Positive inotropic drugs and drugs used in dysrhythmias

C H A P T E R

16 Positive inotropic drugs and drugs used in dysrhythmias Kerry Anne Rambaran, PharmD, BCPS*,1, Saeed Alzghari, BCPS, MS, MBA† *KGI School of Pharmacy and Health Sciences, Claremont, CA, United States † Baylor Scott & White Medical Center, Waxahachie, TX, United States 1 Corresponding author: [email protected]

toxicity may present in a variety of ways, including ventricular tachycardia.

CARDIAC GLYCOSIDES Digoxin Cardiovascular • A 55 YOF presented with dyspnea and tachycardia. Her medical history is significant for mild rheumatic mitral valve disease and paroxysmal atrial fibrillation (AF) for which she was taking digoxin (dose not specified). Her ECG showed ventricular tachycardia with a rate of 150 per min, right bundle branch block, right axis deviation and QRS of 0.13–0.14 s (fascicular ventricular tachycardia). There was obvious alternans with the QRS complex. The serum digoxin level was 6 ng/mL, approximately 8 h after the last dose was ingested. Intravenous lidocaine and DigiFab were administered and the ventricular tachycardia subsided approximately 2 h after the initiation of DigiFab therapy. Her follow-up ECG showed sinus rhythm at a rate of 65/min and non-specific ST-T wave abnormalities. Over the next 7 years, there were no recurrent episodes of ventricular tachycardia [1A]. In this case, the patient had a supra-therapeutic digoxin level which lead to her presentation with ventricular tachycardia. This is the first case with pronounced QRS alternans in fascicular ventricular tachycardia secondary to digoxin toxicity. Details regarding this patients’ renal function were not provided; however, it is of note that digoxin is predominantly cleared through the kidneys and thus in the presence of renal impairment, the digoxin level would increase. This case highlights the importance of ECG monitoring in patients on digoxin therapy as well as remaining cognizant that digoxin

Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.06.002

• A retrospective cohort was conducted in Taiwanese patients with AF who received digoxin and/or amiodarone for 180 days to determine the risk of ischemic stroke with the respective therapy. The patients were divided into three groups: digoxin only (n ¼ 1419), amiodarone only (n ¼ 797), and digoxin plus amiodarone (n ¼ 376). The baseline characteristics were comparable between groups, with the exception of the digoxin only group having more elderly patients. Amiodarone only group showed a higher incidence of CKD, hyperlipidemia, and beta-blocker use. Digoxin only group showed higher incidence of CHF, COPD, asthma, a CHA2DS2VASc score of 4 and use of diuretics. In contrast, higher incidence of warfarin use, cardioversion and coronary heart disease in the amiodarone and digoxin group was observed. There was a higher risk of ischemic stroke in patients receiving digoxin (hazard ratio (HR) ¼ 1.80; 95% CI 1.41–2.31), or amiodarone plus digoxin (HR ¼ 2.00; 95% CI 1.49–2.68), compared to those receiving amiodarone only. Moreover, those receiving digoxin only or amiodarone plus digoxin and had a CHA2DS2VASc score of 2–3 and 4–5, respectively, had higher risk of ischemic stroke. Patients with a CHA2DS2VASc score of 2–3 and received digoxin only had a lower risk of ischemic stroke than those receiving both amiodarone plus digoxin (HR ¼ 1.56; 95% CI 1.00–2.43). The risk was also higher in those receiving anticoagulants and digoxin only or amiodarone plus digoxin. “There was an increase in risk of stroke in those receiving both amiodarone plus

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digoxin and clopidogrel with a CHA2DS2VASc score of 2–3 (HR ¼ 3.81; 95% CI 1.16–12.5) and 4–5 HR ¼ 3.25; 95% CI 1.04–10.2)” [2MC]. This study reported 1.8- and 2.0-fold increases in ischemic stroke in patients with a CHA2DS2VASc score of 2–3 and 4–5 who received digoxin only and amiodarone plus digoxin, respectively, when compared to amiodarone only. This infers that amiodarone may not significantly increase the risk of stroke when used individually. It should be noted that this study was conducted in Taiwanese patients, and thus, lacks generalizability to the general population. Moreover, there was no delineation on the types of AF (permanent vs paroxysmal) between the three groups and information regarding echocardiograms. No additional monitoring data were found. Additionally, patients receiving digoxin are more “likely to be frail with compromised cardiopulmonary function”, thus increasing their risk for stroke. Nonetheless, this study emphasizes the importance of routine monitoring in patients on digoxin and assessing the risk vs benefit of therapy. • An observational post hoc digoxin sub group analysis of the ARISTOTLE trial was conducted to determine if there is an association between the use of digoxin, serum digoxin concentration, and mortality in patients with AF. At baseline, 5824 patients were taking digoxin and 680 had stopped digoxin before the trial ended. A total of 3003 patients taking digoxin had heart failure and 2821 patients taking digoxin did not have heart failure. There was no association with increased risk of death with baseline digoxin use (adjusted HR: 1.09; 95% CI 0.96–1.23; P ¼ 0.19). The authors reported patients with a digoxin level of 1.2 ng/mL (n ¼ 499) had a 56% increased risk of death (adjusted HR: 1.56; 95% CI 1.20–2.01; P ¼ 0.0011) compared to those that were not on digoxin. Additionally, patients with a digoxin level of 0.9 and <1.2 ng/mL had an insignificant (16%) increased risk of death (adjusted HR: 1.16; 95% CI 0.87–1.55; P ¼ 0.32). It was found that for each 0.5 ng/mL increase in baseline digoxin level, “there was an increase in death for the overall population (adjusted HR: 1.19; 95% CI 1.07–1.32; P ¼ 0.0010), which was consistent in patients with heart failure (adjusted HR: 1.22; 95% CI 1.08–1.38; P ¼ 0.0018) and without heart failure (adjusted HR: 1.18; 95% CI 0.97–1.45; P ¼ 0.10)”. “Of the 12 703 patients not taking digoxin at baseline, 873 started digoxin during follow-up”. “Compared with propensity score-matched control participants, the risk of death (adjusted HR: 178; 95% CI 1.37–2.31; P < 0.0001) and sudden death (adjusted HR: 2.14; 95% CI 1.11–4.12; P ¼ 0.0230) was significantly higher in new digoxin users” [3MC].

