Objectively measured sleep fragmentation is associated with incident delirium in older hospitalized patients: Analysis of data collected from an randomized controlled trial.

Delirium may lead to poor outcomes in hospitalized older adults, and sleep deprivation may contribute to its pathogenesis. Thus, we sought to measure sleep duration and fragmentation using wrist-worn actigraphy in older, hospitalized patients with and without delirium, and to determine if actigraphy-based parameters could be used to predict delirium prior to clinical recognition. We conducted a secondary analysis of data from a recent, randomized clinical trial aimed at preventing inpatient delirium. Participants (n = 70) were aged ≥ 65 years admitted to an internal medicine service. Delirium was defined by the Confusion Assessment Method, or altered mental status identified by a clinician. Sleep measurements were actigraphy-based, and included total sleep time, median sleep bout duration and other measures of sleep fragmentation. We found that total sleep duration was similar between patients with (n = 17) and without (n = 53) delirium (mean 384.9 ± SD 162.7 versus mean 456.6 ± SD 135.8 min; p = .081). Mean sleep bout times were shorter in delirious versus never-delirious patients (median 6.1 [interquartile range 4.3-8.9] versus 7.9 [interquartile range 5.7-11.3] min, p = .048). Patients with delirium had more short sleep bouts (< 10 min) and fewer longer sleep bouts (> 30 min) compared with those without delirium. Increased sleep fragmentation was present prior to the clinical recognition of delirium. Overall, delirium was associated with increased sleep fragmentation detected by actigraphy, and sleep fragmentation might be useful as a biomarker for delirium prediction in the future.

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy.

OBJECTIVES: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN: Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING: Academic medical center in La Jolla, California. PATIENTS: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

Developmental nicotine exposure alters AMPA neurotransmission in the hypoglossal motor nucleus and pre-Botzinger complex of neonatal rats.

Developmental nicotine exposure (DNE) impacts central respiratory control in neonates born to smoking mothers. We previously showed that DNE enhances the respiratory motor response to bath application of AMPA to the brainstem, although it was unclear which brainstem respiratory neurons mediated these effects (Pilarski and Fregosi, 2009). Here we examine how DNE influences AMPA-type glutamatergic neurotransmission in the pre-Bötzinger complex (pre-BötC) and the hypoglossal motor nucleus (XIIMN), which are neuronal populations located in the medulla that are necessary for normal breathing. Using rhythmic brainstem slices from neonatal rats, we microinjected AMPA into the pre-BötC or the XIIMN while recording from XII nerve rootlets (XIIn) as an index of respiratory motor output. DNE increased the duration of tonic activity and reduced rhythmic burst amplitude after AMPA microinjection into the XIIMN. Also, DNE led to an increase in respiratory burst frequency after AMPA injection into the pre-BötC. Whole-cell patch-clamp recordings of XII motoneurons showed that DNE increased motoneuron excitability but did not change inward currents. Immunohistochemical studies indicate that DNE reduced the expression of glutamate receptor subunits 2 and 3 (GluR2/3) in the XIIMN and the pre-BötC. Our data show that DNE alters AMPAergic synaptic transmission in both the XIIMN and pre-BötC, although the mechanism by which this occurs is unclear. We suggest that the DNE-induced reduction in GluR2/3 may represent an attempt to compensate for increased cell excitability, consistent with mechanisms underlying homeostatic plasticity.

Objectively measured peri-vaccination sleep does not predict COVID-19 breakthrough infection.

Prior studies have shown that sleep duration peri-vaccination influences an individual's antibody response. However, whether peri-vaccination sleep affects real-world vaccine effectiveness is unknown. Here, we tested whether objectively measured sleep around COVID-19 vaccination affected breakthrough infection rates. DETECT is a study of digitally recruited participants who report COVID-19-related information, including vaccination and illness data. Objective sleep data are also recorded through activity trackers. We compared the impact of sleep duration, sleep efficiency, and frequency of awakenings on reported breakthrough infection after the 2nd vaccination and 1st COVID-19 booster. Logistic regression models were created to examine if sleep metrics predicted COVID-19 breakthrough infection independent of age and gender. Self-reported breakthrough COVID-19 infection following 2nd COVID-19 vaccination and 1st booster. 256 out of 5265 individuals reported a breakthrough infection after the 2nd vaccine, and 581 out of 2583 individuals reported a breakthrough after the 1st booster. There was no difference in sleep duration between those with and without breakthrough infection. Increased awakening frequency was associated with breakthrough infection after the 1st booster with 3.01 ± 0.65 awakenings/hour in the breakthrough group compared to 2.82 ± 0.65 awakenings/hour in those without breakthrough (P < 0.001). Cox proportional hazards modeling showed that age < 60 years (hazard ratio 2.15, P < 0.001) and frequency of awakenings (hazard ratio 1.17, P = 0.019) were associated with breakthrough infection after the 1st booster. Sleep duration was not associated with breakthrough infection after COVID vaccination. While increased awakening frequency during sleep was associated with breakthrough infection beyond traditional risk factors, the clinical implications of this finding are unclear.

