The Effects of Melatonin Supplementation on Sleep Quality and Assessment of the Serum Melatonin in ICU Patients: A Randomized Controlled Trial.

OBJECTIVES: To evaluate whether the use of exogenous melatonin affects sleep, reduces the prevalence of delirium, and decreases the need for analgosedation and to assess whether serum melatonin indices correlate with exogenous administration in critically ill patients. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: Multicenter ICUs of two tertiary hospitals. PATIENTS: A total of 203 adult patients who were admitted to the ICU and administered with analgesics and/or sedatives. INTERVENTIONS: Oral melatonin (10 mg) or placebo for up to seven consecutive nights. MEASUREMENTS AND MAIN RESULTS: The number of observed sleeping hours at night was assessed by the bedside nurse. Sleep quality was evaluated using the Richards Campbell Questionnaire Sleep (RCSQ). The prevalence of delirium, pain, anxiety, adverse reactions, duration of mechanical ventilation, length of ICU and hospital stays, and doses of sedative and analgesic drugs administered were recorded. The use of analgesics and sedatives was assessed daily. Melatonin levels were determined by enzyme-linked immunosorbent assay. Based on the RCSQ results, sleep quality was assessed to be better in the melatonin group than that in the placebo group with a mean (SD) of 69.7 (21.2) and 60.7 (26.3), respectively (p = 0.029). About 45.8% and 34.4% of participants in the melatonin and placebo groups had very good sleep (risk ratio, 1.33; 95% CI, 0.94-1.89), whereas 3.1% and 14.6% had very poor sleep (risk ratio, 0.21; 95% CI, 0.06-0.71), respectively. No significant difference was observed regarding the days free of analgesics or sedatives, the duration of night sleep, and the occurrence of delirium, pain, and anxiety. Melatonin serum peak levels at 2 AM were 150 pg/mL (range, 125-2,125 pg/mL) in the melatonin group and 32.5 pg/mL (range, 18.5-35 pg/mL) in the placebo group (p < 0.001). CONCLUSIONS: Melatonin was associated with better sleep quality, which suggests its possible role in the routine care of critically ill patients in the future.

Prescription Benzodiazepine Use in Privately Insured U.S. Children and Adolescents.

INTRODUCTION: Benzodiazepines are commonly prescribed in the U.S. but entail safety concerns, including dependency. In pediatrics, many indications lack trial data. Authors aimed to describe youth initiating prescription benzodiazepine treatment, identify potential indications and prescribing concerns, estimate the duration of treatment by potential indication, and identify factors that predict long-term use. METHODS: The study cohort included children (aged 3-12 years) and adolescents (aged 13-17 years) initiating prescription benzodiazepine treatment (≥3 days' supply) from January 2010 to September 2015 in a U.S. commercial claims database. Potential indications included selected ICD-9-CM diagnoses (≤30 days prior). Long-term (≥6 months) benzodiazepine treatment was estimated with Kaplan-Meier estimation and modified Poisson regression identified independent predictors of long-term benzodiazepine treatment (analysis completed in 2018). RESULTS: Of 24,504 children and 61,046 adolescents initiating benzodiazepines, 62% of the children and 68% of the adolescents had a potential indication. Anxiety disorders were the most common indication, with mental health indications more common among adolescents (45%) than children (23%) and epilepsy and movement disorders higher in children. Recent opioid prescriptions were common before benzodiazepine initiation (children, 22%; adolescents, 21%). Six percent of the initiators became long-term benzodiazepine users. Potential indication, provider contact, psychotropic medication, and chronic conditions independently predicted long-term benzodiazepine treatment in adolescents and children. CONCLUSIONS: U.S. children and adolescents are prescribed benzodiazepines for various mental health and other medical conditions, many lacking evidence of pediatric efficacy. Long-term benzodiazepine treatment, concurrent opioid prescriptions, psychotropic use, and prior substance use disorder diagnoses suggest safety risks among some youth prescribed benzodiazepines.

Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial.

BACKGROUND: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. METHODS: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. RESULTS: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). CONCLUSIONS: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01360346 . Registered on 25 March 2011.

Pediatric insomnia: new insights in clinical assessment and treatment options.