Even though this was an observational study, it is the largest study involving established and new digoxin users. This study shows that the risk of death is higher in patients with a digoxin level of 1.2 ng/mL and was independently related to heart failure status in new digoxin users. This brings to light the importance of diligent monitoring of the digoxin level in patients with AF to mitigate potential problems. Moreover, an observational multicenter study in patients >70 years with AF and receiving digoxin reported an increase in mortality and/or readmission in those with lower heart rates [4MC]. Thus, it is important to assess the risk vs benefit in patients along with consistent monitoring in these patients. Drug–drug interaction with posaconazole • A 72 YOF was admitted to the leukemia service with complaints of progressive fatigue and an elevated white blood cell count (35.5  103 μ/L) and blast percentage. Her past medical history is significant for: AF, diastolic heart failure with preserved ejection fraction, cerebrovascular accident, and “relapsed antecedent acute myeloid leukemia (AML) arising out of chronic myelomonocytic leukemia”. Her past chemotherapy agents resulted in short-lived remissions and was comprised of decitabine and a combination of azacitidine, high-dose cytarabine and mitoxantrone. She was considered to have refractory AML with a KRAS mutation and was “being evaluated for enrollment on a phase 1 clinical trial involving trametinib (MEK inhibitor) in combination with an investigational AKT inhibitor”. Her home medications included: allopurinol 300 mg twice daily, escitalopram 10 mg daily, torsemide 20 mg daily and digoxin 0.25 mg daily (Monday–Friday). On day 2 of hospitalization she developed a neutropenic fever (38.8°C) and was initiated on vancomycin (loading dose of 2.25 g then 1 g every 12 h), aztreonam (1 g every 6 h), and metronidazole (500 mg every 8 h intravenously). A chest CT revealed pulmonary nodules on day 3, which rose suspicion for fungal pneumonia. She was then started on posconazole 300 mg daily. On day 6 of hospitalization, she became bradycardic without any hemodynamic compromise. On day 7, her posconazole level was 1810 ng/mL and on day 8 she was enrolled in the phase 1 study involving MEK/AKT inhibitor. On day 10 of hospitalization, she had profound bradycardia (42 beats per minute) and a supra-therapeutic digoxin level of 3.1 ng/mL. She was found to have polymorphic ventricular tachycardia and was transferred to the cardiac ICU where her posconazole, digoxin, and trial medications were held. She was initiated on micafungin 150 mg as her anti-fungal

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treatment agent. She was given 2 g of intravenous magnesium sulfate, but this failed to subside the cardiovascular effects of the elevated digoxin level. As such, she was given DigiFab 200 mg; however, she remained bradycardic with episodes of ventricular tachycardia and thus required another 200 mg of DigiFab. Eventually, her bradycardia resolved and her digoxin level was then 2.4 ng/mL. After 11 days of DigiFab administration, the digoxin level was undetectable. She was re-initiated on digoxin and posconazole but the micafungin was discontinued. There were no further reports of cardiac presentations of this patient [5A]. It was suggested, the clearance of digoxin in this patient was 3 days. The patient did not have renal impairment, and thus the likely cause for elevated digoxin levels is the administration of posconazole. In-vitro studies have shown that posaconazole is an inhibitor of P-gp and thus would result in an increase in the AUC of digoxin. Given that the half-life of posconazole is 35 h, it is estimated it takes approximately 7 days to reach steady state. The patient developed profound bradycardia on day 8 which correlates with the time frame in which posconazole reaches steady state. This case highlights the importance of monitoring serum digoxin levels in patients receiving medications that may augment its concentration or decrease its clearance. Sensory system (eyes) • An 89 YOM was referred for complaints of headache, tired eyes with reading, floaters which had turned into geometric patterns with a yellow tint for the past 3 months. His past medical history is significant for open angle glaucoma (using travoprost one drop into both eyes daily), transurethral resection of his prostate, AF (taking digoxin 0.25 mg daily for 20 years), and a cataract extraction from the left eye. Other medications included rivaroxaban 15 mg daily, lisinopril 20 mg daily, atorvastatin 20 mg daily, mirabegron 50 mg daily, acetaminophen 325 mg as needed, vitamins, and a probiotic. The patient stated he saw gray, white, green, blue, red and yellow geometric patterns and spirals which occurred on their own and appeared as if they were moving constantly. He also mentioned seeing little particles that flew, wiggled and floated around “as if they were in a viscous solution”. He mentioned having floaters in the past; however, this time they were colorful and predominantly yellow. “He also complained of tiredness with reading, as though he were reading through a ‘light screen’, and worsening headache at the top of his head and the left temple”. He stated he takes acetaminophen or ibuprofen once a week for the headache. Upon

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ophthalmology exam, his intraocular pressure was 13 mmHg. “He had advanced glaucomatous cupping and peripapillary conus in both eyes. There was a disturbance of the retinal pigment epithelium with yellowing around the disc on the right eye and some splotchy pigmentation in the posterior pole on the left”. His digoxin level was supra-therapeutic at 1.4 ng/mL and he was advised to discontinue digoxin. The day after discontinuation, the patient reported “90% improvement” in his vision and colored floaters. He had complete resolution of his vision 12 days post discontinuation. During follow-up, the patient reported seeing floaters occasionally; however, they were not colorful. His headache decreased in frequency and intensity after 5 weeks of cessation and the patient thought it was due to the digoxin. The patient agreed to a trial of digoxin to ascertain if the colored floaters were digoxin induced; however, the patient stopped the digoxin within 3 days due to an intolerable exacerbation of his headache [6A]. Digoxin toxicity can manifest as visual disturbances such as snowy vision, flashing and flickering lights, green and yellow vision, and colored floaters. These disturbances while mostly common with supra-therapeutic levels of digoxin can occur with sub-therapeutic levels of digoxin, albeit uncommon. It is proposed that this occurs due to NA/K-ATPase inhibition at the cellular level in the retina and photoreceptor cells. Thus, with the elderly, as photoreceptor cells are lost, there is an increased risk of these visual disturbances. This case highlights the importance of frequent eye examinations in patients taking digoxin long term, particularly in the elderly.

