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: Original Contribution

PROSPECTIVE VALIDATION OF CLINICAL CRITERIA TO IDENTIFY EMERGENCY DEPARTMENT PATIENTS AT HIGH RISK FOR ADVERSE DRUG EVENTS

Short running title: VALIDATING THE ADVERSE DRUG EVENT RULE

Corinne M. Hohl, MD, FRCP(C)1,2,3 Katherin Badke, BPharm4 Amy Zhao, BPharm5 Maeve E. Wickham,

MSc1,2 Stephanie A Woo, BPharm6 Marco L.A. Sivilotti, MD, FRCP(C)7 Jeffrey J. Perry, MD, CCPF (EM)8

1

Department of Emergency Medicine, University of British Columbia, 855 West 12thAvenue Vancouver, British Columbia V5Z 1M9, Canada

2

Centre for Clinical Epidemiology & Evaluation, Vancouver Coastal Health Research Institute, 900 West 10th Ave, Vancouver, British Columbia V5Z 1M9, Canada 3

Vancouver General Hospital Emergency Department, 855 West 12thAvenue Vancouver, British Columbia V5Z 1M9, Canada 4

Department of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada 5

Department of Pharmaceutical Services, The Ottawa Hospital, 1053 Carling Ave. Ottawa ON, K1Y 4E9

6

Clinical Pharmacy Services, Vancouver General Hospital, Vancouver, Canada

7

Department of Emergency Medicine and of Biomedical and Molecular Sciences, Queen’s University, Kingston, 76 Stuart Street, Kingston ON K7L 2V7 8

Department of Emergency Medicine, University of Ottawa, 1053 Carling Ave., E-Main Room EM206, Box 227 Ottawa, Ontario, K1Y 4E9

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/acem.13407 This article is protected by copyright. All rights reserved.

Corresponding Author: Dr. Corinne M. Hohl;

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E-mail: [email protected]

Meetings:

This work was presented at the Canadian Association of Emergency Physicians Meeting in Quebec City, Canada, in June 2016.

Grants:

This work was supported by grants from the Canadian Medical Protective Association and the Ontario AFP Innovation Fund, both non-profit organizations.

Conflicts of Interest:

None to declare.

Author Contributions: The study was designed by CMH, JJP and MLAS. CMH, JJP and MLAS secured funding to conduct the study. MEW obtained ethics approval; KB, AZ and MEW collected the data; MEW, KA and AZ cleaned, and MEW analyzed the data; and all authors interpreted study findings. CMH drafted the manuscript, and all authors review the manuscript critically for content. All authors take full responsibility for the manuscript.

ABSTRACT Objectives: Adverse drug events cause or contribute to one in nine emergency department presentations in North America, and are often misdiagnosed. Emergency departments have insufficient clinical pharmacists to complete medication reviews in all incoming patients, even though pharmacist-led medications reviews have been associated with improved health outcomes. Our objective was to validate clinical decision rules to identify patients presenting with adverse drug events so they could be prioritized for pharmacist-led medication review.

This article is protected by copyright. All rights reserved.

Methods: This multicentre, prospective study was conducted in two tertiary and one community

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hospital in Canada. We enrolled 1529 adults presenting to emergency departments over 12 months. We applied two clinical decision rules and collected baseline variables prior to assessments by clinical pharmacists and physicians. We compared the physician and pharmacist diagnoses with the decision rule results. The primary outcome was a moderate or severe adverse drug event, defined as an unintended and harmful event related to medication use or misuse, which required a change in medical therapy, diagnostic testing, consultation, or admission. An independent committee adjudicated uncertain and discordant cases. We calculated the diagnostic accuracy of both rules.

Results: Among 1529 patients, 184 (12.0%) were diagnosed with an adverse drug event. Rule 1 contained the variables (i) having a pre-existing medical condition or having taken antibiotics within one week, and (ii) age >80 or having a medication change within 28 days. They had a sensitivity of 91.3% (95%CI: 86.3 to 95.0%) and a specificity of 37.9% (95%CI: 35.3 to 40.6%) for adverse drug events.

Conclusions: Our study validated clinical decision rules that can be applied by clinical pharmacists to limit the number of patients requiring medication review, while identifying the majority of patients presenting with clinically significant adverse drug events.


INTRODUCTION

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Background Preventable adverse events related to medical care are a common cause of emergency department visits and hospitalizations, and a leading cause of dealth.1,2 Of deaths attributable to medical care, those related to medications are the most common.3,4 Prospective studies indicate that adverse drug events cause or contribute to one in nine emergency department visits, indicating a large burden of disease.5,6 With the population aging and medication use expanding, these numbers are expected to continue to rise.

Physicians working in emergency departments and on inpatient units do not recognize a medicationrelated cause in 20-50% of adverse drug events.7-10 Lack of timely recognition, correction, and communication of adverse drug events may prolong harmful medication use, and contributes to the excess morbidity, health services use and costs associated with these events.9,11-15 In contrast to physicians, clinical pharmacists whose training and professional practice focus on medication management, are more likely to recognize medication-related presentations.16 Pharmacist-led medication review in high-risk patients in the emergency department has been associated with reduced hospital length of stay among those requiring admission.17,18 Clinical pharmacists remain a scarce and expensive resource, making routine medication review in all incoming patients untenable.19-21 As a result, the majority of patients presenting to emergency departments with clinically significant adverse drug events—recognized or not—are discharged without medication review.5 Evidence-based criteria can enhance the identification and treatment of patients presenting with adverse drug events, and are needed to ensure that high-risk patients are evaluated by clinical pharmacists to optimize their outcomes and reduce subsequent health services utilization.


Our group previously prospectively derived clinical decision rules that allow care providers in

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emergency departments to identify incoming patients presenting with adverse drug events.6 In the derivation study, the objective was to derive clinical decision rules that were sensitive for the detection of adverse events. This would allow their identification early in a patient’s hospital course so that patients could be referred to a clinical pharmacist for medication review. In the present study, our goal was to validate these rules (Figures 1 and 2) by assessing their diagnostic accuracy in a new cohort of patients. A secondary aim was to evaluate the accuracy of variables collected by nurses, to evaluate whether nurses could apply the rules. Based on derivation, our hypothesis was that at least one rule would maintain a sensitivity of >90% in identifying patients with moderate or severe adverse drug events.

METHODS

Study design and setting This was a prospective cohort study that was conducted in two Canadian teaching hospitals (Vancouver General Hospital, Vancouver, British Columbia, and the Ottawa Civic Hospital, Ottawa, Ontario) and one urban community center (Lions Gate Hospital, North Vancouver, British Columbia) with a combined annual emergency department census of 215,000 visits. One of these sites had participated in the previous derivation study.6 The research ethics boards of all participating sites approved the study protocol, and waived the need for informed consent for study enrollment, prospective data collection and subsequent chart review (for follow-up after the emergency department visit). Written informed consent was mandated for any follow-up telephone calls. We set out to validate two clinical decision rules in this study, as evaluating more than one rule at a time increases the chances of successfully validating at least one rule and allowed us to target different performance metrics for different emergency departments.


Selection of participants

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All patients who presented to a participating emergency department between August 2014 and September 2015 during a scheduled data collection shift were eligible for enrollment. We scheduled day (0800h-1559h), evening (1600h-2359h), and weekend shifts proportional to the volume of incoming patients during the same time interval in the prior fiscal year. We did not schedule data collection shifts between 0000h and 0759h as the number of eligible patients presenting at nighttime had been small during the prior derivation study, rendering nighttime enrollment inefficient and costly.6

Enrollment of consecutive eligible patients during data collection shifts would have overwhelmed our ability to complete data collection forms and outcome assessments without disrupting the flow of patients through the emergency departments. In order to minimize the study’s impact on patient flow and enrol a representative sample of patients, research pharmacists used a previouslydeveloped algorithm to systematically select patients for the study from among all incoming patients.5,6 Pharmacists tallied the number of patients presenting in the hour prior to their start time, from which they randomly selected one patient using an online random number generator. As sicker patients tend to linger in the emergency department, and are systematically different from patients discharged rapidly, this strategy allowed us to avoid the selection bias that would have occurred had pharmacists randomly selected from among all patients in the emergency department. After completing enrollment and data collection on the first patient, research pharmacists used fixed time intervals (e.g., 45min) from the first patient’s presentation to approach subsequent eligible patients. This was quicker than re-tallying patients who had presented within the past hour, and ensured that lingering patients could not be sampled more than once. When applied in a previous study,5 this algorithm yielded a sample representative of the age, gender and triage acuity of all presenting patients (unpublished data).


We enrolled patients who were 19 years of age or older, reported using at least one prescription or

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over-the-counter medication in the two weeks prior to presentation, and who either spoke English or had a translator available when they presented to the emergency department. We excluded patients if they exhibited violent behaviour, presented with intentional self-poisoning, needlestick injury or sexual assault, were previously enrolled, presented for a scheduled revisit, transferred directly to an admitting service, triaged to a fast track zone (in which the time to patient disposition was too rapid for enrollment), or left against medical advice or prior to seeing the physician and pharmacist.

