The Feasibility and Validity of Objective and Patient-Reported Measurements of Cognition During Early Critical Illness Recovery.

BACKGROUND: Cognitive outcomes are an important determinant of quality of life after critical illness, but methods to assess early cognitive impairment and cognition recovery are not established. The objective of this study was to assess the feasibility and validity of objective and patient-reported cognition assessments for generalized use during early recovery from critical illness. METHODS: Patients presented from the community with acute onset of either intracerebral hemorrhage (ICH) or sepsis as representative neurologic and systemic critical illnesses. Early cognitive assessments comprised the Glasgow Coma Scale (GCS), three NIH Toolbox cognition measures (Flanker Inhibitory Control and Attention Test, List Sorting Working Memory Test and Pattern Comparison Processing Speed Test) and two Patient Reported Outcomes Measurement Information System (PROMIS) cognition measures (Cognition-General Concerns and Cognition-Abilities) performed seven days after intensive care unit discharge or at hospital discharge, whichever occurred first. RESULTS: We enrolled 91 patients (53 with sepsis, 38 with ICH), and after attrition principally due to deaths, cognitive assessments were attempted in 73 cases. Median [interquartile range] Sequential Organ Failure Assessment scores for patients with sepsis was 7 [3, 11]. ICH cases included 13 lobar, 21 deep and 4 infratentorial hemorrhages with a median [IQR] ICH Score 2 [1, 2]. Patient-reported outcomes were successfully obtained in 42 (58% overall, 79% of sepsis and 34% of ICH) patients but scores were anomalously favorable (median 97th percentile compared to the general adult population). Analysis of the PROMIS item bank by four blinded, board-certified academic neurointensivists revealed a strong correlation between higher severity of reported symptoms and greater situational relevance of the items (ρ = 0.72, p = 0.002 correlation with expert item assessment), indicating poor construct validity in this population. NIH Toolbox tests were obtainable in only 9 (12%) patients, all of whom were unimpaired by GCS (score 15) and completed PROMIS assessments. Median scores were 5th percentile (interquartile range [2nd, 9th] percentile) and uncorrelated with self-reported symptoms. Shorter intensive care unit length of stay was associated with successful testing in both patients with ICH and sepsis, along with lower ICH Score in patients with ICH and absence of premorbid dementia in patients with sepsis (all p < 0.05). CONCLUSIONS: Methods of objective and patient-reported cognitive testing that have been validated for use in patients with chronic medical and neurologic illness were infeasible or yielded invalid results among a general sample of patients in this study who were in early recovery from neurologic and systemic critical illness. Longer critical illness duration and worse neurocognitive impairments, whether chronic or acute, reduced testing feasibility.

Stress-Induced Behavioral Quiescence and Abnormal Rest-Activity Rhythms During Critical Illness.

OBJECTIVES: To characterize acute alterations of circadian and ultradian rest-activity rhythms in critically ill patients and their association with brain dysfunction, systemic multiple organ dysfunction, and melatonin rhythms. DESIGN: Prospective study observing a cohort for 48 hours beginning within the first day of ICU admission. SETTING: ICUs within an academic medical center. PATIENTS: Patients presenting from the community with acute onset of either intracerebral hemorrhage or sepsis as representative neurologic and systemic critical illnesses. Healthy control patients were studied in the community, during hospital bedrest, and during sleep deprivation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Circadian and ultradian characteristics of rest-activity patterns were measured by wrist actigraphy, severity of neurologic and systemic illness by Glasgow Coma Scale and Sequential Organ Failure Assessment, and central circadian rhythm by melatonin profile. We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage, along with 53 control participants. Total daily activity was markedly reduced and rest-activity rhythmicity was undetectable, neither of which was replicated by hospital bedrest in healthy controls. Circadian rest-activity rhythm fragmentation and attenuation and ultradian disorganization was associated with Glasgow Coma Scale and Sequential Organ Failure Assessment in adjusted models. Rest-activity rhythms showed no detectable phase coherence with melatonin rhythms. CONCLUSIONS: Critically ill patients rapidly enter a state of behavioral quiescence proportionate to their illness severity with concomitant disturbance of circadian and ultradian rest-activity rhythms and loss of phase coherence with the melatonin rhythm. Quiescence characteristics in rest-activity rhythms were not different in patients with and without delirium, suggesting them to be distinct phenomena. Animal models of severe physiologic stress have shown that specific neural pathway separate from the sleep-wake regulatory pathway induce behavioral quiescence and rest-activity arrhythmia, and facilitate recovery of cellular homeostasis. Whether quiescence is a conserved protective response pathway in humans is not yet understood.