ANTIDSYRHYTHMIC DRUGS Adenosine Cardiovascular • A 45 YOF presented with an acute onset of palpitations, a BP of 116/70, and narrow complex tachycardia on the ECG. After the administration of 6 mg of IV adenosine, she developed a transient AV block and then irregular wide complex tachycardia with hypotension, which required DC cardioversion. Her ECG revealed sinus rhythm with pre-excitation and “electrophysiological evaluation documented left free wall accessory pathway with inducible atrioventricular reentrant tachycardia”. She then underwent radiofrequency ablation utilizing a transseptal approach. Once the delta wave was no longer apparent post ablation, she was given IV adenosine (dose not specified) in which a self-terminating

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occurrence of AF occurred following transient AV block [7A]. Adenosine is a routinely utilized medication in the treatment of supraventricular tachycardia. Of note, the pro-arrhythmic effects of adenosine have been reported, particularly in the presence of pre-excited AF. Adenosine is also known to induce atrial and ventricular fibrillation [8c,9c]. In this case report, adenosine converted the atrioventricular tachycardia to pre-excited AF, which is rare. Thus, it is important to have prompt access to resuscitation and defibrillation in settings where this drug is being utilized.

Amiodarone Cardiovascular • A 44 YOM with a recent diagnosis of AF was initiated on amiodarone (dose not specified) with planned direct current cardioversion in 4 weeks. He also has a medical history of hypertension and type 2 diabetes mellitus. He presented to the emergency department 10 days later with complaints of syncope (4 episodes) while sitting on his couch, which were self-limiting. His ECG upon admission indicated AF with a QT of 500 milliseconds and a heart rate in the 50 s. Additionally, his serum magnesium was 1.4 and EF of 50% upon admission. He suffered an episode of ventricular tachycardia and “required defibrillation prior to achieving return of spontaneous circulation”. A bolus of amiodarone was administered followed by an amiodarone drip (doses not specified). Upon admission of the cardiac intensive care unit, he suffered another ventricular tachycardia episode without requiring intervention. His EKG strip showed significant polymorphic ventricular tachycardia/ Torsade’s de Pointes (TdP). Amiodarone was stopped, magnesium was repleted and isoproterenol was administered intravenously to obtain a heart rate of >70. Over the next 5 days, the patient remained asymptomatic without any episodes of ventricular tachycardia. The patient was discharged and remained asymptomatic in his 1-month follow-up [10A]. The risk factors for TdP include: female sex, bradycardia, underlying heart disease, prolonged QT at baseline, and electrolyte imbalance (hypokalemia, hypomagnesmia). This case emphasized the importance to remember amiodarone’s proarrhythmic inducing ability and increasing the risk of TdP, although rare.

defibrillator. He was put on amiodarone 200 mg daily due to frequent antitachycardia pacing and defibrillation. Shortly after amiodarone therapy, he complained of worsening arthritis and underwent a total knee replacement. He developed an infection 2 months later, which warranted removal of his prosthesis and he was implanted with a temporary gentamicin cement spacer. The prosthesis was reimplanted 6 months later and the specimens obtained during the procedure revealed multiple and multi-resistant infections. He was subsequently treated with rifampicin 900 mg daily and vancomycin. The physicians were aware of the drug–drug interaction with amiodarone and rifampicin; however, there were no other viable alternatives. To ensure efficacy of therapy, the serum concentrations of amiodarone and its active metabolite desethylamiodarone were monitored at baseline and the cumulative value was used as a target concentration during and after rifampicin therapy. The baseline amiodarone and desethylamiodarone concentration was 1.72 mg/L, which was within the normal range of 1–4 mg/L. The cumulative amiodarone and desethylamiodarone concentration was 0.83 mg/L after 10 days of rifampicin therapy. Amiodarone dose was subsequently increased to 600 mg daily; however, his cumulative amiodarone and desethylamiodarone levels were 0.65 mg/L 1 week later. This led to the decision to increase the amiodarone dose to 900 mg daily that resulted in a therapeutic cumulative amiodarone and desethylamiodarone level of 1.52 mg/L. Rifampin was discontinued (reason not specified) and 2 weeks later the amiodarone dose was readjusted to 200 mg daily. The cumulative amiodarone and desethylamiodarone levels remained therapeutic during a subsequent 90 day follow-up without any arrhythmia occurrences. This patient’s leg was amputated later due to the uncontrolled infection [11A]. Rifampin is a strong inducer of amiodarone metabolism. Thus, the combination of amiodarone and rifampin leads to sub-therapeutic concentrations of amiodarone and its active metabolite. In this case, the drug–drug interaction occurred relatively quickly, and, therefore, warranted a dose increase of amiodarone within 2 weeks. It is important to take into consideration the pharmacokinetic properties of drugs that are known to have drug– drug interactions to ensure efficacy of therapy. Endocrine

Drug–drug interaction with rifampin • A 69 YOM with a history of left knee arthritis and arrhythmogenic right cardiomyopathy (ARVC) was treated with beta-blockers, several endocardial ablations, and implantation of a cardioverter

• A 48-year-old male presented with complaints of chest pain in January 2014. An exerciser stress test revealed evidence of inducible ischemia and a stress ECHO showed left ventricular dilation and severe left ventricular impairment. In February 2015, he

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underwent a triple vessel coronary artery bypass grafting and subsequently suffered two cardiac arrests secondary to ventricular tachycardia. Subsequently, he was initiated on amiodarone. His ejection fraction improved from 25% to 40% post surgery and remained on amiodarone therapy for 10 months (discontinued in December 2015). His thyroid functions tests were normal at baseline, during therapy with amiodarone and post discontinuation. In January 2017, he presented with complaints of chest palpitations, and his thyroid function tests were indicative of thyrotoxicosis (TSH 0.007 mU/L, FT4 36.1 pmol/L). He was prescribed carbimazole 40 mg daily; however, 8 weeks later, his TSH was <0.005 mU/L and FT4 33 pmol/L, indicating suboptimal response to therapy. As a result, carbimazole was increased to 60 mg daily. A small non-tender goiter with no palpable cervical lymph nodes was present on examination. He developed mild pharyngitis with a WBC of 1.5  109/L with no neutrophils. Carbimazole was stopped, and he was put on prednisolone 60 mg daily. His WBC count returned to baseline within a week and a Technetium scan “revealed generalized poor tracer uptake of 0.1% in the thyroid glands suggestive of amiodarone induced thyrotoxicosis type 2 (AIT-2)”. His follow-up visit at 3 months had no indication of thyroid dysfunction [12A]. Amiodarone is known to cause hypo and hyperthyroidism, as well as thyrotoxicosis. Amiodarone induced thyrotoxicosis type 2 (AIT-2) is destructive in nature and is typically treated with glucocorticoids. In type 1, there is excessive thyroid hormone synthesis due to iodine loading such as in Graves’ disease or in patients with a nodular goiter and is typically treated with thionamides and is more likely to recur. It should be noted that mixed forms could exist (type 2 with a goiter). Thus, it is important to determine which type a patient has as treatments differ. More importantly, AIT is associated with increased cardiac complications and mortality. In a retrospective study of 64 patients treated for AIT, 33 were euthyroid with initial treatment alone and took longer to have normalized FT4 when thionamides were used vs glucocorticoids. Additionally, 21 patients became euthyroid only after thyroidectomy [13c]. Of note, in adults as well as pediatric patients, there may be a latency period in the development of AIT [14c]. This literature emphasizes the importance of obtaining baseline thyroid function labs prior to initiating amiodarone as well as monitoring the thyroid function throughout the course of therapy and discontinuation. Hematologic • A retrospective review of 11 patients was conducted to determine the effect of short-term IV amiodarone on the anticoagulant effect of warfarin on patients who