Sleep disorders in children can compromise quality of life of both children and families and chronic sleep deprivations is associated with poorer developmental outcome, overweight and behavioral disturbances. Clinicians should incorporate questions about sleep into their routine health assessment, and the assessment of insomnia should follow a medical approach primary and secondary contributing factors should be assessed, as well as maladaptive behaviors related to sleep. A careful examination of sleep/wake schedule, abnormal movements or behavior during sleep, and daytime consequences of sleep disruption or deprivation is mandatory. Sleeping environment, and bedtime routines should be examined to identify behavioral issues related to sleep. Polysomnography is not routinely indicated for children with insomnia, but actigraphy can give an objective estimation of sleep parameters. The Authors propose a new classification of pediatric insomnia, based on both genetic and clinical aspects, and suggest specific treatment options, including sleep hygiene, behavioral strategies and pharmacological treatment.

Use and abuse of prescribed opioids, central nervous system depressants, and stimulants among U.S. active duty military personnel in FY 2010.

OBJECTIVES: This study establishes rates of use/abuse of Schedule II-IV prescription medications in U.S. active duty military personnel, and characterizes correlates of such use/abuse. METHODS: All active duty personnel serving for 12 months during fiscal year 2010 were included. Data were obtained from medical and pharmacy claims and drug screening results. Logistic regression models were used to examine predictors of drug use, along with bivariate analyses to compare abuse of prescribed and illegal drugs. RESULTS: Nearly one-third of active duty service members received at least one prescription for opioids, central nervous system depressants, or stimulants, with 26.4% having received at least one prescription for opioids. About 0.7%, 1.4%, and 0.6% of the total force received >90-day prescriptions for opioids, central nervous system depressants, or stimulants, respectively. Battlefield injury, receipt of psychotropic medications, and substance abuse adverse events were predictive of >90-day supply of opioids. About 0.7% of the total force had documented known drug abuse for prescribed drugs compared to 0.4% for illegal drug abuse. CONCLUSIONS: We recommend systematic monitoring of prescriptions for controlled substances which may carry serious consequences, evaluation of the impact of controlled substances on military readiness, and examination of the rationale for prescribing controlled drugs.

The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS).

BACKGROUND: Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems. OBJECTIVE: To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems. DESIGN: Randomised, double-blind, placebo-controlled, parallel study. SETTING: Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues. PARTICIPANTS: Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6-week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks. INTERVENTIONS: Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose. MAIN OUTCOME MEASURES: The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQL™), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated. RESULTS: A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant. CONCLUSIONS: On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05534585. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information.

Melatonin for primary insomnia?

Melatonin, a hormone produced by the pineal gland, has a key role in regulating circadian rhythms, most importantly, the sleep-wake cycle. Melatonin's action has led to its being tried as a treatment for a wide range of sleep disorders, such as jet lag, primary insomnia, sleep-wake cycle disruption and sleep problems in children with neuro-developmental disorders. Until recently, it had not been licensed in the UK for any indication. Prolonged-release melatonin (Circadin - Lundbeck) has now been licensed as a treatment for primary insomnia. Here we consider whether this product has a place in the management of people with this condition.

Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients.

BACKGROUND: Although known to be an independent predictor of poor outcomes in medical intensive care unit (ICU) patients, limited data exist regarding the prevalence of and risk factors for delirium among surgical (SICU) and trauma ICU (TICU) patients. The purpose of this study was to analyze the prevalence of and risk factors for delirium in surgical and trauma ICU patients. METHODS: SICU and TICU patients requiring mechanical ventilation (MV) >24 hours were prospectively evaluated for delirium using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the ICU (CAM-ICU). Those with baseline dementia, intracranial injury, or ischemic/hemorrhagic strokes that would confound the evaluation of delirium were excluded. Markov models were used to analyze predictors for daily transition to delirium. RESULTS: One hundred patients (46 SICU and 54 TICU) were enrolled. Prevalence of delirium was 73% in the SICU and 67% in the TICU. Multivariable analyses identified midazolam [OR 2.75 (CI 1.43-5.26, p = 0.002)] exposure as the strongest independent risk factor for transitioning to delirium. Opiate exposure showed an inconsistent message such that fentanyl was a risk factor for delirium in the SICU (p = 0.007) but not in the TICU (p = 0.936), whereas morphine exposure was associated with a lower risk of delirium (SICU, p = 0.069; TICU p = 0.024). CONCLUSION: Approximately 7 of 10 SICU and TICU patients experience delirium. In keeping with other recent data on benzodiazepines, exposure to midazolam is an independent and potentially modifiable risk factor for the transitioning to delirium.

