Sleep in the intensive and intermediate care units: Exploring related factors of delirium, benzodiazepine use and mortality.

AIM OF THE STUDY: The primary purpose was to examine sleep difficulties and delirium in the Intensive and Intermediate Care Unit. Secondarily, factors impacting night-time sleep duration and quality, mortality, and the impact of benzodiazepine use on sleep outcomes were investigated. MATERIALS AND METHODS: This retrospective study encompassed data from 323 intensive and intermediate care unit admissions collected in the Netherlands, spanning from November 2018 to May 2020. Sleep quality was measured using the Richards-Campbell Sleep Questionnaire. Night-time sleep duration was nurse-reported. We investigated associations of these sleep outcomes with age, sex, length-of-stay, natural daylight, disease severity, mechanical ventilation, benzodiazepine use, and delirium using Generalized Estimating Equations models. Associations with one-year post-discharge mortality were analyzed using Cox regression. RESULTS: Night-time sleep duration was short (median 4.5 hours) and sleep quality poor (mean score 4.9/10). Benzodiazepine use was common (24 % of included nights) and was negatively associated with night-time sleep duration and quality (B = -0.558 and -0.533, p <.001). Delirium and overnight transfers were negatively associated with sleep quality (B = -0.716 and -1.831, p <.05). The day-to-night sleep ratio was higher in the three days before delirium onset than in non-delirious individuals (p <.05). Age, disease severity and female sex were associated with increased one-year mortality. Sleep quality was negatively, but not-significantly, associated with mortality (p =.070). CONCLUSIONS: Night-time sleep in the critical care environment has a short duration and poor quality. Benzodiazepine use was not associated with improved sleep. Sleep patterns change ahead of delirium onset. IMPLICATIONS FOR CLINICAL PRACTICE: Consistent sleep monitoring should be part of routine nursing practice, using a validated instrument like the Richards-Campbell Sleep Questionnaire. Given the lack of proven efficacy of benzodiazepines in promoting sleep in critical care settings, it is vital to develop more effective sleep treatments that include non-benzodiazepine medication and sleep hygiene strategies.

Narcolepsy type 1 and Sydenham chorea - Report of 3 cases and review of the literature.

OBJECTIVES/BACKGROUND: Narcolepsy type 1 (NT1) is an immune-mediated disorder characterized by excessive daytime sleepiness, cataplexy, low levels of hypocretin-1 in the cerebrospinal fluid, and a strong association with the HLA DQB1*06:02 allele. There is evidence for streptococcal infections as one pathogenic factor that may lead to NT1 as part of a multifactorial pathogenesis. Elevated titers of Antistreptolysin-O antibodies and increased inflammatory activity in response to streptococci antigens have been described in patients with NT1. Sydenham chorea (SC) results from a post-streptococcal autoimmune process targeting basal ganglia neurons. Despite this common trigger, SC has been interpreted as a misdiagnosis in a few described cases of patients who were first diagnosed with SC and later with NT1. Our goal was to analyze the association between SC and NT1. PATIENTS/METHODS: We reviewed the literature and report three patients from three European sleep centers who were diagnosed with both SC and NT1 within a few months. RESULTS: We describe the cases of one male (age 10) and two female (age 22 and 10) patients. CONCLUSIONS: We argue that in those cases both diagnoses are justified, unlike reports of previous cases in which SC was considered a misdiagnosis in patients with NT1. It remains, however, unclear if the conditions occur independently or if there is an overlap disorder- an SC-like subtype of narcolepsy with a particular sequence of symptoms. Further studies need to clarify the causality of the relationship and the pathophysiology of the reported rare association.

Skin temperature as a predictor of on-the-road driving performance in people with central disorders of hypersomnolence.

Excessive daytime sleepiness is the core symptom of central disorders of hypersomnolence (CDH) and can directly impair driving performance. Sleepiness is reflected in relative alterations in distal and proximal skin temperature. Therefore, we examined the predictive value of skin temperature on driving performance. Distal and proximal skin temperature and their gradient (DPG) were continuously measured in 44 participants with narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia during a standardised 1-h driving test. Driving performance was defined as the standard deviation of lateral position (SDLP) per 5 km segment (equivalent to 3 min of driving). Distal and proximal skin temperature and DPG measurements were averaged over each segment and changes over segments were calculated. Mixed-effect model analyses showed a strong, quadratic association between proximal skin temperature and SDLP (p < 0.001) and a linear association between DPG and SDLP (p < 0.021). Proximal skin temperature changes over 3 to 15 min were predictive for SDLP. Moreover, SDLP increased over time (0.34 cm/segment, p < 0.001) and was higher in men than in women (3.50 cm, p = 0.012). We conclude that proximal skin temperature is a promising predictor for real-time assessment of driving performance in people with CDH.

The therapeutic potential of opioids in narcolepsy type 1: A systematic literature review and questionnaire study.