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underwent cardiac surgery. Patients received warfarin orally before and after surgery (dose not specified) and a loading dose of 125–150 mg or a continuous infusion of 750 mg of amiodarone within 5 days after surgery (n ¼ 11). These patients were compared to those that only received warfarin (n ¼ 15). The PT/INR values were monitored frequently (frequency not specified) and the doses of warfarin were adjusted to maintain a therapeutic PT-INR of 1.5–2.0. The average warfarin dose at baseline in the amiodarone vs control group was 2.64  0.89 vs 3.07  1.22, respectively, P ¼ 0.370. The mean PT-INR values were not significantly different in the control group before and after surgery (2.27  0.58 vs 2.25  0.47, respectively, P ¼ 0.912) and amiodarone group (2.13  0.58 vs 2.29  0.50, respectively, P ¼ 0.643). When compared to baseline, the mean PT-INR values were significantly elevated after administration of amiodarone (0.92  0.45 vs 1.54  0.62, respectively, P ¼ 0.002). Even though all patients received cefazolin, the authors concluded the increase in the PT-INR/dose was due to the amiodarone [15c]. This study was retrospective in nature with a small sample size and thus underpowered to clearly ascertain if the elevation was due to amiodarone. More so, these patients were cardiac patients undergoing surgery, thus there are confounding factors that could affect anticoagulation that cannot be accounted for. That being said, this study does highlight the importance of monitoring the pharmacokinetics of medications that are co-administered with amiodarone to ensure efficacy of therapy, in this case, anticoagulation with warfarin. Liver • A 62 YO Japanese male with a diagnosis of cardiac sarcoidosis complicated with ventricular tachycardia (VT) was admitted with general malaise and systemic edema. His family history was non-contributory and he had a history of smoking. He was treated with prednisolone 10 mg daily, amiodarone 150 mg daily, enalapril 5 mg daily, metoprolol 20 mg daily, and lansoprazole 15 mg daily. Over the course of 13 years, after amiodarone was initiated, his ALT and AST levels rose to 161 and 106 IU/L, respectively, but were kept on amiodarone by his physician for his treatment of VT. Upon admission he was afebrile with a BP of 95/66 mmHg and a heart rate of 69 beats per minute. In his physical exam, he had marked distention of the abdomen, and “the liver and spleen were palpable from the abdominal wall”. His echocardiogram revealed a mild left ventricular systolic dysfunction with an ejection fraction of 45% and mild mitral and tricuspid regurgitation. He was found to be thrombocytopenic and had an AST of 135 IU/L and ALT of 91 IU/L, total bilirubin of 2.4 mg/dL, albumin

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of 3.1 g/dL and γ-glutamyl transpeptidase of 202 IU/L. Viral hepatitis and other chronic liver disease tests were negative. His abdominal CT showed diffuse high attenuation of the liver parenchyma and the abdominal ultrasound showed liver cirrhosis, splenomegaly and massive ascites. The amiodarone was then discontinued as it was suspected the patient had amiodarone-induced hepatotoxicity; however, the patient died of hepatic insufficiency. Autopsy results included yellow liver specimens with a rough surface indicating cirrhosis. H&E stained section revealed “regenerative nodules and well-developed bridging fibrosis”. The authors also report “marked neutrophilic infiltrates, a remarkable amount of Mallory bodies, hepatocellular ballooning, and numerous whorled or laminar bodies in the lysosomes”. The patient was diagnosed with amiodarone-induced hepatotoxicity with irreversible liver cirrhosis [16A]. Amiodarone is known to cause transient increases in the liver enzymes which either resolves on its own or with a dose reduction. Amiodarone accumulates in the lysosomes that inhibit phospholipase A1 and A2 and thus inhibits the removal of lysosomal lipids resulting in phospholipidosis that can progress to steatohepatitis and ultimately cirrhosis. Additionally, the patients plasma level was not significantly elevated, thus the plasma level may be poorly correlated with toxicity. This highlight amiodarone-induced hepatotoxicity, with the first case being irreversible and the second reversible. While amiodarone-induced hepatocellular complications are rare, timely diagnosis can significantly reduce mortality. Thus it is important to monitor patients’ liver enzyme function during the course of therapy in addition to obtaining liver biopsies and CT imagining when warranted. Respiratory • A 76-year-old female presented with a complaint of a 4-week cough with purulent sputum and dyspnea. She reported she was a nonsmoker, had not travelled recently, nor had any pets. She was on amiodarone 200 mg daily for 30 years to deal with her ongoing AF and also had a history of hypertension, hypothyroidism, and type 2 diabetes mellitus. Bibasilar crackles were heard upon physical examination, and her SpO2 was 95% in room air. Her pulmonary function tests indicated moderate restrictive lung disease with decreased diffusion capacity. A chest X-ray showed bilateral infiltrates and a high resolution CT scan showed significant ground glass appearance in the lower lobes of both lungs with airspace consolidations. She underwent a ‘fiber optic bronchoscopy for bronchial wash and bronchoalveolar lavage (BALF)’.

