CI, -18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]). There were significant differences favoring acetaminophen vs placebo for 3 prespecified secondary outcomes: delirium duration (median, 1 vs 2 days; difference, -1 [95% CI, -2 to 0]), ICU length of stay (median, 29.5 vs 46.7 hours; difference, -16.7 [95% CI, -20.3 to -0.8]), and breakthrough analgesia (median, 322.5 vs 405.3 µg morphine equivalents; difference, -83 [95% CI, -154 to -14]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 328.8 vs 397.5 µg; difference, -69 [95% CI, -155 to -4]; P = .04). Fourteen patients in both the placebo-dexmedetomidine and acetaminophen-propofol groups (46% and 45%) and 7 in the acetaminophen-dexmedetomidine and placebo-propofol groups (24% and 23%) had hypotension. Conclusions and Relevance: Among older patients undergoing cardiac surgery, postoperative scheduled IV acetaminophen, combined with IV propofol or dexmedetomidine, reduced in-hospital delirium vs placebo. Additional research, including comparison of IV vs oral acetaminophen and other potentially opioid-sparing analgesics, on the incidence of postoperative delirium is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02546765.

Investigation of a Mobile Health Texting Tool for Embedding Patient-Reported Data Into Diabetes Management (i-Matter): Development and Usability Study.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly being used in the management of type 2 diabetes (T2D) to integrate data from patients' perspective into clinical care. To date, the majority of PRO tools have lacked patient and provider involvement in their development, thus failing to meet the unique needs of end users, and lack the technical infrastructure to be integrated into the clinic workflow. OBJECTIVE: This study aims to apply a systematic, user-centered design approach to develop i-Matter (investigating a mobile health [mHealth] texting tool for embedding patient-reported data into diabetes management), a theory-driven, mobile PRO system for patients with T2D and their primary care providers. METHODS: i-Matter combines text messaging with dynamic data visualizations that can be integrated into electronic health records (EHRs) and personalized patient reports. To build i-Matter, we conducted semistructured group and individual interviews with patients with T2D and providers, a design thinking workshop to refine initial ideas and design the prototype, and user testing sessions of prototypes using a rapid-cycle design (ie, design-test-modify-retest). RESULTS: Using an iterative user-centered process resulted in the identification of 6 PRO messages that were relevant to patients and providers: medication adherence, dietary behaviors, physical activity, sleep quality, quality of life, and healthy living goals. In user testing, patients recommended improvements to the wording and timing of the PRO text messages to increase clarity and response rates. Patients also recommended including motivational text messages to help sustain engagement with the program. The personalized report was regarded as a key tool for diabetes self-management by patients and providers because it aided in the identification of longitudinal patterns in the PRO data, which increased patient awareness of their need to adopt healthier behaviors. Patients recommended adding individualized tips to the journal on how they can improve their behaviors. Providers preferred having a separate tab built into the EHR that included the personalized report and highlighted key trends in patients' PRO data over the past 3 months. CONCLUSIONS: PRO tools that capture patients' well-being and the behavioral aspects of T2D management are important to patients and providers. A clinical trial will test the efficacy of i-Matter in 282 patients with uncontrolled T2D. TRIAL REGISTRATION: ClinicalTrials.gov NCT03652389; https://clinicaltrials.gov/ct2/show/NCT03652389.

Nocturnal heart rate variability moderates the association between sleep-wake regularity and mood in young adults.

STUDY OBJECTIVES: Sleep-wake regularity (SWR) is often disrupted in college students and mood disorders are rife at this age. Disrupted SWR can cause repetitive and long-term misalignment between environmental and behavioral cycles and the circadian system which may then have psychological and physical health consequences. We tested whether SWR was independently associated with mood and autonomic function in a healthy adult cohort. METHODS: We studied 42 college students over a 3 week period using daily sleep-wake diaries and continuous electrocardiogram recordings. Weekly SWR was quantified by the interdaily stability of sleep-wake times (ISSW) and mood was assessed weekly using the Beck Depression Inventory-II. To assess autonomic function, we quantified the high-frequency (HF) power of heart rate variability (HRV). Linear mixed effects models were used to assess the relationship between repeated weekly measures of mood, SWR, and HF. RESULTS: Low weekly ISSW predicted subsequent poor mood and worsening mood independently of age, sex, race, sleep duration, and physical activity. Although no association was found between ISSW and HF, the ISSW-mood association was significantly moderated by nocturnal HF, i.e. reported mood was lowest after a week with low ISSW and high HF. Prior week mood scores did not significantly predict the subsequent week's ISSW. CONCLUSIONS: Irregular sleep-wake timing appears to precede poor mood in young adults. Further work is needed to understand the implications of high nocturnal HRV in those with low mood and irregular sleep-wake cycles.

