Toxicité sérotoninergique résultant d’une interaction médicamenteuse entre le bleu de méthylène et les inhibiteurs de la recapture de la sérotonine

Background:

Methylene blue is used in medical practice for various reasons. Recent findings point to a potential interaction with serotonin reuptake inhibitors (SRIs) that could lead to serotonergic toxicity.

Objective:

To describe the risk of serotonergic toxicity associated with the interaction between methylene blue and SRIs.

Data sources:

Relevant publications were searched systematically via MEDLINE (1946 to March 21, 2013) and Embase (1974 to 2013, week 11) with the following search terms: “methylene blue”, “methylthioninium”, “monoamine oxidase inhibitors”, “serotonin reup-take inhibitors”, and “serotonin syndrome”. No restrictions were applied in relation to the indication for methylene blue or the language of publication. The reference lists of identified articles were also searched.

Study selection and data extraction:

Eighteen case reports and 2 case series were identified for inclusion. To date, no randomized controlled trials have been published.

Data synthesis:

The first case report indicating suspicion of an interaction between methylene blue and SRIs was published in 2003. Seventeen other case reports describing the same type of interaction have been published since then. The 2 case series provided data from about 325 parathyroidectomies in which methylene blue was used for staining. The 17 patients who experienced central nervous system toxicity were all taking SRIs in the preoperative period.

Conclusion:

When administered in combination with SRIs, methylene blue may lead to serotonergic toxicity at doses as low as 0.7 mg/kg. Methylene blue would seem to have monoamine oxidase A inhibitory properties. Precautions should be taken to avoid this interaction.[Publisher’s translation]     

Vasoplegic Shock Treated with Methylene Blue Complicated by Severe Serotonin Syndrome

Introduction

Management of severe vasoplegic shock in overdose can be very challenging. We describe a case of severe refractory vasodilatory shock in poisoning where methylene blue (MB) was used with success. However, the patient subsequently developed severe Serotonin Syndrome (SS) as a result of an interaction between serotonergic drugs and MB.

Case Report

A 15-year-old male developed severe vasoplegic shock 1.5 hours after overdosing on several different medications including quetiapine slow release, quetiapine immediate release, desvenlafaxine slow release, venlafaxine, amlodipine, ramipril, fluoxetine, promethazine and lithium. His vasoplegic shock was resistant to high doses of noradrenaline and vasopressin. MB was administered 6.5 hours post ingestion and within 1 hour there was an improvement in his hemodynamic status and reduction of catecholamine requirements. Twelve hours post ingestion, he developed severe Serotonin Syndrome that lasted 5 days as a result of interaction between MB, a reversible monoamine oxidase inhibitor (MAO-I), and the antidepressants taken in overdose. MB had a calculated half-life of 38 hours.

Conclusion

MB is a useful additional strategy for severe drug induced vasodilatory shock and may be potentially life-saving. Clinicians should be aware that it can interact with other drugs and cause life-threatening Serotonin Syndrome. Lower doses or shorter durations may be wise in patients at risk of this interaction.

     

Enzyme therapy in Fabry disease: severe adverse events associated with anti-agalsidase cross-reactive IgG antibodies

AIMS

To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease.

METHODS

Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments.

RESULTS

A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion-related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin-test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department.

CONCLUSION

The negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion.     

Pharmacists' role in targeted cancer therapy in Australia and implications for pharmacy education

Objectives

To investigate the pharmacists'' role in providing targeted therapies to patients and its implications for pharmacy education.

Methods

Nine pharmacy faculty members, 12 clinical pharmacists, and 4 oncologists from across Australia and New Zealand participated in semistructured interviews, which were analysed using the framework method.

Results

Education about targeted therapies was seen as being important, although content about pharmacodiagnostic tests was taught inconsistently among 7 universities. Issues including funding, clinical and diagnostic validity of tests, and time taken for turnaround of tests were perceived as impediments to the acceptance by clinicians of the utility of pharmacodiagnostic tests.

Conclusions

Pharmacists may be the ideal professionals to interpret test results and provide counselling for patients to assist them in compliance with targeted cancer therapies. Pharmacy education in cancer therapies is critical to training pharmacists who can assist patients in the correct use of these therapies.     