The BALF showed the presence of fat-laden macrophages. Extracellular oily droplets were found on sputum examination, suggesting lipoid pneumonia. The patient denied aspirating or inhaling mineral or vegetable oils. It was concluded her lipoid pneumonia was induced by amiodarone. The amiodarone was discontinued and she was initiated on digoxin 0.25 mg daily as well as prednisolone 20 mg daily. The latter was tapered over a period of 6 months [17A]. Amiodarone interferes with the movement of phospholipids across intracellular membranes and inhibits phospholipid catabolism resulting in accumulation. In this case, there was no prior exposure or use of oil-base products, resulting in a diagnosis of endogenous lipoid pneumonia. Diagnosis of lipoid pneumonia is often difficult as its presentation often mimics that of other pulmonary complications such as ARDS. Moreover, druginduced lung injury may mask potential infections such as tuberculosis [18A]. If not treated, it may progress into pulmonary fibrosis or end stage lung disease. There are no consensus guidelines on the treatment of lipoid pneumonia and it is suggested through anecdotal case reports that a trial of steroids may help alleviate the inflammation. Ultimately, cessation of the offending agent is the mainstay of therapy and a trial of steroids may help with the inflammatory process. Thus, it is important to appropriately screen these individuals if pulmonary function compromise is suspected. Sensory systems (balance, taste) • A retrospective review of 126 patients with bilateral vestibulopathy (BVP) revealed 15 patients had a history of being treated with amiodarone prior to their BVP diagnosis (12% incidence). The average age of these 15 patients was 70 years (range of 47–92), with 10 being female and five male. The patients were prescribed amiodarone for AF (12 patients), ventricular tachycardia (2 patients), and Wolf Parkinson White syndrome (1 patient). It was reported that all patients had progressively worsening dizziness/gait and two patients reported falls. The patients were taking amiodarone for a median of 13 months prior to the onset of symptoms and a median of 24 months prior to being diagnosed with BVP. The average daily maintenance dose was 214 mg (range of 100–400 mg) [19C]. Amiodarone is particularly important in controlling life-threatening arrhythmias and is known to induce several adverse effects including pulmonary toxicity, thyroid abnormalities and neurological toxicities. However, a frequent under reported adverse effect is that of balance/gait abnormalities. This study supports the hypothesis that amiodarone can impact vestibular function when used long term, which is further corroborated in a meta-analysis

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and earlier case reports [20A,21M,22A]. Thus, it is important to perform a vestibular examination periodically in patients taking amiodarone to allow for early detection of drug induced balance-related problems. • A 73 YOF was admitted with complaints of chest pain and palpitations. Her EEG showed paroxysmal AF, paroxysmal supraventricular tachycardia, atrial premature beats, and ventricular premature beats. Mild aortic valvular regurgitation and left ventricular diastolic dysfunction were reported and a coronary artery CT showed “stenosis of the left anterior descending artery (50%)”. The patient was started on metoprolol 47.5 mg/day; however, she developed an olfactory disorder while on metoprolol (approximately 3 months), which resolved upon tapering and discontinuation. However, the patient reported worsening palpitations post metoprolol discontinuation and an ECG showed premature atrial beats and increasing paroxysmal AF. She was then prescribed amiodarone 400 mg/day for 1 week to treat her arrhythmias, which was then tapered to 200 mg daily. Approximately 2 weeks into treatment with amiodarone, the patient expressed difficulty in distinguishing bitter and spicy tastes. She was asked to stop her amiodarone and radiofrequency ablation was recommended. Two weeks post discontinuation, her ability to distinguish between tastes returned [23A]. Hypogeusia or taste disorder related to amiodarone is rarely reported in literature and clinical research is lacking. Taste disturbances are not life threatening and often times go unnoticed and under reported by patients and caregivers. Hypogeusia may affect a patient’s compliance with medication as well as affect appetite which in turn may lead to weight loss and depression. Albeit a rare adverse effect, it is important to remain aware of hypogeusia secondary to amiodarone use to prevent issues such as non-compliance. Skin • A retrospective review of 57 patients who were prescribed amiodarone was conducted to determine the incidence and predictors of amiodarone adverse effects in adults with congenital heart disease (CHD). The mean age was 36.3  12.6 years (range 16–65), with an average time on amiodarone of 2.7  4.3 years. Amiodarone was prescribed for: atrial tachycardia/ flutter in 34 patients, AF in 8 patients, both atrial flutter and fibrillation in 4 patients, supraventricular tachycardia on 2 patients, ventricular tachycardia in 8 patients and both atrial flutter and ventricular tachycardia in 1 patient. Five patients were also taking beta-blockers and six were on digoxin. Four patients required therapy cessation with amiodarone due to severe dermatological side effects: “one rash early after

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commencement, two with severe photosensitivity, and one with both blue-grey discoloration and marked photosensitivity” [24c]. Though not very common, skin discoloration and photosensitivity are two adverse effects reported with amiodarone [25A]. These adverse effects subside with discontinuation of the medication. Thus, it is important to ensure patients are educated on the skin discoloration as well as to perform routine medical exams on these patients.

Diltiazem Cardiovascular • A 39-year-old African American female presented to the ED complaining of sweating, palpitations, agitation, dyspnea, chest pain, and diarrhea. Her past medical history is significant for hyperthyroidism for which she takes methimazole (dose not specified) and is compliant. Her vital signs upon admission were: BP 158/88 mmHg, heart rate 169 beat per minute. The ECG showed AF with rapid ventricular response and the chest X-ray showed airspace opacity in the left hilar and right infra-hilar region. Her ECG showed an ejection fraction of 15–20%, “global hypokinesia, moderate left atrial dilation, and moderate tricuspid valve regurgitation”. Her basic metabolic profile and complete blood count were unremarkable. She scored 75 points on the Burch-Wartofsky scale that was highly suggestive of a thyrotoxic storm. Her free T4 level was 6.6 ng/dL, TSH< 0.008 μ IU/mL, AlkPhos 163 U/L, ALT 63 U/L, AST 209 U/L and lactic acid of 2.3mmol/L. Intravenous ceftriaxone, hydrocortisone, oral methimazole and IV diltiazem drip at 10 mg/h were initiated. She went into asystole with a BP of 60/30mmHg and a heart rate of 42 beats per minute after 3h of the diltiazem drip. Return of spontaneous circulation was achieved after she received 3min of C reactive protein, two doses of atropine and one dose of epinephrine. She was intubated and initiated on milrinone, norepinephrine, and vasopressin (doses not specified) to obtain a mean arterial pressure of >65 mmHg. Vancomycin and cefepime were also initiated as well as propylthiouracil 250mg every 4 h and Lugol iodine. She underwent plasmapheresis for refractory thyroid storm on her fifth day of hospitalization, following which, her heart rate improved. The milrinone was “discontinued after achieving a mean arterial pressure of >65 mmHg”. She developed acute renal failure warranting treatment with continuous renal replacement therapy on day 6 of hospitalization. She suffered another asystole episode on day 10 of hospitalization and her family withdrew care. She then expired on day 11 of hospitalization [26A]. Diltiazem was administered to stop the cardiac effects of the thyrotoxic storm; however, the patient became