Intervention After enrollment, research assistants placed data collection forms containing standardized clinical variables and the clinical decision rules to be validated in patient charts (Figures 1 & 2). The standardized clinical variables were ones that were associated with adverse drug events in the derivation study, but were not used in our final models.6 Emergency department nurses who were unfamiliar with the study were briefly oriented to the study procedures and data collection forms at the beginning of data collection shifts by research assistants. Nurses completed data collection forms during their initial patient assessments, and prior to the research pharmacist’s assessments. Nursing data collection forms were removed from patient charts prior to research pharmacist assessments. We incentivized nurses to use the forms with monthly prize draws; each completed form was counted as one entry toward the prize. Research pharmacists, both residency-trained clinical pharmacists (KB and AZ) who normally worked in the emergency department or on a hospital ward, collected demographic and clinical information in the emergency department, including diagnostic test and imaging findings from emergency physicians and by chart review. They obtained best-possible medication histories using provincewide electronic medication dispensing data from PharmaNet and the Ontario’s Drug Profile Viewer


for all patients in whom data were available, and from patient, family and care provider interviews:

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The pharmacists reviewed the electronic information for medication accuracy, completeness and adherence by interviewing patients and care providers. They determined any over the counter or alternative therapies by patient and care provider interviews. When required, they called the patients’ family physicians and community pharmacists for clarification. Given the inclusion of patients who might not be able to provide an accurate history (e.g., patients with delirium) and the difficulty of asking nurses to collect detailed, high-quality medication data in busy emergency departments, we pre-specified that when nursing variables were missing or inaccurate, we would replace them with variables derived from hospital registration, laboratory and medicationdispensing data (i.e., PharmaNet for patients enrolled in BC, and Ontario Drug Benefits Program for low-income and >65 year-old patients enrolled in Ontario). Variables derived from electronic medication-dispensing data were verified by research pharmacists when collecting a best possible medication history, and were documented prior to outcome assessments. Outcome ascertainment Research pharmacists evaluated whether or not the patient presented with an adverse drug event using a validated causality algorithm, previously adapted to our adverse drug event definition.22 After completing and documenting their outcomes assessments, pharmacists interviewed the treating physician using a standardized questionnaire to determine whether or not the physician believed the patient had suffered an adverse drug event (yes/no/uncertain), and to identify any alternative diagnoses for the patient’s presentation. When the physician and pharmacist determinations of a patient’s adverse drug event status were concordant (ratings yes/yes or no/no), this was considered the criterion standard. If there was any disagreement (ratings yes/no, yes/uncertain or no/uncertain), or if both ratings were uncertain, an independent committee, comprising of a pharmacist and physician otherwise uninvolved in the study, adjudicated the case using a previously-developed algorithm (Figure 4).5


If enrolled patients were admitted to hospital, we followed their course of care until discharge by

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chart review, and telephoned consenting patients after hospital discharge, if follow-up was necessary to determine whether or not an adverse drug event was present upon presentation (e.g., for the results of C.difficile toxin assays pending at discharge).

Outcome definition Varying case definitions of adverse drug events exist.23-26 We defined the primary outcome, an adverse drug event, as an “untoward and unintended event arising from the appropriate or inappropriate use of a prescription or over-the counter medication.”23,25,26 Adverse drug events included adverse drug reactions, a response to a prescription or over-the-counter drug that is noxious and unintended, and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease,26 and events due to non-adherence or drug withdrawal, errors in prescribing, dispensing or medication administration, drug interactions, supra or subtherapeutic dosing, untreated indications and inappropriate drug use. The severity of all adverse drug events was rated as: (a) severe, if the event caused death or required admission; (b) moderate, if it resulted in a change in medical management (medical therapy, a diagnostic procedure or consultation); and (c) mild, if the event required no change in therapy.5 To meet the outcome definition we pre-specified that events had to be categorized as at least moderate in severity, based on the actions of the treating physician. All events identified in this study are described in more detail in Appendix A. Events were categorized as related to the chief complaint, if the patient’s chief complaint was a direct result of the adverse drug event (e.g., “vomiting blood” in a patient with an non-steroidal antiinflammatory induced gastric ulcer), and categorized as incidentally found if it the chief complaint was unrelated to the adverse drug event (e.g., “fall” in a patient found to have an INR of 6).


Analysis

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We calculated the inter-rater reliability of the outcome measure during the pilot period using Cohen’s κ, and reported it with 95% confidence intervals (CIs).27 The sample size calculation was based on the clinical decision rule maintaining a sensitivity of >90% with a desired precision of +5%.6,28 Given a conservative prevalence of 10% for moderate and severe adverse drug events in prior studies, we estimated requiring a sample size of 1500 to capture 150 outcomes.5,6 This would yield an accuracy of 95%CIs between 85% to 94% for a rule with an estimated 90% sensitivity.

We performed a planned interim analysis at midpoint of data collection. First, we assessed the quality of data collected by nurses by evaluating the proportion of patients misclassified for four key variables for which objective comparisons were available in administrative data: age category (i.e., > or < 80 years), renal failure (i.e., creatinine > or or < 4 medications) and recent medication changes. To be acceptable for uptake into clinical practice, our goal was to validate rules that were parsimonious and accurate. A priori, we aimed for fair specificity while maintaining sensitivity above 90%.19 We collected additional potential predictor variables and measured their univariate associations with the study outcome using two-sided Student’s t-tests and the Pearson χ2 test.

We calculated the sensitivity, specificity, and post-test predictive values for each of two rules for identifying patients presenting with one or more adverse drug events with 95% CIs. For the purpose of estimating the proportion of patients who would be identified as high-risk by the rules if implemented in clinical practice, we emulated a prior implementation study, in which we categorized all excluded patients as low-risk, as they were either clinically deemed to be a very lowrisk of an ADE (e.g., on no medications within 2 weeks, presenting with needlestick injuries, sexual


assault, imaging results, etc.), or medication review in the ED would not be feasible without incurring

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substantial additional resources or changes in patient flow (e.g., not English speaking and no translator available, or presented for a direct admission).17,18 Thus, we determined the proportion of patients who would be identified as high-risk by the rules in clinical practice, by determining the proportion who screen positive, over all approached patients (N=2513). We used Stata/SE, version 13 for all analyses. RESULTS

Characteristics of study subjects We enrolled 1529 patients between September 2014 and August 2015. The patient flow diagram is depicted in Figure 3. The average age of enrolled patients was 59.3 years, 55.7% were female, and the median number of prescribed medications was 5 (interquartile range [IQR] 3, 9; Table 1).

Assessment of outcomes The inter-rater reliability of the pharmacist assessments of adverse drug events during the pilot period was 0.86 (95%CI 0.6 - 1.0). In 1369 (89.5%) of patients, the clinical pharmacist’s and treating physician’s outcome assessment was concordant; all others were adjudicated by an independent committee (Table 2). In total, 170 patients with missing physician assessments (n=46), or discordant or uncertain ratings (n=124) were adjudicated, of whom 85 met the final outcome definition. Three patients with a missing physician assessment were ultimately diagnosed with an ADE. Physicians did not recognise the ADE in 63/181


(34.8%) patients, and were uncertain about 28/181 (15.5%) patients who met the final

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outcome definition.

Among enrolled patients, 184 (12.0%, 95% CI 10.4-13.8%) were diagnosed with 202 moderate or severe adverse drug events meeting the primary outcome definition, and thus required a change in medical management according to the treating emergency physicians (Figure 3, Appendix A). These included 96 (6.3%, 95% CI 5.1-7.6%) adverse drug reactions. Of 184 patients, 76.6% (95% CI: 69.8-82.5%) experience adverse drug events that were chief complaint-related, and 23.4% (95%CI: 17.5-30.2%) had events that were incidentally found by pharmacists. None of these were fatal. In 34.5% (95% CI 27.5– 42.1%) of cases ultimately attributed to adverse drug events, emergency physicians did not attribute the presentation to a drug (Appendix B). They were uncertain about whether an adverse event had occurred in an additional 16.1% (95% CI 11.0-22.4%).

Main results Standardized variables strongly associated with adverse drug events included age, use of opioids, antihypertensives or antibiotics, recent medication changes, and the number of prescription medications (Table 2). Nurses misclassified 2.7% (8/311) of patients over 80 years old as being younger, 60.5% (26/43) of patients with creatinine values of over 150 µmol/L as not having renal failure, 45.4% (465/1023) of patients taking four or more regular medications as taking less, and 40.7% (319/783) of patients with recent medication changes as having not had changes to their medications. As a result, we assessed the rules’ accuracy


using variables derived from hospital registration, laboratory, and PharmaNet data for

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medication-related variables.

Rule 1 identified 168/184 patients experiencing an adverse drug event for a sensitivity of 91.3% (95% CI 86.3 to 95.0%), and a specificity of 37.9% (95% CI 35.3 to 40.6%; Figure 1). These criteria identified 39.9% of all incoming patients as high-risk, after excluding patients who did not meet inclusion criteria and would have therefore been deemed “low risk” by the rule (N = 2513 patients).

Rule 2 identified 176/184 adverse drug events, yielding a sensitivity of 95.7% (95%CI: 91.6 to 98.1%) and a specificity of 22.8% (95%CI: 20.6 to 25.2%; Figure 2). These criteria identified 48.3% of all incoming patients as high-risk after excluding patients who did not meet inclusion criteria and would have therefore been deemed “low risk” by the rule (N = 2513 patients).

DISCUSSION

We validated criteria to identify emergency department patients presenting with clinically significant adverse drug events in a new cohort of patients. Both sets of criteria we evaluated were sensitive for the detection of this outcome. Implementation of either tool would allow clinical pharmacists to rapidly screen patients entering emergency departments for their risk of adverse drug events prior to proceeding with full medication review. We previously demonstrated the value of this strategy in a prospective implementation study in one tertiary and two community hospitals, in which pharmacist-led medication review in the emergency department was associated with a reduction in subsequent hospital-bed utilization in high-risk patients.17,18 Given the multitude of other tasks


pharmacists are expected to fulfill in busy emergency departments, these criteria can help identify

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high-risk patients likely to benefit from medication review, as well as low-risk patients in whom the intervention can safely be omitted. In addition to validating the clinical decision rules, our study confirms the high proportion of patients who present to emergency departments with clinically significant adverse drug events,5,6,29 as well as the significant proportion of events that physicians are unlikely to attribute to a medication-related cause without pharmacist assessment,7,8,10 highlighting the need to improve care for this patient group.

Even though the specificity of our rules was limited, adverse drug events were so common that pharmacists identified clinically significant events in every 5th high-risk patient. Without the rules in place, all patients would have needed to be seen by a clinical pharmacist in order to redress the high rate of adverse drug events that would not have been attributed to a medication-related cause by physicians. We believe that reducing this number by 60% represents a substantial improvement.

