Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center

Context: Poison centers (PCs) frequently manage patients with antimuscarinic delirium. However, controversy surrounds the antidotal use of physostigmine for its treatment. The aim of this study was to prospectively investigate physostigmine versus non-antidote therapy for the management of antimuscarinic delirium in a single regional PC.

Methods: This was a prospective observational analysis of patients diagnosed with antimuscarinic delirium and treated in consultation with a regional PC. Certified Specialists in Poison Information (CSPIs) use a clinical guideline to recommend the use of physostigmine. Using a previously derived altered mental status score, we quantified the rate of delirium improvement with physostigmine compared to non-antidote therapy two hours after initial patient identification. We also recorded adverse events (defined a priori as bradycardia, vomiting, seizures) and resource utilization (intubation and physical restraint).

Results: We identified 245 patients and included 154 in the analysis. The most common exposure classes were antihistamines (68%), analgesics (19%), and antipsychotics (19%). CSPIs recommended physostigmine in 81% (125) of cases and the treatment team administered it in 37% (57) of these. We observed delirium control in 79% of patients who received physostigmine versus 36% of those who did not. The odds of delirium control were six times greater for patients receiving physostigmine than for patients treated with non-antidote therapy (OR 6.6). Adverse events were rare and did not differ significantly between the groups. Physostigmine was not associated with changes in the incidence of intubation or restraint.

Conclusions: This study provides further evidence of both the safety and efficacy of physostigmine in the treatment of antimuscarinic delirium.     

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 μg/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery–Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group × block interaction (F=21.0, p<0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F=8.4, p=0.006). The treatment group × block interaction was also significant in males (F=3.8, p=0.043) and females (F=35.6, p<0.001) separately. A block × gender interaction (F=7.4, p=0.009) indicated that the response magnitude was larger in women. The treatment × block interaction was significant for the HAM-A across gender (F=12.0, p<0.001), and was significant for females (F=24.9, p<0.001) but not for males (F=1.3, p=0.30). When comparing the baseline block to study end, the block × gender interaction (F=12.6, p=0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.     

Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective,head‐to‐head,placebo‐controlled trial

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? A previous trial found greater efficacy with the maximum available dose of fesoterodine 8 mg compared with the maximum available dose of tolterodine ER 4 mg and placebo for improving overactive bladder symptoms, and patient‐reported outcomes were demonstrated by a recent placebo‐controlled, head‐to‐head trial. The results of this trial, the largest to date to compare antimuscarinic efficacy, confirms the superior efficacy of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of OAB symptoms, and further emphasize the clinical advantage of the availability of an additional 8‐mg dose over single‐dose tolterodine ER 4 mg.

OBJECTIVE

? To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo‐controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient‐reported outcomes.

MATERIALS AND METHODS

? In this 12‐week, double‐blind, double‐dummy trial, subjects reporting >1 urgency urinary incontinence (UUI) episode and ≥8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. ? Subjects completed 3‐day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12.

RESULTS

? A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05). ? Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo. ? Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively.

CONCLUSIONS

? In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self‐reported patient assessments of bladder‐related problems, urgency, symptom bother and health‐related quality of life. ? The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER.     

At Surgeons' Sessions: A Focus on Adjunctive Immunotherapy

Abstract

Background: Antimuscarinic drug prescribing scoring systems might better identify patients at risk of adverse drug reactions. The recently developed Anticholinergic Risk Scale (ARS) score is significantly associated with the number of antimuscarinic side effects in older outpatients. We sought to identify the clinical and demographic patient-level correlates of the ARS, including a modified version adjusted for daily dose, in elderly hospitalized patients. Methods: Clinical and demographic patient characteristics known to be associated with antimuscarinic prescribing, ARS and dose-adjusted ARS scores, and full medication exposure on admission were recorded in 362 consecutive patients (aged 83.6 ± 6.6 years) admitted to 2 geriatric units (NHS Grampian, Aberdeen, Scotland, UK) between February 1, 2010 and June 30, 2010. Results: Each year of increasing age was associated with reduced number of antimuscarinic drugs (incidence rate ratio [IRR], 0.963; 95% confidence interval [CI], 0.948–0.980; P < 0.001), non-antimuscarinic drugs (IRR, 0.991; 95% CI, 0.985–0.997; P = 0.006), and total number of drugs (IRR, 0.988; 95% CI, 0.983–0.994; P < 0.001). Multivariate Poisson regression showed that increasing age and history of dementia were negatively associated with the ARS score (IRR, 0.97; 95% CI, 0.94–0.99; P = 0.001 and IRR, 0.62; 95% CI, 0.41–0.92; P = 0.019, respectively). By contrast, institutionalization (IRR, 1.32; 95% CI, 1.00–1.74; P = 0.050), Charlson comorbidity index (IRR, 1.06; 95% CI, 1.01–1.11; P = 0.015), and total number of non-antimuscarinic drugs (IRR, 1.13; 95% CI, 1.08–1.18; P < 0.001) were all positively associated with the ARS score. Similar results were observed for the dose-adjusted ARS score. Conclusion: Institutionalization, comorbidities, and non-antimuscarinic polypharmacy show independent positive associations with the ARS and dose-adjusted ARS scores in older hospitalized patients. Increasing age and dementia are negatively associated with the ARS score.     

