Annotated Abstracts of Journal Articles
2014, 1st Quarter
Annotations by Shamim Nejad, MD
ANNOTATION (Shamim Nejad)
The Finding: In randomized rater-blinded placebo-controlled trial, conducted in 4 university hospitals and 1 general hospital involving 67 patients (24 patients in intensive care units and 43 admitted to regular acute wards) between the ages of 65 to 89 years old, ramelteon was associated with a lower risk of delirium (3% versus 32%; P=0.003). After risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P=0.01; odds ratio, 0.07 [95% CI].
Strength and Weaknesses:: The primary strength of this study was its randomized placebo-controlled design. Despite a relatively low number of patients in the trial, both groups were reasonably similar with regards to risk factors for development of delirium. Limitations of the study included that this was not a double-blind study, but was rater-blinded. In addition, although the number of patients enrolled was above that needed for power analysis, the study had a relatively small sample size. Other weaknesses include the exclusion of patients with hepatic dysfunction, diagnoses of mood disorders (including bipolar mood disorder and depression), and those with psychotic disorders. These groups not only represent those patients who often have sleep/wake dysfunction and circadian rhythm disturbances, but who have also been shown to be at higher risk for the development of delirium in the ICU setting; their exclusion from the study deviates from real clinical practice.
Relevance: During the last several years, varying strategies with regard to delirium prevention, particularly in ICU patients, have been studied including use of dopamine antagonists, cholinesterase inhibitors, and even benzodiazepines, all with varying results. This particular study, despite its limitations, is one that is the first to show a significant prophylactic effect on the incidence of delirium, in elderly ICU patients with the use of the melatonin analogue, ramelteon. Interestingly, no published studies exist to show if ramelteon is more effective (or if more safe) than melatonin in clinical trials with human subjects.
Importance: No highly effective interventions to prevent delirium have been identified.
Objective: To examine whether ramelteon, a melatonin agonist, is effective for the prevention of delirium.
Design, Setting, and Participants: A multicenter, rater-blinded, randomized placebo-controlled trial was performed in intensive care units and regular acute wards of 4 university hospitals and 1 general hospital. Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally. Patients were excluded from the study if they had an expected stay or life expectancy of less than 48 hours.
Interventions: Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/d; 33 patients) or placebo (34 patients) every night for 7 days.
Main Outcomes and Measures:
Incidence of delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).
Results: Ramelteon was associated with a lower risk of delirium (3% vs 32%; P=.003), with a relative risk of 0.09 (95% CI, 0.01-0.69). Even after risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P=.01; odds ratio, 0.07 [95% CI, 0.008-0.54]). The Kaplan-Meier estimates of time to development of delirium were 6.94 (95% CI, 6.82-7.06) days for ramelteon and 5.74 (5.05-6.42) days for placebo. Comparison by log-rank test showed that the frequency of delirium was significantly lower in patients taking ramelteon than in those taking placebo (Χ2=9.83; P=.002).
Conclusions and Relevance: Ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium. This finding supports a possible pathogenic role of melatonin neurotransmission in delirium.
ANNOTATION (Shamim Nejad)
The Finding: In an observational cohort study involving 662 patients in a mixed type ICU, at-risk drinking was independently associated with ICU mortality (hazard ratio [HR] = 1.83; 95% CI, 1.16–2.89). This finding, however, was no longer significant after excluding patients with alcohol abuse (HR = 1.72; 95% CI, 0.90–3.31). Among ICU survivors, 24% at-risk and 15% non–at-risk died during 1-year follow-up (p = 0.008). After adjusting for age, severity of illness, comorbidities, and body mass index less than 18.5 kg/m2, at-risk drinking was associated with 70% increased risk in 1-year mortality after ICU admission (HR = 1.70; 95% CI, 1.15–2.52).
Strength and Weaknesses: This is one the largest non-trauma ICU patient cohorts with AUDs identified prospectively from patient and surrogate interviews. It is possible that conducting prospective beside interviews with patients and surrogates may have improved the accuracy of AUD measurement, which may partially explain some of the findings but at the same time this may have affected the results via bias as well. Alcohol withdrawal syndromes (AWS) and delirium were not included in the prognosis variable and are likely mediators of poor outcomes in the ICU population. Given that heavy drinkers accounted for more than half of at-risk drinkers, it would be important to note alcohol withdrawal delirium contributed to the excess mortality associated with this subgroup. Furthermore, alcohol use following discharge was not assessed and thus ongoing alcohol use and its contribution to mortality cannot be fully elucidated.
Relevance: At-risk drinking and AUDs are associated with a significant number of ICU admissions both directly and indirectly. AUDs and AWS may often complicate management of ICU patients and increase risk for ICU complications that can be associated with mortality. Identification of patients with at-risk drinking during their hospitalization may provide an opportunity to motivate change to help decrease alcohol use and initiate treatment following hospital discharge.
Objectives: The impact of at-risk drinking on the outcomes of nontrauma patients is not well characterized. The aim of this study was to determine whether at-risk drinking is independently associated with the survival of nontrauma patients in an ICU and within 1 year following ICU discharge.
Design: Observational cohort study.
Setting: A 21-bed mixed ICU in a university hospital.
Patients: A total of 662 patients who experienced an ICU stay of 3 days or more and for whom alcohol consumption could be assessed.
Measurements and Main Results: ICU-related variables were collected prospectively, and a 1-year follow-up was determined retrospectively. Analyses were adjusted based on prognostic determinants of short- and long-term outcomes, as previously described in ICU patients and alcohol abusers. Two hundred and eight patients (33%) were identified as at-risk drinkers according to the National Institute on Alcohol Abuse and Alcoholism criteria. Additionally, 111 patients (17%) died in the ICU, and 97 (15%) died after ICU discharge. From the ICU admission until the end of the 1-year follow-up period, the at-risk drinkers exhibited poorer survival than the non-at-risk drinkers (p = 0.0004, as determined by the log-rank test). More specifically, 50 at-risk drinkers (24%) versus 61 non-at-risk drinkers (13%) died in the ICU (p = 0.0009 for the comparison). After adjustment, at-risk drinking remained independently associated with mortality in the ICU (adjusted odds ratio of 1.83; 95% CI of 1.16-2.89; p = 0.01) and with mortality within the year following ICU discharge (adjusted hazard ratio of 1.70; 95% CI of 1.15-2.52; p = 0.008). The causes of death in the at-risk and non-at-risk drinkers were similar.
Conclusions: In this population of critically ill nontrauma patients, at-risk drinking was independently associated with death in the ICU and within the year following ICU discharge.