Actigraphy-based sleep and activity measurements in intensive care unit patients randomized to ramelteon or placebo for delirium prevention.

Patients in the ICU often sleep poorly for various reasons, which may predispose to delirium. We previously conducted a clinical trial in which we tested the efficacy of ramelteon, a melatonin-receptor agonist used to treat insomnia, versus placebo, in preventing ICU delirium in patients who underwent elective pulmonary thromboendarterectomy (PTE) surgery. Here we examine sleep, activity, and circadian patterns, measured with actigraphy, to understand changes in these metrics with our intervention and in those with and without delirium. Participants wore wrist actigraphy devices while recovering post-operatively in the ICU. For sleep analysis, we extracted total sleep time and sleep fragmentation metrics over the 22:00 to 06:00 period nightly, and daytime nap duration from the daytime period (0:600 to 22:00) for each participant. For activity analyses, we extracted the following metrics: total daytime activity count (AC), maximum daytime AC, total nighttime AC, and maximum nighttime AC. Next, we performed a nonparametric circadian analysis on ACs over each 24-h day and extracted the following: interdaily stability (IS), intra-daily variability (IV), relative amplitude (RA), and low and high periods of activity (L5 and M10) as well as their start times. These metrics were compared between patients who received ramelteon versus placebo, and between patients who became delirious versus those who did not develop delirium. We additionally made comparisons between groups for daytime and nighttime light levels. No differences in sleep, activity, circadian metrics or light levels were found between drug groups. Delirious patients, when compared to those who were never delirious, had a lower IS (0.35 ± 0.16 vs. 0.47 ± 0.23; P = 0.006). Otherewise, no differences in IV, L5, M10, or RA were found between groups. L5 and M10 activity values increased significantly over the post-extubation for the whole cohort. No differences were found for daytime or nighttime light levels between groups. Overall, ramelteon did not impact sleep or circadian metrics in this cohort. Consistent with clinical experience, delirious patients had less inter-daily stability in their rest-activity rhythms. These data suggest that actigraphy might have value for individual assessment of sleep in the ICU, and for determining and detecting the impact of interventions directed at improving sleep and circadian activity rhythms in the ICU.Trial registration: REGISTERED at CLINICALTRIALS.GOV: NCT02691013. Registered on February 24, 2016 by principal investigator, Dr. Robert L. Owens.

The freshman sleep and health (FRoSH) study: Examining sleep and weight gain in incoming college freshmen.

OBJECTIVE: Examine how changes in sleep duration, objectively measured by activity trackers, impact weight gain in incoming college freshman. Participants: Incoming college freshmen, age ≥ 18. Methods: We measured weight and daily sleep duration before college entry and through the 1st college quarter. Additionally, we examined changes in sleep variability, activity levels and smartphone screen time use as possible predictors of weight gain. Results: 75 participants completed the study. Total sleep duration decreased from 437.9 ± SD 57.3 minutes at baseline to 416.5 ± SD 68.6 minutes by the end of the first quarter (p = 6.6 × 10-3). (BMI) did not change significantly in this cohort. Higher sleep variability at baseline and an increase in sleep variability were associated with increases in BMI. Smartphone screen use was note to be high (235.2 ± SD 110.3 minutes/day) at the end of the first quarter. Conclusions: College weight gain may be affected by factors other than sleep duration, including sleep variability.Supplemental data for this article can be accessed online at https://doi.org/10.1080/07448481.2022.2032720.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

Background: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods: The Pass ive I mmunity T rial for O ur N ation (PassITON), is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the United States to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial Registration: ClinicalTrials.gov: NCT04362176. Date of trial registration: April 24, 2020, https://clinicaltrials.gov/ct2/show/NCT04362176.

Melatonin and Sleep in Preventing Hospitalized Delirium: A Randomized Clinical Trial.