Association between prescribing of antimuscarinic drugs and antimuscarinic adverse effects in older people

Many commonly prescribed medications have antimuscarinic side effects. These can be severe and disabling, but it is not always possible to predict which patients will suffer these effects. The development of practical tools that predict the likelihood of adverse drug reactions would aid rational prescribing, thereby improving patient safety and outcomes. Avoiding predictable adverse drug reactions would also make significant cost savings. This paper discusses the current knowledge on the association between the prescribing of antimuscarinic drugs and adverse outcomes, and proposes novel ways to improve trial design, and data collection and interpretation in order to better identify those patients at the highest risk of antimuscarinic side effects.     

Sustained improvement in patient-reported outcomes during long-term fesoterodine treatment for overactive bladder symptoms: pooled analysis of two open-label extension studies

Study Type – Outcomes (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Short‐term (12‐week) trials have demonstrated that subjects with OAB who receive treatment with fesoterodine 4‐ and 8‐mg, either in fixed‐dose or flexible‐dose regimens, show significant improvements in measures of HRQL and other patient‐reported outcomes. The results of this long‐term, open‐label study show that treatment with fesoterodine for up to 24 months resulted in sustained improvement in measures of HRQL and severity of bladder‐related problems in subjects with OAB symptoms. Throughout the study, a high percentage of subjects reported satisfaction with fesoterodine treatment. The results were similar in men and women and across age groups (<45 years; 45–64 years; 65–74; ≥75 years). Long term treatment with fesoterodine is beneficial to patients with overactive bladder.

OBJECTIVES

• ? To evaluate the effects of long‐term fesoterodine treatment on health‐related quality of life (HRQL) and treatment satisfaction in subjects with overactive bladder (OAB) symptoms.
• ? To determine the impact of gender and age on these effects.

PATIENTS AND METHODS

• ? This is a post hoc analysis of data pooled from identically designed open‐label extensions of two randomized, double‐blind, 12‐week fesoterodine studies.
• ? Initial treatment was once‐daily fesoterodine 8 mg; subjects had the opportunity to receive open‐label fesoterodine for ≥24 months.
• ? After 1 month, subjects could elect dose reduction to 4 mg and subsequent re‐escalation to 8 mg; dose reduction and re‐escalation were each allowed once annually.
• ? Changes in scores on the King's Health Questionnaire (KHQ), International Consultation on Incontinence Questionnaire–Short Form (ICIQ‐SF) and a Likert scale evaluating severity of bladder‐related problems were assessed at open‐label baseline and months 12 and 24; treatment satisfaction was assessed at open‐label baseline and at months 4, 12 and 24.

RESULTS

• ? A total of 864 enrolled subjects were included (men, n= 182; women, n= 682; aged <45 years, n= 134; 45–64 years, n= 432; 65–74 years, n= 204; ≥75 years, n= 94); most subjects (77%) who continued treatment maintained the 8‐mg dose.
• ? Among subjects in the overall population, there were significant improvements in all KHQ domains, ICIQ‐SF scores, and bladder‐related problems at open‐label baseline vs double‐blind baseline (P < 0.05); additional significant improvements were observed at months 12 and 24 vs open‐label baseline in all outcomes (P < 0.05) except for the KHQ General Health Perception domain.
• ? When data were stratified by gender or age, significant improvements at open‐label baseline vs double‐blind baseline were further significantly enhanced or sustained at months 12 and 24 for most KHQ domains, and for ICIQ‐SF scores and bladder‐related problems for all groups. Women had significantly greater improvements than men in the KHQ Emotion (P= 0.0173) and Severity/Coping (P= 0.0112) domains and ICIQ‐SF scores (P= 0.0276) during open‐label treatment. Subjects aged <45 years had significantly greater improvement in the Personal Relationships domain compared with those aged 45–64 years (P= 0.0357) and in the Sleep/Energy domain compared with all other groups (all P < 0.02).
• ? Treatment satisfaction was high (≥92%) throughout open‐label treatment regardless of gender or age.

CONCLUSIONS

• ? Long‐term fesoterodine treatment was associated with sustained improvement in measures of health‐related quality of life and bladder‐related problems and with high treatment satisfaction in subjects with overactive bladder symptoms.
• ? Effects of gender and age were minimal.