Guided meditation as an adjunct to enhance postoperative recovery after cardiac surgery: study protocol for a prospective randomized controlled feasibility trial.

BACKGROUND: Cardiac surgical procedures are associated with postoperative neurological complications such as cognitive decline and delirium, which can complicate recovery and impair quality of life. Perioperative depression and anxiety may be associated with increased mortality after cardiac surgeries. Surgical prehabilitation is an emerging concept that includes preoperative interventions to potentially reduce postoperative complications. While most current prehabilitation interventions focus on optimizing physical health, mind-body interventions are an area of growing interest. Preoperative mind-body interventions such as Isha Kriya meditation, may hold significant potential to improve postsurgical outcomes. METHODS: This is a prospective, randomized controlled feasibility trial. A total of 40 adult patients undergoing cardiac surgery will be randomized to one of three study groups. Participants randomized to either of the two intervention groups will receive meditative intervention: (1) commencing two weeks before surgery; or (2) commencing only from the day after surgery. Meditative intervention will last for four weeks after the surgery in these groups. Participants in the third control group will receive the current standard of care with no meditative intervention. All participants will undergo assessments using neurocognitive, sleep, depression, anxiety, and pain questionnaires at various time points in the perioperative period. Blood samples will be collected at baseline, preoperatively, and postoperatively to assess for inflammatory biomarkers. The primary aim of this trial is to assess the feasibility of implementing a perioperative meditative intervention program. Other objectives include studying the effect of meditation on postoperative pain, sleep, psychological wellbeing, cognitive function, and delirium. These will be used to calculate effect size to design future studies. DISCUSSION: This study serves as the first step towards understanding the feasibility of implementing a mind-body intervention as a prehabilitative intervention to improve postoperative surgical outcomes after cardiac surgery. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03198039 . Registered on 23 June 2017.

Dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial.

BACKGROUND: Postoperative delirium is common in elderly cardiac surgery patients. It is multifactorial and is influenced by the patient's baseline status and the nature of the medical and surgical interventions that the patient receives. Some of these factors are potentially modifiable, including postoperative sedation and analgesia protocols. This study has been designed to evaluate the effectiveness of postoperative intravenous acetaminophen in conjunction with either dexmedetomidine or propofol in decreasing the incidence of delirium. METHODS: This is a prospective, randomized, placebo-controlled, double-blinded, factorial trial that includes patients who are at least 60 years old and who are undergoing cardiac surgeries involving cardiopulmonary bypass, including coronary artery bypass graft (CABG) and combined CABG/valve surgeries. Patients are randomly assigned to receive one of four postoperative analgesic-sedation regimens: (1) acetaminophen and dexmedetomidine, (2) acetaminophen and propofol, (3) dexmedetomidine and placebo, or (4) propofol and placebo. The primary outcome, incidence of delirium, will be assessed with the Confusion Assessment Method (CAM or CAM-ICU). The secondary outcome, postoperative cognitive decline, will be assessed with the Montreal Cognitive Assessment. Additional secondary outcomes, including duration of delirium, postoperative analgesic requirement, length of stay, and incidence of adverse events, will also be reported. Data will be analyzed in 120 randomly assigned patients who received at least one dose of the study medication(s) on a modified intention-to-treat basis. DISCUSSION: This study has been approved by the institutional review board at Beth Israel Deaconess Medical Center, and the trial is currently recruiting. This study will systematically examine the implications of modification in postoperative sedative/analgesic protocols after cardiac surgery, specifically for short- and long-term cognitive outcomes. Any positive outcomes from this study could direct simple yet effective practice changes aimed to reduce morbidity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02546765 , registered January 13, 2015.