Medication and laboratory-based variables collected by nurses at the point-of-care were inaccurate. Therefore, we validated the criteria using variables derived from hospital registration, laboratory and outpatient medication dispensing data with clinical pharmacists verifying the medication history with the patient or their family. As a result, the rules can be implemented by clinical pharmacists as a rapid screening tool in centres that do not yet have access to electronic medication dispensing or other electronic data, allowing those hospitals to reduce hospital bed utilization in high-risk patients. 17,18

With the near universal adoption of electronic health records in the United States over the past decade, their accelerating uptake throughout Canada, and plans to develop electronic drug information hubs in the Canadian provinces, these rules may be automated and integrated into


electronic medical records to provide patient-level decision support.30,31 Even in jurisdictions

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without access to electronic medication dispensing data, algorithms can be developed which allow the electronic medical record to auto-populate the rules with known data elements (e.g., age), so that the pharmacists can efficiently screen patients by entering only data not already contained in the electronic medical record. Once integrated into electronic medical records, automated screening is likely to facilitate their widespread uptake.

Strengths of this study include adherence to methodological standards for the validation of clinical decision rules, and patient enrollment from tertiary care and community hospitals in two provinces, enhancing their generalizability.32 Study subjects were selected using a standardized enrollment algorithm to ensure a representative sample. The outcome measure was clearly defined, prospectively ascertained, and independently assessed by two raters, a pharmacist and a physician. If any disagreement or uncertainty occurred, an independent committee adjudicated the case. Clinical variables used as predictors were standardized, and collected prior to determination of the patient’s outcome. The most commonly implicated culprit medications and adverse drug events were consistent with those identified in population-based estimates from the United States, and therefore, the rules are likely generalizable to other hospitals and jurisdictions.33,34 We tested the accuracy and effectiveness to two different sets of criteria; less sensitive but simpler criteria for centers with less clinical pharmacists, and more sensitive criteria for centres with greater pharmacist availability.


Limitations

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There is generally a trade-off between the sensitivity and specificity of diagnostics tests. As a result, we deliberately did not set the desired sensitivity of our criteria to 100%, allowing us to maintain a higher specificity which would facilitate the uptake of this tool into clinical practice. While some clinicians may view this as a disadvantage, recognition of 90% of events represents a substantial improvement of the current practice in which only 51-62% of events are identified by emergency physicians.7,8,10

We assessed the accuracy of nursing variables given the challenges experienced with prospective data collection in busy emergency departments in other studies, and found their accuracy inconsistent. In retrospect, we might have been able to mitigate this by training nurses more carefully on the application of the rules. However, based on our obserations we concluded that rules based on data collected by nurses at the point-of-care may not achieve high accuracy, and used variables derived from hospital registration, laboratory and medication dispensing data that had been verified by clinical pharmacists. This means that the criteria can be applied by clinical pharmacists who work in emergency departments as rapid screening tools to identify high-risk patients. Alternatively, the criteria can be integrated as electronic algorithms into electronic medical records with access to electronic data to provide automated patient-level decision support tools; however, this will be limited by the ability of medication dispensing data to reflect the real-world medication regimen of the patient. Due to a restrained study budget, we were unable to enroll patients at night-time, limiting the generalizability of our findings, as night-time data collection was inefficient and costly in derivation.6 While we hope future validation studies will address this limitation, current pharmacist staffing models in most North American emergency departments generally exclude nighttime coverage, making our study generalizable to those patients in whom the rules would applied in.35 Finally, as we regarded adverse drug events as diagnoses of exclusion, some


presentations that are commonly multifactorial (e.g., falls, delirium) may have been

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underrepresented in our outcomes, as we would have categorized these as non-adverse drug events unless alternative diagnoses had been ruled out.

Conclusions

We validated clinical criteria that enable emergency department pharmacists to rapidly and efficiently screening patients for adverse drug events, allowing them to capture the majority of these events at the earliest time point within a hospital encounter, and limit harm. The enthusiasm for more widespread application of medication management interventions and current Canadian hospital accreditation standards, refect the relevance of this strategy to current healthcare practices. In future studies, these rules can serve as a starting point to develop risk stratification methods for patients in other practice settings in which adverse drug events are common.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the physicians and nurses working at Vancouver General, Lions Gate and the Ottawa Civic Hospitals. This study would not have been possible without their dedication and support. A particular thanks to Drs. Gina Gill, Frank Scheuermeyer and Christina Bui for their service on the adjudication committee. Thanks to Dr. Vi Ho, Kelsey Seal, Puneet Vashisht, Carl Chan and Robert Yao for their assistance in data collection. Lastly, the entire research team thanks all patient participants for their willingness to be involved in the research process and patience with data collection.


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Figure 1. Rule 1 used to screen for moderate or severe adverse drug events, and its classification performance

Has the patient taken medications in the past 2 weeks?*  Yes

 No

→

LOW RISK

↓ Does the patient have any pre-existing medical problems or has the patient taken antibiotics in the past 7 days?  Yes

 No

→ LOW RISK

↓ Is the patient >80 years old or has the patient changed any medications in the past 28 days?**  Yes

 No

→ LOW RISK

↓ HIGH RISK

* During clinical decision rule derivation having taken medication in the previous 2 weeks was an inclusion criterion; however, during piloting the triage nurses applying the rule asked that this criteria be built into the first step of each rule to enhance its ease of use and functionality. ** Medication changes included medication stops and starts, and changes to dose, frequency or route of administration.


Accepted Article

ADE

Decision Rule

Yes

No

Positive

168

835

Negative

16

510

Sensitivity 91.3% (95% CI 86.3 to 95.0%) Specificity 37.9% (95% CI 35.3 to 40.6%) Negative Predictive Value 97.0% (95% CI 95.2 to 98.1%) Positive Predictive Value 16.8% (95% CI 15.9 to 17.6%) Positive Likelihood Ratio 1.47 (95% CI 1.38 to 1.56) Negative Likelihood Ratio 0.23 (95% CI 0.14 to 0.37)


Accepted Article

Figure 2. Rule 2 used to screen for moderate or severe adverse drug events, and its classification performance.

1. Has the patient taken medications in the past 2 weeks? *  Yes

 No → LOW RISK

↓ 2. Does the patient have any pre-existing medical problems, or has the patient taken antibiotics in the past 7 days?

 Yes

 No → LOW RISK

↓ 3. Any moderate-risk criteria present: - Change in medications within 28 days - Arrival by ambulance & CTAS 1 - 3 - Admission to hospital within 1 month - History of renal failure or creatinine >150umol/L - Taking 4 or more prescription drugs  Yes

 No → LOW RISK

↓ HIGH RISK

*During derivation having taken medication in the previous 2 weeks was an inclusion criterion; however, during piloting the nurses applying the rule asked that this criteria be built into the first step of each rule to enhance its ease of use and functionality. ** Medication changes included medication stops and starts, and changes to dose, frequency or route of administration. CTAS: Canadian Triage Acuity Score


Accepted Article

ADE Decision Rule

Yes

No

Positive

176

1038

Negative

8

307

Sensitivity 95.7% (95% CI 91.6 to 98.1) Specificity 22.8% (95% CI 20.6 to 25.2) Negative Predictive Value 97.5% (95% CI 95.1 to 98.9%) Positive Predictive Value 14.5% (95% CI 14.0 to 15.0%) Positive Likelihood Ratio 1.24 (95% CI 1.19 to 1.29) Negative Likelihood Ratio 0.19 (95% CI 0.10 to 0.38)


Accepted Article

Figure 3. Patient flow

2513 Patients selected by the algorithm 747 Excluded  242 No medications within 2 wks  115 Direct transfer for admission  105 Under 19 years of age  81 Scheduled revisit  53 Refused participation  51 Triaged to Rapid Assessment Zone

1766 Patients enrolled

 44 Left against medical advice  29 Intentional overdose, needlestick 232 Excluded injury, sexual assault  Left prior to completion of nursing and assessment available  pharmacist 21 No English/translator

Assessment for study outcomes  6 Violent behavior

1345 Outcomes absent*

202 Outcomes present in 184 pts** Adverse drug reaction=96 Non-adherence=38 Drug withdrawal=7 Sub/supratherapeutic dose=35 Drug interaction=3 Therapeutic failure=10

* No moderate or severe adverse drug events identified

x

** At least one moderate or severe adverse drug event identified

A d v e r s e

Untreated indication=8 Prescription errors=5


d r u g

Accepted Article This article is protected by copyright. All rights reserved.

Table 1. Characteristics of enrolled patients.

Accepted Article

Characteristics

Number of patients (N=1529)

Mean (SD) age in years

59.3 (20.9)

Age > 80 years (%)

331 (21.7%)

Female (%)

851 (55.7%)

Arrived by ambulance (%; n=1492)

496 (33.24%)

Canadian Triage Acuity Score (%) CTAS 1

18 (1.2%)

CTAS 2

418 (27.4%)

CTAS 3

794 (52.0%)

CTAS 4

273 (17.9%)

CTAS 5

23 (1.5%)

Most common chief complaints (%; n=1432) Abdominal Pain

127 (9.72%)

Chest Pain

127 (9.72%)

Shortness of Breath

62 (4.72 %)

Most common comorbid conditions (%) Hypertension

497 (32.5%)

Mental Health Diagnosis

385 (25.2%)

Atrial Fibrillation

153 (10.0%)

Mean (SD) comorbid conditions

0.96 (1.05)

Most common prescription medications (%) Levothyroxine

228 (14.9)

Pantoprazole

218 (14.3)

Atorvastatin

208 (13.6)

Ramipril

165 (10.8)

Metformin

159 (10.4)


Accepted Article

Median (IQR) of prescription medications

5 (3, 9)

Complementary and alternative medication use (%)

708 (47.64%)

Illicit drug use (%)

123 (8.22%)

Followed by a general practitioner (%)

1331 (88.26%)

Hospital Admission (%)

237 (15.5%)

Died in Hospital (%)

0 (0.0%)

SD: standard deviation; CTAS: Canadian Triage Acuity Score; IQR: Interquartile range

Table 2. Outcomes assessment by provider group.