OBJECTIVE: Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. METHODS: We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. RESULTS: The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). CONCLUSIONS: Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.

Warm ears, a red flag for sleepiness?

Core body and skin temperatures are intimately linked to sleep and alertness. The distal-to-proximal skin temperature gradient has been described as a good physiological predictor for sleep onset. Increased ear skin temperature is often caused by increased blood flow reflected in redness, which is commonly noticed in people who are sleepy, especially anecdotally in children. Nonetheless, no prior study investigated the possible relation between sleepiness and ear skin temperature as a separate measurement. We assessed the relation between ear skin temperature and sleepiness in patients undergoing regular electroencephalographic examinations, because of suspicion of epilepsy, both without and after sleep deprivation. Subjective sleepiness was measured using the Stanford Sleepiness Scale, and objective sleepiness by determining sleep onset with electroencephalography. Distal, proximal and ear skin temperature were measured repeatedly using wireless measurement devices (iButtons). Forty-four adult patients were included. Ear skin temperature correlates weakly with distal skin temperature (r = 0.174, p < 0.001) and distal-to-proximal gradient (r = 0.160, p < 0.001), but not with proximal skin temperature (r = -0.001, p = 0.975). Ear skin temperature increased significantly in a subgroup of 13 patients, between 5 and 1 min before sleep onset (p = 0.002; η2  = 0.059), even though this increase was also associated with supine posture. iButtons is a valid method to measure ear skin temperature, which appears to function partly like a distal and partly like a proximal skin temperature measurement. Change in ear skin temperature is associated with sleep onset and supine posture.

Conventional autoantibodies against brain antigens are not routinely detectable in serum and CSF of narcolepsy type 1 and 2 patients.

Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF). Anti-neuronal antibodies were rarely found in patients with narcolepsy (n = 2) and in controls (n = 1). Our results are in line with previous reports. We can therefore support the current evidence, that conventional anti-neuronal antibodies are not routinely detected during the workup of NT1 and other CDH patients.

Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1.

Narcolepsy type 1 is a neurological sleep-wake disorder caused by the destruction of orexin (hypocretin)-producing neurons. These neurons are particularly located in the lateral hypothalamus and have widespread projections throughout the brain, where they are involved, e.g., in the regulation of the sleep-wake cycle and appetite. Interestingly, a higher prevalence of obesity has been reported in patients with narcolepsy type 1 compared to healthy controls, despite a normal to decreased food intake and comparable physical activity. This suggests the involvement of tissues implicated in total energy expenditure, including skeletal muscle, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Recent evidence from pre-clinical studies with orexin knock-out mice demonstrates a crucial role for the orexin system in the functionality of brown adipose tissue (BAT), probably through multiple pathways. Since BAT is a highly metabolically active organ that combusts fatty acids and glucose toward heat, thereby contributing to energy metabolism, this raises the question of whether BAT plays a role in the development of obesity and related metabolic diseases in narcolepsy type 1. BAT is densely innervated by the sympathetic nervous system that activates BAT, for instance, following cold exposure. The sympathetic outflow toward BAT is mainly mediated by the dorsomedial, ventromedial, arcuate, and paraventricular nuclei in the hypothalamus. This review focuses on the current knowledge on the role of the orexin system in the control of energy balance, with specific focus on BAT metabolism and adiposity in both preclinical and clinical studies.

Decreased body mass index during treatment with sodium oxybate in narcolepsy type 1.

Narcolepsy type 1 is characterised by an increase in body weight after disease onset, frequently leading to obesity. It was suggested that this weight gain may be counteracted by treatment with sodium oxybate. We here provide longitudinal body mass index data of patients with narcolepsy type 1 after starting treatment with sodium oxybate, compared with patients in whom treatment with modafinil was initiated. Eighty-one individuals with narcolepsy type 1 fulfilled the entry criteria for this retrospective study: 59 had newly started treatment with sodium oxybate and 22 had newly started modafinil. Gender-specific differences between both treatment groups were compared using Student's t tests and mixed effect modeling. Patients using sodium oxybate lost weight, with a mean body mass index decrease of 2.56 kg/m2 between the first and last measurement (women; p = .001) and 0.84 kg/m2 (men; p = .006). Patients using modafinil, however, gained weight, with a mean body mass index increase of 0.57 kg/m2 (women; p = .033) and 0.67 kg/m2 (men; p = .122). Medication (p = .006) and baseline body mass index (p = .032) were predictors for body mass index decrease. In conclusion, treatment with sodium oxybate is associated with a body mass index reduction in narcolepsy type 1, whereas modafinil treatment is not. This effect is most pronounced in those who already have a higher baseline body mass index.

Correction to: Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer.

Unfortunately, the fourth author's middle name was missed out in the original publication of this article. The complete correct name should read as follows.

Standard radiotherapy but not chemotherapy impairs systemic immunity in non-small cell lung cancer.