Factors Disrupting Melatonin Secretion Rhythms During Critical Illness.

OBJECTIVES: The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile. DESIGN: Prospective study observing a cohort for 24-48 hours beginning within the first day of ICU admission. SETTING: Multiple specialized ICUs within an academic medical center. PATIENTS: Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2. CONCLUSIONS: Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.

Multisite validation of a simple electronic health record algorithm for identifying diagnosed obstructive sleep apnea.

STUDY OBJECTIVES: We examined the performance of a simple algorithm to accurately distinguish cases of diagnosed obstructive sleep apnea (OSA) and noncases using the electronic health record (EHR) across six health systems in the United States. METHODS: Retrospective analysis of EHR data was performed. The algorithm defined cases as individuals with ≥ 2 instances of specific International Classification of Diseases (ICD)-9 and/or ICD-10 diagnostic codes (327.20, 327.23, 327.29, 780.51, 780.53, 780.57, G4730, G4733 and G4739) related to sleep apnea on separate dates in their EHR. Noncases were defined by the absence of these codes. Using chart reviews on 120 cases and 100 noncases at each site (n = 1,320 total), positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: The algorithm showed excellent performance across sites, with a PPV (95% confidence interval) of 97.1 (95.6, 98.2) and NPV of 95.5 (93.5, 97.0). Similar performance was seen at each site, with all NPV and PPV estimates ≥ 90% apart from a somewhat lower PPV of 87.5 (80.2, 92.8) at one site. A modified algorithm of ≥ 3 instances improved PPV to 94.9 (88.5, 98.3) at this site, but excluded an additional 18.3% of cases. Thus, performance may be further improved by requiring additional codes, but this reduces the number of determinate cases. CONCLUSIONS: A simple EHR-based case-identification algorithm for diagnosed OSA showed excellent predictive characteristics in a multisite sample from the United States. Future analyses should be performed to understand the effect of undiagnosed disease in EHR-defined noncases. This algorithm has wide-ranging applications for EHR-based OSA research.

Strengthening sleep-autonomic interaction via acoustic enhancement of slow oscillations.

Slow-wave sleep (SWS) is important for overall health since it affects many physiological processes including cardio-metabolic function. Sleep and autonomic nervous system (ANS) activity are closely coupled at anatomical and physiological levels. Sleep-related changes in autonomic function are likely the main pathway through which SWS affects many systems within the body. There are characteristic changes in ANS activity across sleep stages. Notably, in non-rapid eye-movement sleep, the progression into SWS is characterized by increased parasympathetic activity, an important measure of cardiovascular health. Experimental manipulations that enhance slow-wave activity (SWA, 0.5-4 Hz) can improve sleep-mediated memory and immune function. However, effects of SWA enhancement on autonomic regulation have not been investigated. Here, we employed an adaptive algorithm to deliver 50 ms sounds phase-locked to slow-waves, with regular pauses in stimulation (~5 s ON/~5 s OFF), in healthy young adults. We sought to determine whether acoustic enhancement of SWA altered parasympathetic activity during SWS assessed with heart rate variability (HRV), and evening-to-morning changes in HRV, plasma cortisol, and blood pressure. Stimulation, compared with a sham condition, increased SWA during ON versus OFF intervals. This ON/OFF SWA enhancement was associated with a reduction in evening-to-morning change of cortisol levels and indices of sympathetic activity. Furthermore, the enhancement of SWA in ON intervals during sleep cycles 2-3 was accompanied by an increase in parasympathetic activity (high-frequency, HRV). Together these findings suggest that acoustic enhancement of SWA has a positive effect on autonomic function in sleep. Approaches to strengthen brain-heart interaction during sleep could have important implications for cardiovascular health.