Physician Ratinga Pharmacist Rating

No ADE

ADE

Uncertain

Total

1,200

13b

20b

1,233

ADE

79b

99

15b

193

Uncertain

32b

7b

18b

57

1,311

119

53

1483

No ADE

Total

a. Physician assessments were missed in 46 patients; all of which went to adjudication b. All discordant and uncertain cases (n=124) were adjudicated

All cases in whom a rating was missing, or in whom ratings were discordant or uncertain were adjudicated by an independent committee otherwise uninvolved in the study. Cases in which the pharmacistss and physcian’s ratings were concordant (ADE/ADE or no ADE/no ADE) were considered final.


Table 3. Univariate association between standardized variables and adverse drug events.

Accepted Article

Outcome Measure, No. (%)

Difference (95% CI)

No ADE

ADE

(n=1345)

(n=184)

Mean age, yrs (SD)

58.4 (20.9)

66.1 (19.8)

7.7 (4.5 - 10.9)*

Age cutoff > 80 (%)

274 (20.4)

57 (31.0)

10.6 (4.0 - 17.9)*

Female (%)

742 (55.2)

109 (59.2)

4.1 ( -3.6 - 11.4)

CTAS 1

16 (1.2)

2 (1.1)

0.1 (0.0- 1.2)

CTAS 2

357 (26.6)

61 (33.3)

6.6 (0.0 - 14.1)

CTAS 3

692 (51.5)

102 (55.4)

3.9 (-3.7 - 11.5)

CTAS 4

257 (19.1)

16 (8.7)

10.4 (5.1 - 14.4)*

CTAS 5

21 (1.6)

2 (1.1)

0.5 (0.0 - 1.6)

Creatinine > 150mmol/L (%)**

25 (5.4)

18 (19.2)

13.8 (6.9 - 22.7)*

Illicit Drug Use (%)

106 (7.9)

17 (8.9)

1.0 (-2.7 - 6.1)

Antihypertensives

436 (32.4)

90 (48.9)

16.5 (8.9 - 24.1)*

Aspirin

254 (18.9)

43 (23.3)

4.5 (-1.5 - 11.4)

Opioid

157 (11.7)

43 (23.3)

11.7 (5.9 - 18.5)*

Antibiotic

149 (11.1)

35 (19.0)

7.9 (2.6 - 14.4)*

Insulin/hypoglycemic

110 (8.2)

31 (16.8)

8.7 (3.7 - 14.9)*

Benzodiazepines

136 (10.2)

20 (10.9)

0.8 (-3.4 - 6.3)

44 (3.3)

9 (4.7)

1.6 (-1.0 - 5.8)

64 (4.8)

17 (9.2)

4.5 (0.9 - 9.6)*

136 (10.1)

31 (16.9)

6.7 (1.7 - 13.0)*

Heart failure

97 (7.2)

24 (13.0)

5.8 (1.5 - 11.6)*

Atrial fibrillation

107 (8.0)

22 (12.0)

4.0 (0.0 - 9.6)

Characteristic

Canadian Triage Acuity Score (%)

Present medication use (%)

Antiepileptic

Medical history (%) Renal failure Diabetes


Mental health diagnosis

212 (15.8)

33 (17.9)

2.1 (-3.1 - 8.6)

684 (52.4)

141 (82.0)

25.8 (18.6 - 31.9)*

On >4 prescription medications (%)**

560 (42.8)

126 (73.3)

26.8 (19.3 - 33.6)*

Antibiotic use within 7 days

146 (10.9)

38 (19.9)

9.0 (3.6 - 15.4)*

Ambulance arrival (%)**

424 (32.2)

72 (40.7)

7.6 (0.4 - 15.2)*

Hospitalized in the past 28d (%)**

217 (18.8)

40 (25.2)

5.6 (0.0 - 12.4)

Med Changes within 28d (%)

863 (64.2)

154 (83.7)

19.5 (12.7 - 24.9)*

Assistance taking medications (%)**

229 (17.5)

45 (25.7)

7.4 (1.4 - 14.4)*

Accepted Article

On >3 prescription medications (%)**

* Statistically significant at p < 0.05 ** Denominator less than 1345 for patients without, and 184 for patients with ADEs. ADE: adverse drug event; SD: standard deviation; CTAS: Canadian Triage Acuity Score


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Appendix A. Adverse Drug Events meeting the primary outcome definition (N = 202) identified in 184 of 1529 patients.

ID

Symptom/Diagnosis

Culprit Medication(s)

Laboratory Value

Severity

Case Description

Moderate

48F presented with a 1-day history of nausea and vomiting after starting doxycycline 3 days ago for a lung infection. Doxycycline was discontinued.

Severe

77F presented with nausea and vomiting for 3 weeks. She was admitted for the management of acute kidney injury. She was treated for hyperkalemia, and ramipril was stopped.

Moderate

66M presented with falls, ataxia, and slurred speech secondary to carbamazepine. Carbemazepine was switched to levetiracetam and his symptoms resolved.

Moderate

73M presented with shortness of breath and a BP of 74/51. He had been discharged from hospital 3 days prior with a diagnosis of metastatic lung cancer. During that admission, his candesartan and furosemide were held before being restarted prior to discharge. On the index ED visit his hypotension was thought to be due to volume depletion from furosemide. He refused to be admitted. His atenolol dose was halved, and candesartan and furosemide were stopped.

Adverse Drug Reactions 1047

Nausea, vomiting

Doxycycline

1058

Hyperkalemia

Ramipril

1071

Ataxia, slurred speech, falls

Carbamazepine

1089

1089

Hypotension

Acute kidney injury

K 8.2 mmol/L

Furosemide, atenolol

Candesartan, recent CT contrast dye, furosemide


SCr 2.9 mg/dL

Moderate

73M presented with shortness of breath and found to have an increased creatinine (baseline 1.55mg/dL). He had been discharged from hospital 3 days prior with a diagnosis of metastatic lung cancer. During that admission, candesartan and furosemide were held before being restarted prior to discharge. On the index visit the acute kidney injury was thought to be due to volume depletion from furosemide, with candesartan and

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contrast dye contributing. He refused to be admitted; candesartan and furosemide were stopped.

1123

Subdural and subarachnoid hemorrhage

Warfarin

INR 5.2

Severe

81F presented with a traumatic subarachnoid hemorrhage and subdural hematoma post fall. She was admitted to hospital, where her warfarin was held and not re-prescribed.

1153

Diarrhea

Amoxicillin/clavulanate

C. diff. +

Severe

45F with a history of severe C. difficile colitis was prescribed amoxicillin/clavulanate for sinusitis. She developed recurrent colitis requiring hydration and metronidazole.

Severe

36F presented with severe neck pain after a naturopath had been injecting her with multivitamins multiple times a week without a medical indication. She was diagnosed with cervical osteomyelitis and required 6 weeks of antibiotics.

Severe

84F presented with confusion and acute renal failure. Culprit medications were held on admission, and her kidney function improved. No alternative causes were identified.

1155*

Discitis

Intravenous vitamins

1163

Hyperkalemia & increased acute kidney injury

Candesartan

1174*

Gastritis, ulcer

Naproxen

Moderate

62F presented with abdominal pain while on naproxen. She was diagnosed with NSAID-induced gastritis and an ulcer. Naproxen was discontinued and pantoprazole initiated.

1178

Gastritis

Ibuprofen

Moderate

20F presented with a 3-day history of abdominal pain, nausea and vomiting after taking ibuprofen for 1 week. No alternative causes were identified, and ibuprofen was held.

1181

Hypokalemia

Furosemide

Moderate

76F presented with dizziness and found to have hypokalemia on furosemide. Her potassium was replaced, and added her to medication regimen.

1184*

Diarrhea

Doxycycline

K 6.0 mmol/L, SCr 6.6 mg/dL


K 2.9 mmol/L

Moderate

55M presented with nausea, diarrhea and abdominal pain. Antibioticinduced diarrhea was felt to be the most likely cause. Symptoms resolved

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1225*

after discontinuation.

Hyponatremia

Hydrochlorothiazide

Na 125 mmol/L

Moderate

89F was incidentally found to have hyponatremia on presentation. Hydrochlorothiazide was discontinued, and her sodium corrected after several days.

Moderate

84M presented with ataxia after accidentally taking a double dose of clobazam prior to presentation. No alternative cause was found, and the ataxia resolved after discontinuation.

1250

Ataxia

Clobazam

1269

Hyponatremia

Hydrochlorothiazide

Na 114 mmol/L

Severe

88F presented with confusion and weakness. She was admitted to hospital and hydrochlorothiazide was stopped.

1293

Acute kidney injury

Perindopril

SCr 1.8mg/dL

Moderate

90M presented with respiratory distress and found to have and an elevated serum creatinine (baseline 1.2mg/dL). His perindopril dose was decreased.

Moderate

92F on high doses of nitrazepam presented with a fall. She was admitted for work-up that revealed orthostatic hypotension. Fludrocortisone was added to her medications, and nitrazepam stopped as it was felt to have contributed.

1330*

Fall

Nitrazepam

1334

Confusion

Zopiclone, baclofen

Moderate

73F presented with confusion after adding baclofen to her medication regimen. No alternative cause was identified. She returned to baseline after both medications were held.

1347

Dizziness

Diphenhydramine, pseudoephedrine, codeine, triprolidine

Moderate

81F presented with dizziness after starting cough syrup 3 days prior. She was diagnosed with a viral illness and instructed to stop the cough syrup. Her dizziness resolved.