PURPOSE: Studies suggest that melatonin may prevent delirium, a condition of acute brain dysfunction occurring in 20%-30% of hospitalized older adults that is associated with increased morbidity and mortality. We examined the effect of melatonin on delirium prevention in hospitalized older adults while measuring sleep parameters as a possible underlying mechanism. METHODS: This was a randomized clinical trial measuring the impact of 3 mg of melatonin nightly on incident delirium and both objective and subjective sleep in inpatients age ≥65 years, admitted to internal medicine wards (non-intensive care units). Delirium incidence was measured by bedside nurses using the confusion assessment method. Objective sleep measurements (nighttime sleep duration, total sleep time per 24 hours, and sleep fragmentation as determined by average sleep bout length) were obtained via actigraphy. Subjective sleep quality was measured using the Richards Campbell Sleep Questionnaire. RESULTS: Delirium occurred in 22.2% (8/36) of subjects who received melatonin vs in 9.1% (3/33) who received placebo (P = .19). Melatonin did not significantly change objective or subjective sleep measurements. Nighttime sleep duration and total sleep time did not differ between subjects who became delirious vs those who did not, but delirious subjects had more sleep fragmentation (sleep bout length 7.0 ± 3.0 vs 9.5 ± 5.3 min; P = .03). CONCLUSIONS: Melatonin given as a nightly dose of 3 mg did not prevent delirium in non-intensive care unit hospitalized patients or improve subjective or objective sleep.

Raising awareness about sleep disorders.

Sleep disorders affect a substantial number of people worldwide and may be increasing in prevalence. Unfortunately, many of these disorders can go unrecognized and untreated in clinical practice. Although physicians understand that good sleep is essential to patient health, approaching the issue is often glossed over in the primary care setting. Importantly, recent data also suggest that sleep disorders are becoming increasingly recognized in developing nations. Here, we review the pertinent features and treatment of some of the major sleep disorders, including obstructive sleep apnea, central sleep apnea, insomnia, and others, that affect patient health. We aim to promote clinician and public awareness of various sleep disorders with the intent of increasing rates of recognition and treatment.

Sound and Light Levels Are Similarly Disruptive in ICU and non-ICU Wards.

OBJECTIVE: To compare ambient sound and light levels, including SLCs, in ICU and non-ICU environments. DESIGN: Observational study. SETTING: Tertiary-care hospital. MEASUREMENTS: Sound measurements of 0.5 Hz were analyzed to provide average hourly sound levels, sound peaks, and SLCs =17.5 decibels (dB). For light data, measurements taken at 2-minute intervals provided average and maximum light levels. RESULTS: The ICU rooms were louder than non-ICU wards; hourly averages ranged from 56.1 ± 1.3 dB to 60.3 ± 1.7 dB in the ICU, 47.3 ± 3.7 dB to 55.1 ± 3.7 dB on the telemetry floor, and 44.6 ± 2.1 dB to 53.7 ± 3.6 dB on the general ward. However, SLCs = 17.5 dB were not statistically different (ICU, 203.9 ± 28.8 times; non-ICU, 270.9 ± 39.5; P = 0.11). In both ICU and non-ICU wards, average daytime light levels were <250 lux, and peak light levels occurred in the afternoon and early evening. CONCLUSIONS: Quieter, non-ICU wards have as many SLCs as ICUs do, which has implications for quality improvement measurements. Efforts to further reduce average noise levels might be counterproductive. Light levels in the hospital (ICU and non-ICU) may not be optimal for maintenance of a normal circadian rhythm for most people.

Developmental nicotine exposure enhances inhibitory synaptic transmission in motor neurons and interneurons critical for normal breathing.

Nicotine exposure in utero negatively affects neuronal growth, differentiation, and synaptogenesis. We used rhythmic brainstems slices and immunohistochemistry to determine how developmental nicotine exposure (DNE) alters inhibitory neurotransmission in two regions essential to normal breathing, the hypoglossal motor nucleus (XIIn), and preBötzinger complex (preBötC). We microinjected glycine or muscimol (GABAA agonist) into the XIIn or preBötC of rhythmic brainstem slices from neonatal rats while recording from XII nerve roots to obtain XII motoneuron population activity. Injection of glycine or muscimol into the XIIn reduced XII nerve burst amplitude, while injection into the preBötC altered nerve burst frequency. These responses were exaggerated in preparations from DNE animals. Quantitative immunohistochemistry revealed a significantly higher GABAA receptor density on XII motoneurons from DNE pups. There were no differences in GABAA receptor density in the preBötC, and there were no differences in glycine receptor expression in either region. Nicotine, in the absence of other chemicals in tobacco smoke, alters normal development of brainstem circuits that are critical for normal breathing.