Intravenous Lipid Emulsion in the Management of Amlodipine Overdose

Objective:

To report a case of amlodipine overdose successfully treated with intravenous lipid emulsion (ILE).

Case Summary:

A 47-year-old, 110 kg female ingested at least 350 mg of amlodipine with an unknown amount of ethanol. Initial blood pressure was 103/57 mm Hg, mean arterial pressure (MAP) 72 mm Hg, and heart rate 113 beats per minute. In the early clinical course, activated charcoal, intravenous fluid, and calcium boluses were administered. Worsening hypotension prompted a 100 mL bolus of 20% ILE. Stable hemodynamics were maintained for 2 hours. Subsequently, profound hypotension and shock developed (MAP 38 mm Hg), which failed to fully respond to 3 vasopressor agents, calcium, and glucagon. With continuing shock despite optimized vasopressors, an infusion of 2,300 mL 20% ILE was administered over 4.5 hours (20.9 mL/kg infusion total). By completion of the infusion, 2 vasopressors were tapered off and MAP remained above 70 mm Hg; within 12 hours, no further interventions were required. Possible adverse events of ILE, lipemia and hypoxia, were experienced but quickly resolved. The patient survived to hospital discharge within 8 days.

Discussion:

Toxicity of amlodipine presents similar to distributive shock as both are due to marked peripheral vasodilation. There are numerous interventions in the management of amlodipine overdose, despite which many patients continue to suffer life-threatening shock as observed with this patient. ILE has been used with promising preliminary results as salvage therapy in case reports of other lipophilic molecules. This is the first report of lone amlodipine overdose treated with ILE.

Conclusion:

ILE is a novel antidote for overdoses of lipophilic substances and demonstrated efficacy in this case of amlodipine overdose without the use of hyperinsulinemic euglycemia.Cardiovascular medications were the second leading cause of death from medication overdose in 2010, with amlodipine contributing to 24 of those fatalities.¹ Calcium channel blocker (CCB) toxicity presents a particular clinical challenge due to the negative cardiac conduction and contractility properties, along with potent peripheral vasodilatory effects. All CCBs act through blockade of voltage gated L-type calcium channels.^2-4 At therapeutic doses, dihydropyridine CCBs (amlodipine, nifedipine, felodipine, nimodipine, and nicardipine) act by relaxation of smooth muscle surrounding blood vessels in the periphery and heart.³ Non-dihydropyridine CCBs (diltiazem and verapamil) work in the cardiac nodal tissue to slow conduction and demonstrate negative chronotropic, dromotropic, and inotropic effects.³ However, at toxic levels this difference in site of effect between classes is less pronounced,^2,5 thus all dihydropyridine and non-dihydropyridine CCBs may cause hypotension, bradycardia, heart block, and shock.There are a number of therapeutic modalities used in the management of CCB overdose, including fluid resuscitation, intravenous calcium, glucagon, atropine, hyperinsulinemic euglycemia, and vasopressor agents. Despite these interventions, CCB toxicity continues to cause significant mortality. We report the successful use of an emerging treatment strategy, intravenous lipid emulsion (ILE), in the management of amlodipine toxicity, despite hyperinsulinemic euglycemia not being provided.     

Appropriateness of adrenocorticotropic hormone stimulation test for critically ill patients

Background:

In earlier work, it was shown that patients with septic shock who also have adrenal insufficiency experience a benefit in terms of lower mortality rates with hydrocortisone supplementation. As such, the adrenocorticotropic hormone (ACTH) stimulation test has been used frequently to identify these patients. However, recent evidence has suggested that the identification and treatment of adrenal insufficiency in patients with septic shock does not reduce mortality. These results call into question the utility of the ACTH stimulation test in this patient population.

Objectives:

To determine the indications for ordering the ACTH stimulation test for critically ill patients at a tertiary care hospital and to classify the indications as either appropriate (e.g., primary adrenal insufficiency or medication-induced suppression of the hypothalamus–pituitary–adrenal axis) or inappropriate (e.g., patients with septic shock, prior etomidate exposure, or absence of steroid use).