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hypotensive and bradycardic which in turn lead to the development of cardiogenic shock. Current thyroid storm guidelines do not provide a treatment pathway for thyrotoxicosis in patients with decompensated heart failure with reduced ejection fraction. One recommendation in the treatment of patients with a thyroid storm and reduced output thyrocardiac failure is to utilize short acting beta 1 selective beta-blockers. Another recommendation is to utilize plasma exchange to clear the thyroid hormone from circulation and possibly utilize it as a bridge in therapy until the onset of the antithyroid medication. Overdose/intoxication • A 53 YOF was found at home with a reduced level of consciousness, urinary incontinence, and vomiting. She has a history of epilepsy, diabetes mellitus, coronary microvascular disease, COPD, and alcohol abuse. While in the ambulance her blood pressure was 70/40 mmHg and a heart rate of 16 beats per minute. Two atropine bolus (dose not specified) and normal saline (rate not specified) was administered without resolution of shock. Upon arrival to the ED, she was administered a third dose of atropine (dose not specified) and multiple fluid challenges and a continuous infusion of isoprenaline. Her cardiogenic shock still persisted with a lactic acid of 12.5 mmol/L and a pH of 7.01. She was then initiated on noradrenaline 0.54 μg/kg/min, dobutamine 8–13 μg/ kg/min, adrenaline 0.04–0.06 μcg/kg/min, and was then intubated and mechanically ventilated. Since her potassium was 7.1 mmol/L, she was given calcium gluconate 1000 mg (route not specified) and insulin (0.15 IU/kg/h) was initiated due to her glucose level of 36.7 mmol/L. Her ECG showed a complete AV block for which temporary external pacemaker was inserted. Her diltiazem level was 2.2 mg/L and diltiazem intoxication was suspected as it was revealed she allegedly took 4800 mg of diltiazem retard. She was given activated charcoal and magnesium sulfate (dose not specified), which induced her to vomit twice and the decontamination was stopped. A calcium gluconate infusion was started until the calcium levels were 5.05 mmol/L followed by the initiation of glucagon 5 mg continuous infusion of 1 mg/h. As the diltiazem levels decreased, the patient stabilized with normalizing hemodynamics. The patient developed necrotizing pancreatitis secondary to the high calcium levels and prior alcohol use. Calcitonin was initiated and the pancreatitis was successfully treated with analgesics and fluids [27A]. The patient was decontaminated due to the ingestion of the retard diltiazem formulation as well as the fact that it slows gastric motility and delays gastric emptying. The

glucagon was initiated to increase the cAMP levels that in turn improves the calcium uptake intracellularly, and thus produces a positive chronotropic and inotropic effect on the heart. Literature has shown that administering a continuous infusion of calcium is effective in reducing hemodynamic instability and mortality when cardiovascular manifestations are present with calcium channel blocker intoxication. Frequent monitoring of the calcium level should be performed and adjusted according to the patient’s clinical status. Moreover, the utilization of high-dose insulin euglycemic therapy is recommended on the treatment of calcium channel blocker intoxication. Urinary tract (kidneys) • A retrospective review of 635 hospitalized patients with AF who received IV diltiazem was divided into two groups: normal ejection fraction (EF 50%) and low ejection fraction (EF ≪ 50%). There were 473 patients in the normal ejection fraction group and 162 patients in the low ejection fraction group (52 had an ejection fraction 30%). Diltiazem infusions were administered at 5–15 mg/h and titrated to a heart rate of <100 beats per minute. Baseline characteristics between groups were similar, except the low EF group had a higher incidence of coronary artery disease, valvular heart disease, hospital length of stay, and use of beta-blockers and digoxin. The incidence of mortality and hypotension was higher, but not statistically significant in patients with a normal ejection fraction vs low ejection fraction: 25 vs 4, OR 0.45 (0.16–1.32) and 109 vs 48, OR 1.41 (0.94–2.10), respectively. There were statistically significant increases in acute kidney injury (AKI) in the low ejection fraction group vs normal ejection fraction group (17 vs 16, P ¼ 0.002, OR 2.94 (1.45–5.97)) [28C]. The AKI reported was most likely due to creatinine changes within 48 h of starting the diltiazem infusion. In heart failure patients, the GFR is affected by cardiac output, renal venous pressure and other changes. It should be noted, the low ejection fraction group also had a higher incidence of using beta-blockers and digoxin and thus this study cannot determine causality, but rather infer a strong association between IV diltiazem use and AKI in patients with a low ejection fraction.

Dofetilide [SEDA-37, 209] Cardiovascular • A retrospective review of patients who received dofetilide for the treatment of AF or atrial flutter was conducted to assess the incidence of life-threatening arrhythmias that required modification of therapy. Over a 4-year period, 1552 patients received dofetilide