Moderate

77M was admitted for the management of septic arthritis. He had a 4-day history of narcotic-induced constipation. Docusate was added to his medication regimen.

Moderate

65M presented for a wound check for a necrotic leg, and was found incidentally to be hyperglycemic. The patient had not previously been

1351*

Constipation

Methadone, oxycodone

1365

Hyperglycemia

Prednisone


BG 822.6 mg/dL

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diagnosed with diabetes. Prednisone was discontinued and his hyperglycemia treated.

1384

Febrile neutropenia

Eribulin

WBC 0.3 x109/L

Severe

69F with breast cancer presented with fever 7 days after receiving chemotherapy. She was hospitalized and treated with intravenous antibiotics.

1408

Hematoma

Warfarin

INR 3.9

Moderate

30M presented with swelling and pain in his right calf after getting kicked 5 days prior. His warfarin was felt to have contributed, and his dose was decreased.

1423*

Nausea

Hydromorphone

Moderate

44F presented with nausea after taking hydromorphone for cancer related pain. Her nausea was treated, and she was switched to a fentanyl patch.

1431*

Constipation

Hydromorphone

Moderate

43M sent in to rule out a post-operative infection. He had been constipated since starting hydromorphone, and was started on sennosides.

Moderate

68F presented with fever, diaphoresis, chest discomfort, vomiting and weakness since receiving chemotherapy 4 days ago. The nausea and vomiting were felt to be related to chemotherapy, and treated symptomatically.

Severe

68F presented with fever, diaphoresis, chest discomfort, vomiting and weakness since receiving her chemotherapy 4 days prior. She was hospitalized and treated with intravenous antibiotics for a suspected infection.

Moderate

97F presented with hypotension (BP 85/63) and a fall causing a lumbar spine compression fracture. Daily doses of furosemide and ramipril were felt to have contributed. Both drugs were held, and the patient was admitted.

Moderate

67F presented with urinary retention since starting desmopressin for nocturia. Desmopressin was discontinued, and her symptoms resolved.

1439

1439

Nausea

Pancytopenia

Paclitaxel, carboplatin

Paclitaxel, carboplatin

1449

Hypotension, fall

Ramipril, furosemide

1472

Hyponatremia, abdominal pain, urinary retention

Desmopressin


9

ANC 1.3 x10 /L

Na 127 mmol/L

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Moderate

77M presented with weakness after treatment for a recent prostate abscess. He was found to have acute kidney injury, and was admitted to hospital. After hydration and removal of nephrotoxic medications, his kidney function improved.

Bisoprolol

Moderate

82M presented with a HR of 39, and diagnosed with second degree type 2 AV block. Bisoprolol was held.

Doxycycline

Moderate

75F developed a rash after taking doxycycline. A skin biopsy confirmed the diagnosis of a drug eruption.

Hyperkalemia, acute kidney injury

Ramipril, trimethoprim/

K 6.8 mmol/L,

sulfamethoxazole

SCr 2.9 mg/dL

1558

Bradycardia

1597

Rash

1478

1637

Acute kidney injury

Furosemide, losartan

SCr 2.6 mg/dL

Moderate

80F presented after a collapse while on furosemide and losartan, and was found to have an elevated creatinine (baseline 2.1mg/dL). Furosemide was held.

1645*

Hypokalemia

Hydrochlorothiazide

K 3.0 mmol/L

Moderate

93F presented with weakness and chest tightness. She was found to be hypokalemic. Hydrochlorothiazide was stopped.

1674*

Oral thrush

Fluticasone

Moderate

93F presented with recurrent oral thrush while on fluticasone for COPD. She was treated with nystatin.

Severe

27M presented with pancytopenia after chemotherapy for hemaphagocytic lymphohistiocytosis. He was transfused. Even though he was later diagnosed with a gastrointestinal bleed, chemotherapy was felt to have contributed.

1716

Anemia, thrombocytopenia

Ifosfamide, carboplatin, etoposide

Hb 87 g/dL, platelets 34 x109/L

1739*

Hyponatremia

Hydrochlorothiazide

Na 116 mmol/L

Severe

65M had been recently admitted for hyponatremia while on hydrochlorothiazide. Hydrochlorothiazide had been restarted on discharge and he returned to the ED with symptomatic hyponatremia. Hydrochlorothiazide discontinued.

1741

Hypokalemia

Furosemide

K 3.0 mmol/L

Moderate

87F presented with hematuria. She was found to have hypokalemia. Potassium was added to her medications.

1750*

Hypokalemia, acute

Furosemide

K 3.0 mmol/L,

Moderate

74F with chronic lymphocytic leukemia presented to the ED with


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kidney injury

1752

Anemia

1783

Medication overuse headache

1804

Systemic inflammatory response syndrome

1804

Nausea, vomiting

SCr 3.1 mg/dL

weakness, and was admitted for cellulitis and acute kidney injury. Her potassium was replaced and furosemide discontinued. Moderate

77M presented with weakness after receiving chemotherapy for colon cancer 3 weeks prior. He was transfused.

Moderate

54F with a history of headaches presented with headache while on multiple NSAIDs. Topiramate was restarted and NSAIDs were discontinued.

Gemcitabine

Severe

81F presented with a fever, hypotension, tachycardia, vomiting and diarrhea after receiving chemotherapy for uterine cancer 3 days prior. She was admitted for presumed sepsis, but was eventually diagnosed with gemcitabine-related systemic inflammatory response syndrome.

Gemcitabine

Moderate

81F presented with a fever, hypotension, tachycardia, vomiting and diarrhea after receiving chemotherapy for uterine cancer 3 days prior. She was treated for nausea and vomiting related to chemotherapy.

Moderate

60F presented with weakness and shortness of breath. She had an incidental finding of hypokalemia 2 weeks after starting furosemide. Potassium was added to her regimen.

Moderate

33F presented with anxiety and a weight gain of 30 lbs since starting pregabalin 3 weeks previously for chronic pain. Pregabalin was stopped. No alternative cause was found.

Moderate

33F presented with anxiety and dizziness since starting pregabalin for chronic pain 3 weeks prior. Pregabalin was discontinued. No alternative cause was found.

Moderate

73F was found to have decreased level of consciousness secondary to hypoglycemia. She had taken glyburide despite skipping dinner. She was switched to gliclazide.

Fluorouracil, irenotecan

Hb 62 g/dL

Meloxicam, ketorolac, ibuprofen

1805*

Hypokalemia

Furosemide

1832

Weight gain

Pregabalin

1832

Dizziness

Pregabalin

1870

Hypoglycemia

Glyburide


K 3.3 mmol/L

BG 30.6 mg/dL

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1957

Diarrhea

Divalproex

1962

Diarrhea

Cefuroxime, possibly nitrofurantoin

1967

Upper GI Bleed

Warfarin

2001

C. diff. +

Moderate

52F presented with 1 day of diarrhea after increasing her divalproex dose 1 week prior. Divalproex was stopped, and her symptoms resolved. No alternative cause was identified.

Severe

92F presented with a fall and diarrhea a week after receiving nitrofurantoin followed by cefuroxime for a urinary tract infection. She was hospitalized with C. difficile colitis.

Severe

63F presented with melena. She required transfusion and was admission for an upper GI bleed. Warfarin was stopped.

Moderate

85F presented with nausea and abdominal pain after taking hydromorphone for pain. She had similar reactions to hydromorphone in the past. Hydromorphone was stopped.

Severe

65F presented with fatigue, epigastric pain, anorexia, pruritus, and dark urine while on atovaquone/proguanil. She was diagnosed with druginduced hepatitis, and atovaquone/proguanil was discontinued.

Hb 110g/dL, INR 5.2

Epigastric pain

Hydromorphone

LFT > 5x upper limit of normal

2011

Hepatitis

Atovaquone/proguanil

2021

Constipation

Oxycodone, ferrous sulfate

Moderate

20M presented with chest pain and constipation after knee surgery. Laxatives were added to his medication regimen.

2046

Constipation

Codeine

Moderate

28M presented with constipation on codeine. Tylenol 3 was discontinued.

2063

Hypokalemia, supraventricular tachycardia

Hydrochlorothiazide

Moderate

67F presented with chest pain. She was diagnosed with supraventricular tachycardia secondary to hypokalemia. Her potassium was replaced.

2065

Anaphylactoid reaction

CT contrast

Moderate

40F presented with throat swelling, shortness of breath and after receiving CT contrast dye.

2071*

Hives, rash


Moderate

54F presented with respiratory distress secondary to a COPD exacerbation. He had a 2-day history of hives after taking amoxicillin/clavulanate, and was switched to doxycycline.


K 2.8 mmol/L

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2081*

Hemoptysis

Warfarin, clopidogrel, acetylsalicylic acid

2084

Anaphylaxis

Cephalexin

2085*

Acute kidney injury

Ramipril

2120

Fall

Lorazepam

INR 3.1

SCr 2.3 mg/dL

82M presented with hemoptysis while on warfarin and dual antiplatelet therapy. Warfarin was held. No alternative cause was identified.

Moderate

36F presented with pruritic rash and facial swelling after 1 dose of cephalexin for a skin infection. Cephalexin was changed to moxifloxacin.

Moderate

68M presented with abdominal pain, and was incidentally found to have an elevated creatinine (baseline 1.1mg/dL). He had had no blood work since starting on ramipril a year prior. Ramipril was held.

Moderate

79F presented after a fall. Her family had given her lorazepam the last 7 nights for insomnia. Lorazepam was discontinued and no alternative cause was identified.

Moderate

76M presented bleeding from a plasmacytoma in his mouth. He was stabilized with embolization of the maxillary artery. Acetylsalicylic acid was stopped.

2146

Bleed

Acetylsalicylic acid

2159

Delirium

Hydromorphone

Moderate

82F presented with confusion and dehydration 4 days after starting hydromorphone for post-surgical pain. No alternative cause for the delirium was identified.