Introduction: Advanced non-small cell lung cancer (NSCLC) is traditionally treated with platinum-based chemotherapy and radiotherapy. Since immunotherapy holds promise for treating advanced NSCLC, we assessed the systemic effects of the traditional therapies for NSCLC on immune cell composition and function. Methods: 84 pulmonary adenocarcinoma patients, treated either with chemotherapy or radiotherapy, were studied. A prospective study of 23 patients was conducted in which the myeloid and lymphoid cell compartments of peripheral blood were analyzed. Changes in cell populations were validated in a retrospective cohort of 61 adenocarcinoma patients using automated differential counts collected throughout therapy. Furthermore, the functional capacity of circulating T cells and antigen-presenting cells (APC) was studied. Blood samples of healthy individuals were used as controls. Results: In comparison to healthy controls, untreated adenocarcinoma patients display an elevated frequency of myeloid cells coinciding with relative lower frequencies of lymphocytes and dendritic cells. Standard chemotherapy had no overt effects on myeloid and lymphoid cell composition nor on T-cell and APC-function. In contrast, patients treated with radiotherapy displayed a decrease in lymphoid cells and a relative increase in monocytes/macrophages. Importantly, these changes were associated with a reduced APC function and an impaired response of T cells to recall antigens. Conclusions: Platinum-based standard of care chemotherapy for NSCLC has no profound negative effect on the immune cell composition and function. The negative effect of prolonged low-dose radiotherapy on the immune system warrants future studies on the optimal dose and fraction of radiotherapy when combined with immunotherapy.

Endosonography for lung cancer staging: predictors for false-negative outcomes.

OBJECTIVES: Non-small cell lung cancer (NSCLC) guidelines recommend endosonography (endobronchial [EBUS] and/or transesophageal ultrasound [EUS]) as the initial step for mediastinal tissue staging. Identifying predictors for false negative results could help establish which patients should undergo confirmatory surgical staging. MATERIALS AND METHODS: 775 NSCLC patients staged negative by EBUS, EUS or combined EUS/EBUS were retrospectively analyzed. Predictors of false-negative outcomes were identified by logistic regression analysis. RESULTS AND CONCLUSION: Three predictors for false-negative outcomes were identified: central location of the lung tumor (OR 3.7/4.5/3.6 for EBUS, EUS and EUS/EBUS respectively, p<0.05), nodal enlargement on CT (OR 3.2/2.5/4.9 for EBUS, EUS and EUS/EBUS respectively, p<0.05) and FDG-avidity of N2/N3 lymph node stations on PET (OR 4.2/4.0/7.5 for EBUS, EUS and EUS/EBUS respectively, p<0.05). One subgroup (peripheral lung tumor, nodal enlargement on CT without FDG-avidity for N2/N3) had a low predicted probability (7.8%) for false-negative EUS. For combined EUS/EBUS, two subgroups were identified: peripheral located tumor with nodal enlargement on CT but without FDG-avidity for N2/N3 (predicted probability 4.7%) and centrally located tumor without affected lymph nodes on CT or PET (predicted probability 3.4%). In conclusion, for specific well-defined subsets of NSCLC patients the low predicted probability of metastasis after negative endosonography might justify omitting confirmatory surgical staging.

Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer.

PURPOSE: The aim of this study was to evaluate the efficacy of post-operative radioiodine ablation with 1,850 MBq after recombinant human thyrotropin (rhTSH) administration in patients with differentiated thyroid carcinoma (DTC). We also aimed to assess the prognostic role of several patient features on the outcome of ablation. METHODS: We retrospectively analyzed data from a total of 125 patients with DTC who underwent post-operative radioiodine ablation with 1,850 MBq of ¹³¹I after preparation with rhTSH. One injection of 0.9 mg rhTSH was administered on each of two consecutive days; ¹³¹I therapy was delivered 24 h after the last injection, followed by a post-therapy whole-body scan. Successful ablation was assessed 6-12 months later and defined as an rhTSH-stimulated serum thyroglobulin (Tg) level ≤1.0 ng/ml and a normal neck ultrasound. RESULTS: Patients were stratified according to the American Thyroid Association (ATA) Management Guidelines for Differentiated Thyroid Cancer. Successful ablation was achieved in 82.4 % of patients, with an ablation rate of 95.1 % in low-risk patients and 76.2 % in intermediate-risk patients. Analyzing the correlation between ablation outcome and patient characteristics, we found a statistically significant association between failure to ablate and class of risk based on ATA guidelines (p = 0.025) and a stimulated Tg value at ablation of above 5 ng/ml (p < 0.001). CONCLUSION: The use of 1,850 MBq post-operative radioiodine thyroid remnant ablation in association with rhTSH is effective for low- and intermediate-risk patients. Moreover, in our study, we found a statistical correlation between failure to ablate and class of risk based on ATA guidelines for DTC and a stimulated Tg value at ablation.