ANTIDSYRHYTHMIC DRUGS

during hospitalization of which 138 required dose adjustment (increase dose, decrease dose or reinitiate therapy). Of the 138 patients, 102 were reloaded with the previously tolerated dose, 30 patients received an increased dose, two patients received a decreased dose and four patients received an unknown previous dose. The average age was 64.6  11.7 years with 14.5% having CKD, 21.7% with diabetes mellitus, and 84.4% having hypertension. The average creatinine clearance was 107.4  40.4 mL/min and the average QTc prior to re-loading was 452.9  36.2 ms. Patients who received an “increased dose were older and had a longer QTc prior to re-loading (464.1  39.9 vs 449  32.9 ms, P ¼ 0.038)”. Dofetilide was stopped in one patient with an ICD had a QTc interval of 558 ms and a QRS duration of 178 ms, which was due to an acute kidney injury. Of the 102 patients reloaded with the same dose: 8 patients were started on 125 mcg twice daily, 30 patient received 250 mcg twice daily, 2 patients were started on 375 mcg twice daily and 62 patients received 500 mcg twice daily. A total of seven patients discontinued dofetilide due to ineffectiveness (4) and excessive QTc prolongation (3). Overall, 30 of the same dose patients needed dose adjustment (27 needed dose reduction due to QTc prolongation). In the group of patients receiving an increased dose: one received 125 mcg twice daily, 5 patients were increased to 250 mcg twice daily from 125 mcg twice daily, 1 was increased to 500 mcg twice daily from 125 mcg twice daily, 10 were increased to 375 mcg twice daily from 250 mcg twice daily, 11 were increased to 500 mcg twice daily from 250 mcg twice daily and 2 patients were increased to 500 mcg twice daily from 375 mcg twice daily. A total of eight patients in the increased dose group needed the dose to be decreased due to either prolonged QTc or TdP. In the group that was reloaded with a lower dose, no adjustments were needed. The group in which the previous dose was unknown, four patients were started on 500 mcg twice daily, and three patients required a dose reduction due to developing prolonged QTc. Overall, 44 patients required dose modification due to either prolonged QTc or TdP. There was a trend of higher risk in patients with hypertension (P ¼ 0.076) or diabetes (P ¼ 0.05) [29MC]. This study emphasizes the importance of monitoring patients who are being reinitiated and/or titrated on dofetilide for effects such as prolonged QTc and TdP (when QTc > 500 ms). As is expected, re-initiating on higher doses predisposes to a greater risk of QTc prolongation and proarrhythmic effects. In a retrospective review examining the correlation between the incidence of dofetilide associated QTc prolongation and the weight used for dosing, it was found that the use of total body

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weight may require more dose reductions or therapy discontinuation when compared to using actual and/or ideal body weight [30c]. Given that the half-life of dofetilide is approximately 8–10 h, if a patient misses two doses, reloading may be warranted. Thus it is important to assess patient compliance with therapy and select the best therapeutic agent if adherence is a perceived barrier. Liver • A 33 YOM was admitted with acute hypoxic respiratory failure secondary to congestive heart failure. He presented with complaints of worsening shortness of breath. He stated he experienced dyspnea when walking upstairs and lying flat 4 months ago, which then worsened 2 weeks prior to admission. The patient’s medical history was significant for congenital transposition of the great arteries status post right and left aortopulmonary shunt placement as well as persistent AF for 7 months prior to admission. One month prior to admission, he was successfully cardioverted and initiated on dofetilide 500 mcg twice daily. However, dofetilide was discontinued due to the patient complaining of nausea. The patient also reported taking furosemide 60 mg daily, levothyroxine 50 mcg daily before breakfast, loratidine 10 mg daily and warfarin 6 mg daily. Prior to admission, he had no history of hepatic or renal dysfunction. Jugular venous distension was present upon physical examination as well as rales in the pulmonary exam. He was diagnosed with acute liver failure due to elevation of his hepatic transaminases, elevated total bilirubin, and supra-therapeutic INR. These values continuously rose over 5 days during hospitalization. On day 2 of hospitalization he was re-initiated on dofetilide 250 mcg twice daily. During his hospitalization he also received: “oral acetylcysteine 72 h protocol beginning on day 4, albuterol, bumetanide, furosemide, ipratropium-albuterol, levothyroxine, lorazepam, methylprednisolone, oxazepam, phytonadione, spironolactone, and thiamine”. On day 3 of hospitalization, an abdominal ultrasound was performed which showed “all veins to be patent with a small amount of right upper quadrant ascites and borderline hepatomegaly”. Viral hepatitis serology tests and alpha-1 antitrypsin tests were negative. His hepatic transaminases and total bilirubin slowly returned to baseline starting on day 6. The patient noticed a “diffuse maculopapular rash on his chest and back” on day 11 and on day 13 the patient was discharged as his dyspnea and acute liver injury was resolved. The authors utilized the Roussel Uclaf Causality Assessment Method (RUCAM) score for drug induced liver injury, which resulted in a score of 9 indicating a high probability dofetilide was the cause of liver injury [31A].

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The most significant and common side effect of dofetilide is QTc prolongation. Hepatotoxicity is not commonly reported with dofetilide and is more common with other class III antiarrhythmics such as amiodarone. While acetylcysteine was utilized in this case, currently, there is only anectodal data reporting on the use of acetylcysteine in non-acetaminophen drug induced liver disease. Given that other causes were ruled out, this case report indicates dofetilide as a highly probable causative agent of druginduced liver injury (DILI). Thus, it is important to monitor liver function in patients receiving dofetilide.

Dronedarone is used to maintain sinus rhythm after cardioversion in patients with paroxysmal or persistent AF. There have been numerous case reports published on dronedarone induced liver injury, some of which the liver injury occurred months after utilization of dronedarone, and others a few days after. The mechanism behind drondearone causing liver injury is unknown; however, since it is structurally related to amiodarone, it is theorized to cause liver injury in a similar way. This case highlights the importance of monitoring liver function periodically, as early discontinuation may reverse liver injury as seen with this case.

Neuromuscular function • A 65 YOM with a history of persistent AF was admitted for direct current cardioversion (DCCV) and initiation of dofetilide. His home medications consisted of rivaroxaban 20 mg daily, which he was taking more than 6 weeks prior to admission. He was initiated on dofetilide 500 mcg (frequency not specified) and he was in sinus rhythm post DCCV. He developed a right-sided facial droop after two doses of dofetilide that was consistent with facial paralysis and his CT and MRI of the brain were negative for intracranial infarction. His history and serology were negative for Lyme disease. Dofetilide was discontinued and he was put on prednisone 60 mg daily for 7 days. His 3-week follow-up visit indicated complete resolution of symptoms [32A]. Dofetilide’s packaging reports a frequency of 2% of facial paralysis. Thus, in this patient, early discontinuation allowed for resolution of symptoms along with the initiation of a short course of corticosteroids.

Dronedarone [SEDA-35, 338] Liver • An 83 YOF with a past medical history of hypertension, chronic diastolic heart failure, COPD, provoked deep vein thrombosis, and general anxiety disorder presented with shortness of breath and palpitations and was found to have AF. She self-converted to sinus rhythm with resolution of symptoms and was initiated on dronedarone 400 mg twice daily, and was then discharged on this medication. Four days later, she presented with fatigue, malaise, abdominal pain and nausea. Her AST was >1600 U/L, ALT 1791 U/L, AlkPhos 208 U/L, INR 1.79 and albumin of 2.5 g/dL. Her dronedarone was perceived as the cause for her acute liver failure and was stopped. She was treated with supportive care and her transaminases normalized and her symptoms resolved completely. Her follow-up was not significant for any further liver abnormality [33A].

