Comprehensive signal detection of delirium-associated medication using the Food and Drug Administration Adverse Event Reporting System.

OBJECTIVE: Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system. METHOD: The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates. RESULTS: After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64-1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21-4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20-2.71). CONCLUSIONS: These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications.

[Need for Prescription Suggestions for Long-term Inpatients in the Psychiatric Ward].

Additional fees for ward pharmacists' services have been valued for hospitals in Japan. However, the calculation period for services provided to inpatients in the psychiatric ward is limited to 8 weeks. This study aimed to reveal the need for the services of pharmacists in the hospital ward for inpatients hospitalized for >8 weeks in the psychiatric ward. Patients who were hospitalized in the psychiatric ward from September 2016 to February 2017 were analyzed retrospectively. The pharmacists suggested prescriptions for inpatients admitted for >8 weeks, similar to those admitted for <9 weeks, and this supported pharmacotherapy without exacerbating patient outcomes. Moreover, significant decreases in benzodiazepine doses were found between the prior and post prescription suggestions of the pharmacist for inpatients >8 weeks of admission. Healthcare expenditures were also reduced. These results suggest that the prescriptions suggested by pharmacists for inpatients admitted for >8 weeks in the psychiatric ward were useful. In conclusion, our findings show that ward pharmacists' services were necessary not only for the inpatients hospitalized for <9 weeks, but also for those hospitalized for >8 weeks.

[Effect of Digital Labels on Electronic Medical Records for Reducing the Use of Benzodiazepine Receptor Agonists].

Benzodiazepine receptor agonists (BZDs) should be appropriately used owing to the associated risks of delirium and falls. Since January 2018, the liaison team pharmacist at Iizuka Hospital has been applying digital labels with recommendations for the reduction of use and changes in the medication orders and prescriptions of BZDs on electronic medical records of patients in the surgical ward. This study aimed to verify the effectiveness of reducing the use of BZDs via the implementation of digital labels. Patients in the surgical ward were retrospectively assessed for changes in medication orders and prescription ratios of BZDs before and after the implementation of digital labels. The ratio of the number of digital labels implemented to the number of confirmations of medication orders and prescriptions of BZDs was 15.0% at the start of implementation; however, the ratio gradually and significantly decreased to 3.6%. The medication order ratio of BZDs was 52.2% before the implementation of digital labels; however, this ratio decreased to 2.7% and 5.6% immediately and 4 months after the implementation of digital labels, respectively. The present study showed that medication orders for BZDs were reduced after the implementation of digital labels and that the reduction effect was maintained for a certain period of time. Thus, the liaison team pharmacist-led approach can contribute to the proper use of BZDs.

[Evaluation of Pharmacist-led Interview before Doctor Examination for Psychiatry Outpatients].

Psychiatric treatment is shifting from hospital to ambulatory care. It is important that pharmacists positively support outpatients. Pharmacist-led interviews with outpatients have been conducted in the psychiatric department of Iizuka Hospital before examination by the doctor since 2015. Few studies in this field have reported about the effect of the pharmacist-led interviews using subjective evaluation of outpatients prior to examination by doctors. The aim of this study was to reveal this effect by the evaluation of outpatients. We conducted a questionnaire survey. More than 80% of the patients responded that it was "Good" to have an interview with the pharmacist prior to examination by the doctor. Moreover, 71.7% of the patients were "Satisfied" with the pharmacist-led interview, while 81.7% of them responded to "Agree" about continuing the interview in the future. Patients who were satisfied and wished to continue the pharmacist-led interviews were more likely to report better rapport with the doctor as well, in comparison to the patients who answered negatively. Furthermore, the patients who answered "Satisfied" were significantly less likely to forget reporting to the doctor than those who answered negatively. The pharmacist-led interviews in the psychiatric department were appreciated by the patients. In conclusion, pharmacists can facilitate communication between patients and doctors through these interviews. These results indicate that the pharmacist-led interview before the doctor examination is a useful effort from the perspective of outpatients.

Population Pharmacokinetics and Exposure-Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms.