Remission, relapse, and metastasis/death of small hepatocellular carcinoma treated with percutaneous ethanol injection.

PURPOSE: This study aimed to quantify the full clinical courses characterized by alternating transitions between remission and relapses for small hepatocellular carcinomas treated by percutaneous ethanol injection, and to ascertain the significant predictors for the remission, relapse, and finally to metastasis or death. PATIENTS AND METHODS: A three-state Markov process was used to depict full clinical course. A total of 108 patients who underwent nonsurgical therapy as the first choice of treatment were derived from consecutive clinical series of patients registered in one medical center renowned for their use of percutaneous ethanol injection. RESULTS: We found that approximately 57.19% (95% confidence interval [CI]: 39.82%, 74.56%) patients were promptly responsive to initial treatment, whereas 43.81% had delayed response or were resistant to treatment. The rate of relapse (per month) was higher than the rate of remission (19.20% [95% CI: 15.36%, 23.04%] vs. 13.82% [95% CI: 10.72%, 16.93%]). The results from the multivariate analysis indicate that the significant predictors for the full clinical courses are total bilirubin, alpha-fetoprotein, prothrombin time, globulin, tumor morphology, and alkaline phosphatase. CONCLUSIONS: A three-state remission-relapse-death model was proposed to quantify and ascertain the predictors for the multistate disease progression of small hepatocellular carcinomas treated by percutaneous ethanol injection. This model captures the risk of recurrence of tumor as well as the primary endpoint of death.

Is microbubble-enhanced ultrasonography sufficient for assessment of response to percutaneous treatment in patients with early hepatocellular carcinoma?

The objective of this study was to assess the efficacy of contrast-enhanced ultrasonography (CEUS) with SonoVue to evaluate the response to percutaneous treatment (ethanol injection/radiofrequency) of hepatocellular carcinoma in comparison with spiral computed tomography (CT) immediately and 1 month after treatment. Forty-one consecutive cirrhotic patients with early stage tumor (not suitable for resection) were included. Spiral CT and CEUS were performed in all patients before treatment, in the following 24 h, and 1 month later. The results of each examination were compared with the 1-month spiral CT, considered the gold standard technique. The 24-h CEUS and the 24-h spiral CT sensitivity to detect residual disease were 27% and 20%, respectively. The 24-h CEUS and the 24-h spiral CT positive predictive value of persistent vascularization detection were 75% and 66%, respectively. The 1-month CEUS detected partial responses in ten out of 11 cases (91% sensitivity, 97% specificity, 95% accuracy). Spiral CT and CEUS performed in the 24 h following treatment are slightly useful to evaluate therapeutic efficacy. The 1-month CEUS has a high diagnostic accuracy compared with spiral-CT in the usual assessment of percutaneous treatment response.

National estimates of exposure to prescription drugs with addiction potential in community-dwelling elders.

The use of prescription drugs with addiction potential is an overlooked and growing problem among today's elderly. This paper provides national prevalence estimates of exposure to prescription drugs with addiction potential among community-dwelling elders and explores risk factors for such exposure. Using the Medicare Current Beneficiary Survey, a nationally-representative database of Medicare eligibles, we calculated the prevalence of abusable prescription drug use, overall, by therapeutic class, and by drug. Nearly 22% (7.22 million) of all community-dwelling Medicare elders used at least one prescription medication with addiction potential. Opioid analgesics were used most frequently (14.9%; 95% CI 14.0, 15.8%); central nervous system (CNS) depressants were used by 10.4% of the nation's elders (95% CI 9.5, 10.8%). Using logistic regression analysis, we examined the association of explanatory variables with three outcome variables: any controlled substances use, any opioid analgesic use, and any CNS depressant use. We found that females, whites, those aged 65-79, and those with non-spousal others, were significantly more likely to use one or more prescription drugs with addiction potential, controlling for health status and severity-of-illness. The significance and magnitude of several explanatory variables, including age, race, ethnicity, living arrangement, and health status, varied by therapeutic category. This paper provides an important first step in acknowledging the widespread use of abusable prescription drugs in elders, and provides a foundation for future research and practical solutions to preventing subsequent problem use of prescription drugs.