2180

Hypotension, fall

Hydrochlorothiazide, amlodipine, ramipril

Moderate

63F presented with a collapse, syncope and a BP of 100/65. Hydrochlorothiazide, ramipril and amlodipine were discontinued. Her dizziness resolved.

2203*

Orthostatic hypotension

Sildosin

Moderate

46M had a fall with a BP of 86/44. He was diagnosed with orthostatic hypotension, and sildosin was stopped.

2204

Subarachnoid hemorrhage

Rivaroxaban

Severe

84M collapsed while on rivaroxaban. He was admitted for a subarachnoid hemorrhage, and rivaroxaban was held.

2209

Gastrointestinal bleed

Rivaroxaban, acetylsalicylic acid

Moderate

65M presented with a gastrointestinal bleed while on rivaroxaban and acetylsalicylic acid. The medications were held. No source of bleeding was identified on upper and lower scopes, and his hemoglobin returned to


Hb 113 g/dL

Moderate

Hb 119 g/dL

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2228

2229

normal.

Hemoptysis

Moderate

88M with underlying bronchiectasis presented with hemoptysis while on rivaroxaban. The medication was held, bleeding resolved, and he was switched to warfarin.

C. diff. +

Severe

75F presented with a 3-day history of diarrhea after finishing a course of antibiotics for a urinary tract infection. She was admitted for C. difficile colitis.

QTc 511 ms

Moderate

55M presented with a collapse and found to have prolonged QTc while on methadone.

Rivaroxaban

Trimethoprim/ Diarrhea sulfamethoxazole

2234*

Long QT

Methadone

2253*

Rectal bleed


Moderate

85M experienced rectal bleeding while on acetylsalicylic acid. He had no indication for the medication, and the drug was stopped. No alternative cause was identified.

2255

Hematuria

Rivaroxaban

Moderate

81M presented with hematuria after a Foley insertion for urinary retention while on rivaroxaban. Rivaroxaban was held for 3 days until the hematuria resolved.

2366

Rash

Moderate

69F presented with hives while on trimethoprim/sulfa-methoxazole. They resolved after stopping the medication.

Trimethoprim/ sulfamethoxazole

2393

Diarrhea

Tigecycline

Moderate

44M presented with diarrhea while on antibiotics for recent intraabdominal sepsis. C. difficile assay was negative, but no alternative cause was identified, and the patient was felt to have drug-induced diarrhea.

2401*

Delayed wound healing

Prednisone

Severe

73F presented with impaired sternotomy wound healing and infection after coronary artery bypass grafting. Prednisone likely increased the risk of poor healing and infection.

3026*

Mild leg spasms

Aripiprazole

Moderate

50F presented with leg spasms and hypokalemia. She had developed vomiting after starting aripiprazole 1week prior.


K 2.0 mmol/L

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3027

Allergic reaction

Itraconazole

3036*

Acute kidney injury

Perindopril

3044

Weakness hypokalemia

Hydrochlorothiazide

3050

Constipation

Hydromorphone

3068*

Acute kidney injury, hyperkalemia

Candesartan, hydrochlorothiazide, furosemide

3086

Epistaxis

Rivaroxaban

Moderate

55F presented with severe pruritis, body rash, and facial swelling after starting itraconazole. She was hospitalized for a hypersensitivity drug reaction.

SCr 1.9 mg/dL

Moderate

84M presented with chest pain. He was found to have high serum creatinine (baseline 1.3mg/dL). Perindopril was held.

K 1.9 mmol/L

Moderate

82F presented with a 2-week history of weakness. Potassium was started and hydrochlorothiazide stopped.

Moderate

30F presented with an 11-day history of constipation since starting on hydromorphone for pain following trauma.

Severe

76M presented with weakness. He had a 7-day history of poor intake, vomiting and diarrhea, and was found to be in acute kidney injury. Candesartan, hydrochlorothiazide, and furosemide were thought to have contributed and were held.

Moderate

90M presented with recurrent epistaxis. Rivaroxaban was held and his nose packed.

Moderate

93F presented with chest pain and was found to have a high creatinine (baseline 1.1mg/dL) after having started celecoxib 1 week prior for gout. Celecoxib was stopped.

K 5.5 mmol/L, SCr 17.1 mg/dL

3091

Acute kidney injury

Celecoxib

3104

Diarrhea, abdominal pain

Trimethoprim/sulfamethoxazole, ciprofloxacin

Moderate

37F presented with diarrhea while on multiple courses of antibiotics for a UTI.

3137

Drowsiness, leg rigidity

Quetiapine, donepezil

Moderate

84M was found unresponsive after a fall. Her quetiapine had been increased 7 days ago resulting in increased sedation. The quetiapine dose was decreased.

3152*

Aphasia, leg weakness

Galantamine

Moderate

87M presented with aphasia and leg weakness. High dose galantamine had been started a week prior. She was thought to have had an unwitnessed seizure caused by galantamine. The family declined


SCr 1.6 mg/dL

ccepted Articl

investigations, the medication was stopped, and the patient discharged. Moderate

88M presented with recurrent epistaxis exacerbated by warfarin. He required nasal packing to resolve bleeding.

Trazodone

Moderate

84F presented with decreased level of consciousness after being given trazodone the night prior. Trazodone was held.

GI Bleed

Warfarin

Severe

78M presented with an upper gastrointestinal bleed. He was admitted for endoscopy, and warfarin was held.

3364

Acute kidney injury

Ramipril

SCr 5.1 mg/dL

Severe

78M presented with upper gastrointestinal bleed due to warfarin. He was also found to have an acute kidney injury, to which ramipril could have contributed. He was admitted and the medication held.

3381

Acute kidney injury

Furosemide

SCr 2.4 mg/dL

Severe

55M presented with shortness of breath. His furosemide was recently increased contributing to acute kidney injury.

3252

Epistaxis

Warfarin

3295

Decreased level of consciousness

3364

INR 1.8

3413

Leg cramps

Metolazone

Moderate

76M with lower extremity leg pain. Metolazone found to be contributing to dehydration, worsening leg cramps. He was admitted due to impaired mobility and metolazone was held.

3440

Subdural hematoma

Warfarin

Severe

92F presented with a subdural hematoma while on warfarin. She was admitted to hospital.

3451*

Atrial fibrillation

Ibrutinib

Moderate

63M presented with palpitations after being diagnosed with atrial fibrillation. He had started ibrutinib 6 months previously and noticed an increase in the frequency of atrial fibrillation episodes felt to be ibrutinibrelated.

3459

Vomiting, epigastric pain


Moderate

61M presented with abdominal pain and vomiting after having started amoxicillin/clavulanate.

Drug Interactions


ccepted Articl

1676

1686

3315

INR 5.7

Moderate

75F was started on trimethoprim/sulfamethoxazole 1 week previously for a presumed urinary tract infection without warfarin dose adjustment. She was found to have a high INR. She was given vitamin K and warfarin was held.

INR 5.1

Moderate

85M presented with bilateral leg swelling. He had been prescribed azithromycin and cefuroxime for pneumonia. Warfarin was held and then restarted at a lower dose.

Moderate

55F presented after having been prescribed baclofen 4 days previously in addition to codeine she was already taking. She developed excessive drowsiness and did not experience improved pain relief. The medications were stopped.

Severe

70F presented with a 3-week history of worsening shortness of breath after stopping her puffers. No alternative cause was found, and her medications were restarted.

Moderate

73M presented with respiratory distress. He had self-titrated his furosemide down because of frequent urination. He was admitted to internal medicine for heart failure management.

Moderate

33F presented with poorly controlled asthma. She had not been taking her prescribed puffers that previously controlled her asthma because she could not afford them. Her medications were restarted. No alternative cause identified.

Moderate

85M presented with shortness of breath secondary to noncompliance with ipratropium for COPD, as his family was unable to assist him with its administration every 6h. No alternative cause was found, and he was discharged on tiotropium, a once daily drug.

Warfarin, trimethoprim/ Supratherapeutic INR sulfamethoxazole

Supratherapeutic INR

Drowsiness

Warfarin, azithromycin, cefuroxime

Codeine, baclofen

Non-Adherence 1196*

COPD exacerbation

1199

Heart failure exacerbation

1238

1246

Asthma exacerbation

Shortness of breath

Tiotropium, budesonide/formoterol

Furosemide

Fluticasone/salmeterol

Tiotropium


ccepted Articl

1270

Seizure

Phenytoin

Moderate

41M presented with a seizure. He had stopped phenytoin 3-4 days ago when he ran out of refills. Phenytoin was restarted.

1291

Pain

Tramadol/acetaminophen

Moderate

34F presented with pain after a urological procedure. She had been unable to fill her analgesic prescription due to cost. She was given a prescription for a less expensive drug.

1337*

Panic attacks

Paroxetine, clonazepam

Moderate

73M presented with dizziness after having stopped his medications. He presented with recurrent panic attacks, and medications were restarted.

1529*

Angina

Nitroglycerin

Moderate

71F presented with angina after forgetting to remove her nitroglycerin patch causing tachyphylaxis. Once she removed her nitroglycerin patch regularly at night her angina symptoms decreased.

1536


Moderate

90F presented with shortness of breath after taking furosemide every other day rather than every day as prescribed. She was hospitalized for heart failure.

Moderate

85F was admitted with cellulitis, and incidentally found to be hyperglycemic. The geriatrician determined she was unable to manage her insulin regimen due to cognitive decline. Home care was arranged to help her manage her insulin.

Furosemide

BG 417.6 mg/dL

1546

Hyperglycemia

Insulin

1672

Seizure

Phenytoin

Moderate

32M presented with a seizure, and was found to be non-adherent with his phenytoin. The patient was counselled to re-start his medications.

1707*

Saddle pulmonary embolism

Rivaroxaban

Severe

55F presented with dyspnea after discontinuing rivaroxaban despite being told requires life-long anticoagulation. She was diagnosed with a pulmonary embolism and admitted.