Methods:

A retrospective analysis of health care records was conducted for all patients who had been admitted to the intensive care unit and who had undergone an ACTH stimulation test during 2007. For each patient, the indication for the test was identified and classified as appropriate or inappropriate.

Results:

A total of 35 ACTH stimulation tests were performed during the study period, of which 8 (23%) were classified as having an appropriate indication and 27 (77%) as having an inappropriate indication. Of the tests with an inappropriate indication, 15 (56%) were ordered for patients with septic shock. However, the number of ACTH tests ordered for this indication declined as the year progressed.

Conclusions:

The ACTH stimulation test was often used inappropriately for patients with septic shock. Over time, there appeared to be a trend away from use of this test in this patient population, perhaps reflecting increasing awareness of the lack of benefit.     

Pharmacy students' retention of knowledge and skills following training in automated external defibrillator use

Objectives

To assess pharmacy students'' retention of knowledge about appropriate automated external defibrillator use and counseling points following didactic training and simulated experience.

Design

Following a lecture on sudden cardiac arrest and automated external defibrillator use, second-year doctor of pharmacy (PharmD) students were assessed on their ability to perform basic life support and deliver a shock at baseline, 3 weeks, and 4 months. Students completed a questionnaire to evaluate recall of counseling points for laypeople/the public.

Assessment

Mean time to shock delivery at baseline was 74 ± 25 seconds, which improved significantly at 3 weeks (50 ± 17 seconds, p < 0.001) and was maintained at 4 months (47 ± 18 seconds, p < 0.001). Recall of all signs and symptoms of sudden cardiac arrest and automated external defibrillator counseling points was diminished after 4 months.

Conclusion

Pharmacy students can use automated external defibrillators to quickly deliver a shock and are able to retain this ability after 4 months. Refresher training/courses will be required to improve students'' retention of automated external defibrillator counseling points to ensure their ability to deliver appropriate patient education.     

Virtual patients and problem-based learning in advanced therapeutics

Objective

To enhance student learning of a complex therapeutic concept through the incorporation of 2 case-based, active-learning strategies with lecture in a required advanced therapeutics course.

Design

A virtual patient session using a branched-outcome decision-making model and a problem-based learning (PBL) practica were developed from the course learning objectives for severe sepsis and septic shock. Following lecture of this material, students were required to complete the simulation session and attend the PBL.

Assessment

Student learning was assessed through review of examination scores, as well as quality and accuracy of the pharmaceutical care plan developed as part of the PBL. Satisfaction of the teaching format was assessed through a course evaluation survey. For questions pertaining to sepsis or septic shock on the final examination, the class average was 90%, despite an average of 76% on the examination as a whole. Class average for the pharmacuetical care plan was 90%. Sixty-three percent of students stated the simulation contributed to their learning, and 93% stated the PBL contributed to their learning.

Conclusion

Using a multifaceted teaching approach, combining active- and passive-learning strategies, was well received by students and fostered an effective learning environment.     

Methylene blue inhibits function of the 5-HT transporter

BACKGROUND AND PURPOSE

Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT.

EXPERIMENTAL APPROACH

Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP⁺), [³H]5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function.

KEY RESULTS

In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP⁺ accumulation (IC₅₀: 1.4 ± 0.3 µM). A similar effect was observed in N2A cells. Uptake of [³H]5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca²⁺ levels remained unchanged during MB application. Further experiments revealed that ASP⁺ binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 µM; 10 min) did not alter surface binding of the SERT ligand [¹²⁵I]RTI-55.

CONCLUSIONS AND IMPLICATIONS

MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5-HT toxicity.     

A Genotyping Exercise for Pharmacogenetics in Pharmacy Practice

Objective

To develop a genotype exercise to improve pharmacy students’ comprehension of pharmacogenetic principles that apply to patient care.

Design

Deoxyribonucleic acid (DNA) was collected during class from 10 student volunteers and subjected to genotype analysis. The results were presented to the class and discussed in the context of a patient genetic counseling session. Students completed a survey instrument regarding their attitudes toward this learning experience.