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.

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.

Reduced Tolerance to Night Shift in Chronic Shift Workers: Insight From Fractal Regulation.

Study Objectives: Healthy physiology is characterized by fractal regulation (FR) that generates similar structures in the fluctuations of physiological outputs at different time scales. Perturbed FR is associated with aging and age-related pathological conditions. Shift work, involving repeated and chronic exposure to misaligned environmental and behavioral cycles, disrupts circadian coordination. We tested whether night shifts perturb FR in motor activity and whether night shifts affect FR in chronic shift workers and non-shift workers differently. Methods: We studied 13 chronic shift workers and 14 non-shift workers as controls using both field and in-laboratory experiments. In the in-laboratory study, simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and the sleep-wake cycles (ie, circadian misalignment) while environmental conditions and food intake were controlled. Results: In the field study, we found that FR was robust in controls but broke down in shift workers during night shifts, leading to more random activity fluctuations as observed in patients with dementia. The night shift effect was present even 2 days after ending night shifts. The in-laboratory study confirmed that night shifts perturbed FR in chronic shift workers and showed that FR in controls was more resilience to the circadian misalignment. Moreover, FR during real and simulated night shifts was more perturbed in those who started shift work at older ages. Conclusions: Chronic shift work causes night shift intolerance, which is probably linked to the degraded plasticity of the circadian control system.

Anterior Insula Regulates Multiscale Temporal Organization of Sleep and Wake Activity.

The role of specific cortical regions in sleep-regulating circuits is unclear. The anterior insula (AI) has strong reciprocal connectivity with wake and sleep-promoting hypothalamic and brainstem regions, and we hypothesized that the AI regulates patterns of sleep and wakefulness. To test this hypothesis, we lesioned the AI in rats (n = 8) and compared sleep, wake, and activity regulation in these animals with nonlesioned controls (n = 8) with 24-h sleep recordings and chronic infrared activity monitoring. Compared to controls, animals with AI lesions had decreased wakefulness and increased rapid eye movement (REM) sleep and non-REM (NREM) sleep. AI-lesioned animals had shorter wake bouts, especially during the active dark phase. AI-lesioned animals also had more transitions from NREM to REM sleep, especially during the inactive light phase. Chronic infrared monitoring revealed that AI-lesioned animals also had a disturbed temporal organization of locomotor activity at multiple time scales with more random activity fluctuations from 4 to 12 h despite intact circadian rhythms. These results suggest that the AI regulates sleep and activity and contributes to the regulation of sleep and motor behavior rhythmicity across multiple time scales. Dysfunction of the AI may underlie changes in sleep-wake patterns in neurological diseases.

Progression of Dementia Assessed by Temporal Correlations of Physical Activity: Results From a 3.5-Year, Longitudinal Randomized Controlled Trial.

Cross-sectional studies show that activity fluctuations in healthy young adults possess robust temporal correlations that become altered with aging, and in dementia and depression. This study was designed to test whether or not within-subject changes of activity correlations (i) track the clinical progression of dementia, (ii) reflect the alterations of depression symptoms in patients with dementia, and (iii) can be manipulated by clinical interventions aimed at stabilizing circadian rhythmicity and improving sleep in dementia, namely timed bright light therapy and melatonin supplementation. We examined 144 patients with dementia (70-96 years old) who were assigned to daily treatment with bright light, bedtime melatonin, both or placebos only in a 3.5-year double-blinded randomized clinical trial. We found that activity correlations at temporal scales <~2 hours significantly decreased over time and that light treatment attenuated the decrease by ~73%. Moreover, the decrease of temporal activity correlations positively correlated with the degrees of cognitive decline and worsening of mood though the associations were relatively weak. These results suggest a mechanistic link between multiscale activity regulation and circadian/sleep function in dementia patients. Whether temporal activity patterns allow unobtrusive, long-term monitoring of dementia progression and mood changes is worth further investigation.