1747

Hypertension

Losartan

Moderate

67F presented with uncontrolled hypertension (BP 228/121) and hemoptysis. She halved her losartan dose 2 months ago against medical advice. Her hypertension was treated.

1785

Uncontrolled atrial

Bisoprolol

Severe

92M presented with shortness of breath and rapid atrial fibrillation with a


ccepted Articl

fibrillation

HR of 130 after discontinuing bisoprolol. Bisoprolol was restarted to control his HR.

1787

Dizziness, hypotension

Prednisone

Moderate

80F presented feeling unwell and lightheaded with a BP of 110/65. She had self-tapered long-term prednisone without medical oversight. The sudden decrease in dose contributed to adrenal insufficiency. She was started on a tapering dose.

1863

Psychosis

Olanzapine

Severe

51F presented with paranoia and bizarre behavior since self-discontinuing olanzapine. She was hospitalized for psychosis and antipsychotics were restarted.

1868


Furosemide

Moderate

93M presented with shortness of breath after stopping furosemide for unclear reasons. He was diagnosed with heart failure exacerbation, and furosemide was restarted.

1952*

Hyperosmolar hyperglycemic state

Insulin

Moderate

29M presented with hyperglycemia after discontinuing his insulin. He was hospitalized for hyperosmolar hyperglycemic state.

1976*

Abdominal pain

Mesalazine

Moderate

49M presented with abdominal pain after not filling his mesalazine prescription for newly diagnosed Crohn’s Disease.

2035*

Pyelonephritis

Ciprofloxacin

Moderate

82M presented with dysuria after stopping ciprofloxacin 3 days into treatment for pyelonephritis. He was admitted for intravenous antibiotics.

2164

Back pain

Gabapentin

Moderate

81M presented with acute on chronic lower back pain. He had been prescribed gabapentin, but was non-compliant.

2182

Anxiety

Clonazepam

Moderate

21F presented with anxiety, after not complying with clonazepam dosing. She was referred to outpatient mental health, and started on escitalopram and clonazepam.

2186

Psychosis

Risperidone

Moderate

26M presented with bizarre behavior after not taking risperidone. He was restarted on the medication.


ccepted Articl

2242

Anxiety

Sertraline

Moderate

46M presented with non-cardiac chest pain, and found to be anxious. He had run out of a sertraline 3 weeks ago.

2286

Tachycardia

Bisoprolol

Moderate

50F presented with chest pain and tachycardia. Her HR was 176 on presentation. Despite her history of supraventricular tachycardia, she selfdiscontinued bisoprolol, thinking she did not need it. On follow-up, she was compliant with bisoprolol with no further issues.

2315

Back pain

Acetaminophen, hydromorphone, NSAID

Moderate

77F presented with back pain after discontinuing analgesia as prescribed. She was restarted on the same medications.

Moderate

69M presented with confusion and weakness after not taking his medications. He was found to be hyperglycemic. His medications were restarted.

Moderate

53F presents with hemoptysis. She was found to be hypertensive (BP 182/95) after having run out of her medications. Medications were represcribed.

BG 189.0 mg/dL

2317

Hyperglycemia

Glyburide, metformin

2335*

Hypertension

Quinapril/ hydrochlorothiazide

2336*

Uncontrolled atrial fibrillation

Metoprolol

Severe

51M presented with respiratory distress and palpitations after discontinuing metoprolol in favor of herbal remedies. He was admitted for rate control.

3018

Shortness of breath

Ramipril

Moderate

79F presented to the ED for shortness of breath due to heart failure. She was noncompliant with ramipril, which was felt to have contributed to her exacerbation. No alternative cause was identified.

3063

Seizure

Levetiracetam

Moderate

77F presented with a seizure after having decreased the frequency and dose of medication. The prior dose was restarted.

3076

Seizure

Valproic acid

Moderate

48M presented with seizures after not adhering with antiepileptics secondary to substance abuse and inability to access his prescription refill.

3118

Hypoglycemia

Diabetic medications, not specified

Moderate

83F with dementia presented after a fall. She was found to be hyperglycemic. She refused to believe she had diabetes and had not taken


BG 469.8 mg/dL,

ccepted Articl

HA1c 0.12

3150

Hypotension

3166


Perindopril

Furosemide

her prescribed medications.

Moderate

75F presented with shortness of breath on exertion and was found to be hypotensive (BP 96/56) secondary due to continuing perindopril despite having been instructed to decrease the dose. Perindopril was discontinued.

Moderate

76F presented with increased fatigue, shortness of breath, and palpitations. She had stopped taking furosemide because she felt it was ineffective. She was diagnosed with a heart failure exacerbation and resumed furosemide.

3188

Dyspepsia

Esomeprazole

Moderate

36M presented with abdominal pain after previously having been prescribed esomeprazole. He was only able to afford once daily dosing, even though twice daily dosing had been prescribed. He was restarted on twice daily.

3216

Psychosis

Olanzapine, lithium

Severe

26F was admitted for mania. She had been noncompliant with medications. Her medications were restarted in hospital.

3383*

Gastroesophageal reflux disease

Rabeprazole

Moderate

52F presents with abdominal pain and a history of reflux after running out of rabeprazole.

Atenolol

Moderate

66F presented with syncope and bradycardia (HR 48, BP 82/60). She was sent home after receiving volume, and was told to follow-up with her physician for atenolol dosing.

Moderate

88F was presented for a supratherapeutic INR. She had recently been started on warfarin with no monitoring or follow-up. She was given vitamin K, and warfarin was held.

Moderate

58M presented with syncope and a BP of 102/60. He had recently reduced his antihypertensives, but his hypotension persisted. The medication was discontinued.

Dosage too high 1265

Syncope

1375*


Warfarin

1463

Fall

Olmesartan, hydrochlorothiazide


INR>10.0

ccepted Articl

1573

1637

Fall, hypotension

Amlodipine, irbesartan, hydrochlorothiazide

Moderate

74F presented with general weakness, a fall and a BP of 103/63. Amlodipine was discontinued and no further falls occurred on follow-up several months later.

Moderate

80F collapsed and was found to have a BP of 80/49. She was on furosemide and losartan despite persistent hypotension. The medications were held, and furosemide discontinued.

Syncope, hypotension

Furosemide, losartan

1700

Dizziness

Hydrochlorothiazide, amlodipine, ramipril

Moderate

49M presented with dizziness. He had been dizzy since his antihypertensive doses were doubled. While normotensive in the ED, his BP was considered low for him given his history of severe hypertension. Hydrochlorothiazide was stopped.

1787

Dizziness, hypotension

Atenolol, hydrochlorothiazide

Moderate

80F presented with shortness of breath, lightheadedness and a BP of 110/65. She was on multiple antihypertensives. Her atenolol dose was reduced.

Moderate

90F presented with a fall (BP 128/60 ) while on an aggressive antihypertensive regimen. Ramipril and diltiazem doses were decreased with reduced fall frequency on follow-up.

2246

Fall

Ramipril, diltiazem

2251*

Seizures

Meperidine

Severe

55F presented after a seizure and was hospitalized for work-up. Her meperidine used for chronic pain was thought to be the cause of her seizure. No alternative diagnosis was identified, and meperidine was discontinued.

2282

Hypotension, dizziness

Ramipril, nifedipine

Moderate

99F presented with dizziness and a labile BP (BP 116/61) while on multiple antihypertensives. Her dizziness resolved after nifedipine was discontinued. No alternative cause was identified.

Moderate

87F presented with tachycardia, and was admitted for atrial fibrillation. She was found to have an elevated INR. She was treated with vitamin K, and her warfarin was held.

2287


Warfarin


INR > 9.0

ccepted Articl

2298*


Warfarin

INR 3.6

Moderate

88M presented with respiratory distress. He was incidentally found to have an elevated INR. He was given vitamin K, and warfarin was held.

2361

Hypoglycemia

Insulin

BG 32.4 mg/dL

Moderate

85F presented with hypoglycemia. She had a history of recent hypoglycemic episodes. Insulin was held and adjusted.

Moderate

86F presented with weakness after having started furosemide for treatment of heart failure. She had been left on a high dose without reassessment. She was restarted on a lower dose of furosemide after her kidney function improved.

Moderate

17F presented with anxiety, insomnia and headache after starting a high dose of venlafaxine a few days prior. Venlafaxine was switched to sertraline.

2362

Dizziness, acute kidney injury

3085

Anxiety, insomnia, headache

SCr 2.7 mg/dL

Venlafaxine

Supratherapeutic

3088*

Warfarin

INR 3.4

Moderate

89F presented with palpitations. She was found with an elevated INR for the indication (atrial fibrillation). Her warfarin dose was decreased.

Warfarin

>INR 10.0

Moderate

78M presented with lower extremity pain, and was found to have an elevated INR. She was admitted to hospital, her warfarin was held, and her dose was adjusted.

Warfarin

INR 5.4

Moderate

89M presented with slurred speech after falling. His CT head showed no bleed. However, his INR was found to be high. Warfarin was held and his dose was adjusted.

Warfarin

INR 8.2

Moderate

84F was sent in to the ED for an elevated INR after having started ciprofloxacin for a COPD exacerbation. Warfarin was held and vitamin K was given.

Severe

75F presented with weakness and confusion. She was admitted with delirium following multiple opioid ingestions. No alternative cause was identified.

INR Supratherapeutic

3167 INR Supratherapeutic

3233 INR Supratherapeutic

3236

3384*

Furosemide

INR

Confusion

Oxycodone, hydromorphone, morphine


ccepted Articl

3413


Warfarin

3449*

Inadequate pain control

INR 3.8

Moderate

76M with incidental finding of elevated INR. Warfarin dose was adjusted.

Analgesia

Severe

82F discharged from hospital 4 days prior with hepatocellular carcinoma and lung cancer. She was on opioids in hospital that were not represcribed on discharge.