Assessment

Students indicated that the exercise engaged them with the course content and would positively influence their ability to apply pharmacogenetic principles to patient care.

Conclusion

An applied genotype exercise enhanced learning of pharmacogenetic principles. Based on these findings, conducting a genotype exercise in a large classroom setting is feasible in terms of time and expense, and meaningful in terms of student satisfaction.     

Learning Across the Curriculum: Connecting the Pharmaceutical Sciences to Practice in the First Professional Year

Objectives

To facilitate the student''s ability to make the connection of the core foundational basic science courses to the practice of pharmacy.

Design

In 2000, 10 faculty members from basic science and practice courses created and implemented an integrated Patient Care Project for which students chose a volunteer patient and completed 15 different assignments

Assessment

Evidence of student learning, such as grades and reflective comments along with collected evaluative data, indicated an enhancement in students'' perceived understanding of the connection between basic science and patient care.

Conclusion

The Patient Care Project provided students an opportunity to use knowledge gained in their first-year foundational courses to the care of a patient, solidifying their understanding of the connection between basic science and patient care.     

Care providers' satisfaction with restructured clinical pharmacy services in a tertiary care teaching hospital

Background:

At the time this study was undertaken, clinical pharmacy services at the authors’ institution, a tertiary care teaching hospital, were largely reactive in nature, with patients and units receiving inconsistent coverage.

Objective:

To develop an evidence-based model of proactive practice and to evaluate the satisfaction of pharmacists and other stakeholders after restructuring of clinical pharmacy services.

Methods:

The literature was reviewed to determine a core set of pharmacist services associated with the greatest beneficial impact on patients’ health. On the basis of established staffing levels, the work schedule was modified, and pharmacists were assigned to a limited number of patient care teams to proactively and consistently provide these core services. Other patient care teams continued to receive reactive troubleshooting-based services, as directed by staff in the pharmacy dispensary. A satisfaction survey was distributed to all pharmacists, nurses, and physicians 18 months after the restructuring.

Results:

Of the 26 pharmacists who responded to the survey, all agreed or strongly agreed that the restructuring of services had improved job satisfaction and patient safety and that other health care professionals valued their contribution to patient care. Nurses and physicians from units where pharmacists had been assigned to provide proactive services perceived pharmacist services more favourably than those from units where pharmacist services were reactive. Pharmacists, nurses, and physicians all felt that proactive pharmacist services should be more widely available. Challenges reported by pharmacists included increased expectations for documentation and guilt about “cutting back” services where they had previously been provided.

Conclusions:

Restructuring clinical pharmacy services in an evidence-based manner improved pharmacists’ satisfaction and created demand from other stakeholders to provide this level of service for all patients.     

Pharmacists’ and Pharmacy Students’ Ability to Identify Drug-related Problems Using TIMER (Tool to Improve Medications in the Elderly via Review)

Objective

Determine the effectiveness of TIMER (Tool to Improve Medications in the Elderly via Review) in helping pharmacists and pharmacy students identify drug-related problems during patient medication reviews.

Methods

In a randomized, controlled study design, geriatric patient cases were sent to 136 pharmacists and 108 third-year pharmacy students who were asked to identify drug related-problems (DRPs) with and without using TIMER.

Results

Pharmacists identified more tool-related DRPs using TIMER (p = 0.027). Pharmacy students identified more tool-related DRPs using TIMER in the first case (p = 0.02), but not in the second.

Conclusion

TIMER increased the number of DRPs identified by practicing pharmacists and pharmacy students during medication reviews of hypothetical patient cases.     

Improvisational Exercises to Improve Pharmacy Students' Professional Communication Skills

Objective

To create and implement improvisational exercises to improve first-year pharmacy students'' communication skills.

Design

Twelve 1-hour improvisational sessions were developed and added to an existing/established patient communication course to improve 3 basic skills: listening, observing and responding. Standardized patient examinations were used to evaluate student communication skills, and course evaluations and reflective journaling were used to evaluate students'' perceptions of the improvisational exercises.

Assessment

The improvisational exercises markedly improved the students'' performance in several aspects of standardized patient examination. Additionally, course evaluations and student comments reflected their perception that the improvisational exercises significantly improved their communication skills.