BACKGROUND AND OBJECTIVE: Lithium, which is used to treat bipolar disorder, has a narrow therapeutic blood concentration range and quickly reaches clinically toxic levels. We performed a population pharmacokinetic analysis with a lithium tubular reabsorption model including urinary pH and investigated the relationship between blood lithium concentration and tremor as a side effect. METHODS: Routine clinical data, including 389 serum concentrations, were collected from 214 patients orally administered an adjusted amount of lithium carbonate. Pharmacokinetics were described using a one-compartment distribution model with first-order absorption and elimination. The fractions of the MID (Li+ + LiCO3-) and ION (2Li+ + CO32-) forms were calculated using the Henderson-Hasselbalch equation, and the influences of these fractions on clearance (CL) were evaluated. The rate of tremor development was analyzed using a logit model. RESULTS: Oral apparent CL (CL/F) was explained by nonrenal CL and renal CL, and renal CL was varied by the fractions of lithium forms influenced by urinary pH. The contribution of MID to CL was slightly larger than that of ION. The rate of tremor development was estimated to be more than 30% when the trough lithium concentration was greater than 1.26 mEq L-1. CONCLUSION: Renal function and urinary pH are important indices in lithium treatment, so the serum concentration of lithium may be predicted based on the renal function and urinary pH.

A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation.

Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genetic disorder characterized by the triad of ichthyosis follicularis, alopecia and photophobia. Previous studies have identified five missense mutations in the membrane-bound transcription factor protease, site 2 (MBTPS2) gene in European patients with this syndrome. In this study, we detected the 1286G > A (Arg429His) mutation in MBTPS2 in a Japanese patient with IFAP syndrome. This mutation has previously been detected in a German family with this syndrome. Functional analysis revealed that this mutation was the most severe mutation identified to date for this syndrome. None of the male German patients had been tested for the mutation because they had several visceral and bone anomalies, and had died as neonates or infants. The clinical features of our 5-year-old patient are less severe than those of the German patients. Although he has neurological abnormalities, such as retarded psychomotor development and seizures, he does not have bone or visceral anomalies, except cryptorchidism. This case indicates the existence of other factor(s) that influence the clinical features of this syndrome. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes and to identify such modifying factors.

[Hiccup treated by administration of intranasal vinegar].

A three-year old girl, who had severe cerebral palsy, severe mental retardation, and symptomatic epilepsy, was suffering from intractable hiccup that lasted for more than an hour since she was 2 years and 10 months old when she undertook tracheotomy and laryngotracheal separation. Sometimes this intractable hiccup was followed by respiratory arrest. Although the hiccup was resistant to conventional medications, the nose drops of small amount of vinegar showed a favorable effect on the hiccup. Intranasal vinegar might stimulate dorsal wall of nasopharynx where the pharyngeal branch of the glossopharyngeal nerve, which is thought as an afferent of the reflex arch of hiccup, is distributed. The administration of intranasal vinegar is a safe and handy method to stimulate dorsal wall of nasopharynx. We believe that intranasal vinegar administration could be a useful nonpharmacologic therapy to cease intractable hiccup.

Diphenylarsinic acid poisoning from chemical weapons in Kamisu, Japan.

We noted a new clinical syndrome with prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The well that provided drinking water contained diphenylarsinic acid, a degradation product of diphenylcyanoarsine or diphenylchloroarsine, which were developed for use as chemical weapons, inducing severe vomiting and sneezing. Characteristics of diphenylarsinic acid poisoning include brainstem-cerebellar and cerebral symptoms. Mental retardation associated with brain atrophy in magnetic resonance images was evident in some infants. We must be vigilant to prevent or minimize the effects of further diphenylarsinic acid poisoning in Japan or elsewhere.

Life-threatening vocal cord paralysis in a patient with group A xeroderma pigmentosum.

We report a 19-year-old male with group A xeroderma pigmentosum who presented life-threatening vocal cord paralysis. At 3 months of age, he became sensitive to sunlight, and at the age of 4 years he was diagnosed with group A xeroderma pigmentosum. The neurologic symptoms progressed slowly thereafter. From the age of 18 years, he reported the development of occasional episodic inspiratory stridor and dyspnea, but the cause remained unknown. At the age of 19, he had a common cold and became severely dyspneic and cyanotic. Immediate examination of the glottis upon arrival by an otorhinolaryngologist using a fibroscope indicated complete paralysis of both vocal cords, and tracheal intubation resulted in marked improvement of respiration. Tracheostomy was performed thereafter. Inspiratory stridor and dyspnea are the common symptoms in this disease, and some patients with group A xeroderma pigmentosum undergo a tracheostomy, but the pathogenesis remains unknown. To our knowledge, vocal cord paralysis has never been reported in patients with group A xeroderma pigmentosum. This case is presented to illustrate the importance of fibroscopy in the examination of vocal cords in patients with group A xeroderma pigmentosum before the development of life-threatening events.