Dosage too low 1310

Pain

Pregabalin

Moderate

60M presented with neuropathic pain after having been started on a low dose of pregabalin 2 weeks prior without subsequent dose titration. The pregabalin dose was increased and tramadol added.

2368*

Diarrhea

Metronidazole

Moderate

91F presented with diarrhea after being prescribed a subtherapeutic dose of metronidazole for C. difficile colitis. She was hospitalized for C. difficile colitis.

3044

Hyperglycemia

Insulin

Moderate

82 F presented with increased weakness and constipation. She had an incidental finding of hyperglycemia. She was admitted for hypokalemia, and blood glucose management.

3044

Constipation

Polyethylene glycol

Moderate

82F presented with a 2-week history of constipation. A low dose of polyethylene glycol had been started with no effect. The dose was increased to twice daily.

3050*


Hydromorphone

Moderate

30F presented with pain after a motor vehicle accident despite being prescribed low dose hydromorphone. He was admitted to optimize analgesia.

3080


Fentanyl

Moderate

71F presented with neck pain radiating down her back and legs. Low dose fentanyl patch had not been titrated.

Moderate

58M presented with shortness of breath, and was noted to have a subtherapeutic INR and inadequate warfarin monitoring (indication atrial fibrillation).

BG 338.4 mg/dL

Subtherapeutic

3134*

Warfarin INR


INR 1.7

ccepted Articl

3166

Tachycardia

Metoprolol

Moderate

76F presented with a 1-week history of weakness, fatigue, shortness of breath and a HR of 134. She had stopped taking furosemide and was found to be in heart failure and atrial fibrillation. Her metoprolol was increased.

3191*

Shortness of breath

Fluticasone

Moderate

66F with COPD presented with shortness of breath taking only 250mcg fluticasone once daily, as monotherapy. No alternative trigger was identified. Medications were adjusted.

3235*


Hydromorphone

Moderate

32F presented with shortness of breath, and neck pain. She had been prescribed low dose hydromorphone in a recent ED visit with minimal relief. Her dose was increased.

3237*

Back pain

Hydromorphone

Moderate

89F presented with uncontrolled back pain while on very small doses of hydromorphone and a fentanyl patch. The emergency physician added pregabalin to her regimen.

Moderate

24M presents with pain post-op after rib resection for thoracic outlet obstruction. His pain was inadequately controlled with fentanyl patches, and had not been adjusted by his surgeon earlier that day. His patch was adjusted.

Severe

77M presents with sensory loss and pain in his leg. He was diagnosed with leg ischemia secondary to low INR.

Moderate

79F presented with poorly controlled hypertension and a BP of 231/108. Bisoprolol was added to her medication regimen. 61F presented with acute on chronic pain after running out of fentanyl patches. Her fentanyl patch was re-prescribed.

3337

Pain

Fentanyl

3341

Leg ischemia

Warfarin

INR 1.1

Needs Additional Drug 1581

Triamterene/ Hypertension Hydrochlorothiazide

1607*

Withdrawal

Fentanyl

Moderate

1608

Diverticulitis

Clindamycin

Moderate


74F presented with persistent pain attributed to diverticulitis. She had been prescribed clindamycin monotherapy for diverticulitis. Clindamycin was

ccepted Articl

1805

switched to ciprofloxacin and metronidazole, and her symptoms resolved.

Poor pain control

Hydromorphone, gabapentin

Severe

60F had an stem cell transplant for multiple myeloma a month ago, and presented with weakness and neuropathic pain after running out of hydromorphone a week ago. Gabapentin and long acting hydromorphone were started.

2241

Poorly controlled asthma

Fluticasone

Moderate

27M presented with an allergic reaction. On medication review, it was found that he had poor asthma control. He thought his salbutamol inhaler was his fluticasone inhaler. The emergency physician prescribed fluticasone.

3269*

Chest pain


Moderate

56M presented with angina with a history of cardiac arrest, percutaneous angioplasty and stents. He was only clopidogrel with no reported contraindication to acetylsalicylic acid. Acetylsalicylic acid was started.

3336

Stump cellulitis

Inadequate antibiotic duration

Severe

43F presented with recurrent stump infection. Antibiotics were stopped after 3 weeks without reassessment of her stump. She was admitted to complete 6 weeks of antibiotics.

3427


Required additional analgesia

Moderate

56M presented with back pain while only taking pregabalin. Her family doctor stopped naproxen and started pregabalin not considering the long duration of onset of pregabalin.

Amoxicillin

Moderate

44M presented with a fever and cough. He had been prescribed amoxicillin in the community for pneumonia but saw no improvement. He was switched to moxifloxacin.

Severe

51F presented with flank pain. She had been prescribed nitrofurantoin for a urinary tract infection 5 days ago despite poor renal function. She was admitted for intravenous antibiotics.

Ineffective Drug 1487*

2106*

Unresolved pneumonia

Pyelonephritis

Nitrofurantoin


ccepted Articl

3031*

Urinary tract infection

Nitrofurantoin

Moderate

87F presented with confusion. Five days prior, she had been diagnosed with a urinary tract infection and started on nitrofurantoin. Cultures grew Proteus resistant to nitrofurantoin. She was admitted for intravenous antibiotics.

3189

Urinary tract infection

Nitrofurantoin

Moderate

26F presented with flank pain, after being prescribed with nitrofurantoin despite initial symptoms of pyelonephritis.

3190

Constipation

Lactulose

Moderate

85M presented with constipation while on narcotics after a fall. An additional laxative was prescribed.

3190

Ineffective analgesia

Codeine

Moderate

85M presented with poor pain control while on codeine after a fall. Codeine was switched to hydromorphone.

3091

Ineffective analgesia

Tramadol

Moderate

93M with inadequate pain control. He felt it was ineffective. Hydromorphone was prescribed.

3220*

Supraventricular tachycardia

Digoxin

Moderate

67F with a history of supraventricular tachycardia presented with a HR of 182. She had refused to try medications other than digoxin, despite it being ineffective in the past.

3330

Dyspepsia

Pantoprazole, naproxen

Moderate

60F presented with symptoms of dyspepsia related to naproxen. Pantoprazole had been prescribed without discontinuing naproxen. In the ED, naproxen was stopped and pantoprazole increased to 40mg bid.

3424

Auricular cellulitis

Cloxacillin

Moderate

76M presented with cellulitis despite 2 courses of cloxacillin, which is poorly absorbed. The patient was successfully treated with cefazolin and ciprofloxacin.

Moderate

62F presented with hyperglycemia felt to be due to an error in selfmanagement. She was enrolled in a daily dispensing and medication management program resulting in improved glucose control.

Medication Error 1386*

Hyperglycemia

Insulin


BG 340.2 mg/dL

ccepted Articl

1540

Hypotension, bradycardia

Metoprolol, verapamil, diltiazem

Moderate

70M presented with a collapse and hypotension (BP 84/52). He had recently been hospitalized for coronary bypass surgery, and had been started on verapamil. On discharge, he continued these medications and also restarted medications he took prior admission including metoprolol and diltiazem. Metoprolol and diltiazem were stopped.

2392

Hypotension

Amlodipine, candesartan

Moderate

83F presented with confusion and hypotension (BP 115/50). She had taken multiple days of medications from her blister pack, including multiple doses of antihypertensives. She was enrolled in a medication management program.

2392

Diarrhea

Sennosides

Moderate

83F presented with confusion and diarrhea. She had taken multiple days of medications from her blister pack, including multiple doses of sennosides. She was enrolled a medication management program.

Moderate

90F presented with shortness of breath due to a COPD exacerbation. Trimipramine had been discontinued due to prolonged QTc. Two weeks later the patient moved to a nursing home, and trimipramine was restarted. The medication was discontinued after the index visit.

Moderate

73M newly diagnosed with metastatic lung cancer developed symptomatic hypotension (BP 74/51) while on a rapid dexamethasone taper. No alternative cause was identified. The dexamethasone dose was increased.

3325*

Long QT

Trimipramine

Drug Withdrawal 1089*

Hypotension, adrenal insufficiency

Dexamethasone

1261

Pain

Morphine

Moderate

20M presented with pain. He had a history of narcotic dependence and was on a tapering dose of morphine. He ran out of morphine and presented in withdrawal.

1456

Anxiety, insomnia

Venlafaxine

Moderate

60F presented with insomnia, nightmares and anxiety after her family doctor abruptly stopped venlafaxine. She was restarted on venlafaxine with a slow taper.


ccepted Articl

1488

Dizzy, pain

Hydromorphone

Moderate

45F presented with back pain and in withdrawal after running out of hydromorphone. She was restarted on a tapering dose of hydromorphone.

1706

Anxiety, insomnia

Clonazepam

Moderate

68M presented with anxiety and insomnia after clonazepam was reduced rapidly. The emergency physician prescribed lorazepam, and the patient’s symptoms resolved. The patient’s family physician tapered him off benzodiazepines.

1807

Nausea, vomiting

Hydromorphone

Moderate

75F presented with nausea, vomiting and abdominal cramping since running out of hydromorphone. Hydromorphone was restarted at a lower dose.

2129*

Seizure

Clonazepam

Moderate

60F seized after running out of clonazepam 4 days prior. She had been taking clonazepam for insomnia. She was restarted on a tapering dose of clonazepam.

* Indicates adverse drug events not initially recognized by the physician. All events identified by pharmacists were disclosed to the treating physician at the point-of-care to optimize patient safety. An independent committee adjudicated all events classified as uncertain or discordant.

K=potassium; BP=blood pressure; ED=emergency department; SCr=serum creatinine; INR=international normalized ratio; BG=blood glucose; WBC=white blood cell; ANC=absolute neutrophil count; Na=sodium; HR=heart rate; Hb=hemoglobin; QTc=corrected QT interval; ms=milliseconds; NSAID=non-steroidal anti-inflammatory drug; HA1c=hemoglobin A1c; COPD=chronic obstructive pulmonary disease