Summary

Improvisational exercises are an effective way to teach communication skills to pharmacy students.     

An instrument to evaluate pharmacists' patient counseling on herbal and dietary supplements

Objective

To develop a measure of pharmacists’ patient counseling on herbal and dietary supplements.

Methods

A systematic process was used for item generation, testing, and validation of a measure of pharmacists counseling on herbal and dietary supplements. Because a pharmacist-patient encounter may or may not identify an indication for taking an herb or dietary supplement, the instrument was bifurcated into 2 distinct components: (1) patient counseling in general; and (2) patient counseling related to herbal and dietary supplements.

Results

The instrument demonstrated high reliability and desirable construct validity. After adjusting for item difficulty, we found that pharmacists tended to provide more general patient counseling than counseling related to herbal and dietary supplements.

Conclusion

This instrument can be applied to assess the quality of counseling provided by pharmacists and pharmacy students, and the outcomes of pharmacist and pharmacy student education on herbal and dietary supplements.     

Assessment of anticoagulation management in a simulated ambulatory care clinic

Objectives

To assess the effectiveness of adding a simulated anticoagulation clinic practical examination for formal assessment of PharmD students'' skills.

Design

A practical examination requiring students to review a mock medical record and role-play a follow-up anticoagulation clinic visit with a standardized patient was designed. Students assessed the patient''s vital signs, laboratory values, and subjective complaints during an in-depth interview and documented clinical recommendations in a progress note.

Assessment

Student feedback indicated that the simulated clinic was pertinent to preparation for experiential rotations. Ninety-five percent of the students recommended that it be continued as a required component of the course.

Conclusion

The simulated ambulatory care clinic exercise reinforces principles of anticoagulation management as well as the assessment of clinical data, performance of a patient interview, and written documentation of recommendations.     

Using human patient simulation to prepare student pharmacists to manage medical emergencies in an ambulatory setting

Objective

To implement a simulation-based educational experience focused on medical emergencies in an ambulatory pharmacy setting.

Design

Second-year student pharmacists were assigned randomly to groups and played the role of pharmacists in a community pharmacy setting in which a simulated patient experienced 1 of 5 emergency scenarios: medication-related allergic reaction, acute asthma attack, hypoglycemia, myocardial infarction, and stroke. The students were expected to use patient assessment techniques to determine which emergency the simulated patient was experiencing and the appropriate intervention. Following each simulation, a debriefing session was conducted.

Assessment

Eighty-two student pharmacists completed the simulation activity. Ninety-three percent of student groups correctly identified the emergency. A post-activity survey instrument was administered, and 83% of responders indicated this activity was effective or very effective.

Conclusion

Simulation of emergencies seen in an ambulatory pharmacy setting allowed students to assert knowledge, practice communication skills, apply assessment techniques, and work as a team in a low-risk environment.     

A Simulated Interprofessional Rounding Experience in a Clinical Assessment Course

Objective

To implement a simulated interprofessional rounding experience using human patient simulators as a required activity for third-year pharmacy students in a clinical assessment course.

Design

Interprofessional student teams consisting of pharmacy, medical, and physician assistant students participated in a simulated interprofessional rounding experience in which they provided comprehensive medical care for a simulated patient in an inpatient setting.

Assessment

Students completed a survey instrument to assess interprofessional attitudes and satisfaction before and after participation in the simulated interprofessional rounding experience. Overall student attitudes regarding interprofessional teamwork and communication significantly improved; student satisfaction with the experience was high and students’ self-perceived clinical confidence improved after participation. The mean team clinical performance scores were 65% and 75% for each simulated interprofessional rounding experience.

Conclusion

Incorporating a simulated interprofessional rounding experience into a required clinical assessment course improved student attitudes regarding interprofessional teamwork and was associated with high student satisfaction.     

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

AIMS

To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock.

METHODS

Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling.

RESULTS

The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h⁻¹ (49%), a mean half-life of 9.6 h (range 0.83–28.6 h) and a total volume of distribution of 19.5 l (range 6.48–35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low.

CONCLUSIONS

Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l⁻¹).