Mexiletine [SEDA-34, 298] Nervous system (peripheral) and skin • A 70 YOF was admitted with a subacute gait disturbance. She has a past medical history of hypertension and paroxysmal supraventricular tachycardia (SVT). She was prescribed mexiletine hydrochloride 100 mg daily for 4 weeks to with her SVT. “One week prior to admission, she developed a pruritic rash which started on her face and extremities, and then spread to her trunk”. Mexiletine was discontinued the day prior to presenting to the hospital. Her gait subsequently became unsteady with difficulty standing. Upon admission she was afebrile and normotensive (135/88 mmHg) with a heart rate 83 beats per minute. There was “diffuse edematous erythema on her face, neck, trunk and extremities with swollen lymph nodes”. She had mild weakness in her proximal limbs, absent deep tendon reflexes in her extremities, and “tactile and pain hypesthesia in the distal parts of her legs”. She had a positive pianoplaying finger movement and Romberg’s sign. She had mild leuckocytosis and esniophilia that increased over the next 4 days (623–1386 μL). Atypical lymphocytes were also observed. Her AST was 147 U/L, ALT 156 U/L, AlkPhos 1566 U/L, γ-glutamyl transpeptidase 509 U/L and CRP of 20.4 mg/L. There was a fourfold elevation in her antihuman herpesvirus 6 (HHV-6) IgG antibody from initial visit to 4 weeks later; however, HHV-6 DNA was not detected in her CSF. Her CSF “analysis revealed a protein of 56 mg/dL and a mild mononuclear pleocytosis of 16 cells/μL”. Nerve conduction studies on day-1 were normal but when repeated 3 days later, there was marked reduction in amplitude of the sensory nerve action potential by proximal stimulations. She was diagnosed with drug-induced hypersensitivity syndrome and was treated with methylprednisolone 1 g daily for 3 days followed by prednisone, which was tapered from an initial dose of 30 mg daily. Her skin eruptions resolved; however, the patient’s ability to

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stand remained problematic. She was also diagnosed with acute sensory ganglionopathy for which she received IV immunoglobulin 400 mg/kg/day (type not specified) for 5 days with modest improvement. Her gait disturbance remained during her 6-month checkup and she did not develop neoplasms during her 5-year follow-up [34A]. In this case, the drug-induced hypersensitivity syndrome was caused by mexiletine. This is confirmed by her initial skin eruptions and reactivation of HHV-6. This case emphasizes the importance of monitoring for dermatological side effects upon cessation of therapy to prevent untoward complications.

Quinidine Cardiovascular • A 56 YOM was hospitalized with a diagnosis of malaria due to Plasmodium falciparum and was subsequently treated with intravenous quinidine and clindamycin (doses not specified). His baseline QTc was 22 ms and during treatment with quinidine his QTc interval rose to 530 ms. He was switched to oral quinidine and clindamycin on day 2 of hospitalization as the “load of malarial parasitemia” had deceased. He recovered from malaria after 1 week of therapy [35A]. Quinidine is known to cause QTc prolongation and thus it is important to monitor patients for proarrhythmic effects as they may be life threatening.

Ibutilide Cardiovascular • A retrospective multi-center study investigated 361 patients receiving ibutilide to determine patient characteristics, ibutilide administration patterns, cardioversion rates, and adverse outcomes. Of the patient cohort, two patients developed ventricular tachycardia. The first patient was a 36 YOM with AF and atrial flutter who received an initial 1 mg ibutilide infusion followed by another 1 mg infusion of the same drug. He developed an asymptomatic 3-beat run of monomorphic ventricular tachycardia and remained stable for 4 h. He was discharged without problem. In the second patient case, a 61-year-old male with AF and atrial flutter was treated with two consecutive 1 mg ibutilide infusions following which he had sustained runs of stable polymorphic ventricular tachycardia. He was treated with magnesium sulfate and amiodarone, which resolved his ventricular tachycardia within 20 min [36C].

In both cases, the occurrence of ventricular tachycardia was due to the infusion of ibutilide. The major side effects of ibutilide are QTc prolongation and TdP. Some resources suggest administering magnesium prior to ibutilide to reduce the risk of TdP. It is important to closely monitor potassium, magnesium, QTc and proarrhythmic effects in these patients before and after ibutilide administration.

INOTROPES Dobutamine Cardiovascular • A retrospective analysis of 333 patients undergoing a physiologist led DSE was conducted to determine its safety and efficacy. A total of 306 cases were led by physiologists and 300 of these tests utilized pharmacological agents: dobutamine (low dose) or dobutamine plus atropine. Majority of the patients underwent DSE for coronary artery disease assessment. Patient’s ages ranged from 26 to 90 years, with the average age being 60.8 years. A total of 235 cases were uneventful for atropine and dobutamine side effects. Sixteen patients required early termination of DSE due to minor arrhythmic effects, which resolved upon dobutamine discontinuation. Additionally, five patients receiving 40 mcg/kg/min suffered a drop in systolic blood pressure. The authors reported a total of 67 patients developed dobutamine related side effects and two required urgent fluid resuscitation [37C]. The most common side effects with DSE are tachyarrhythmia, arterial hypotension, ventricular fibrillation and severe symptomatic hypotension. In this review, minor arrhythmic effects were well tolerated and in some cases resolved upon dobutamine discontinuation. In a systematic review, it was found that patients predisposed to experiencing dobutamine induced takotsubo cardiomyopathy were females with a history of hyperlipidemia, hypertension, and smoking as other risk factors [38c]. It should be noted that dobutamine-induced cardiomyopathy can present with wall abnormalities or with focal wall motion abnormalities. It is important to recognize lifethreatening complications of DSE such as myocardial infarction and severe symptomatic hypotension and stop the test to prevent worsening complications.

Norepinephrine [SEDA-17, 238] Skin • A prospective, observational study of 55 patients was conducted in the ED to determine the incidence of

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complications from the administration of vasopressors through peripheral venous catheters in patients with circulatory shock. Extravasations with local erythema were reported in two cases and one patient had local thrombophlebitis. In the case of local thrombophlebitis, a 58 YOF who presented with septic shock received an infusion of norepinephrine 8 mg in 250 mL D5W in her right hand over 40 h with a maximum rate of 7 μg/min. Her infusion was discontinued 3.3 h into therapy due to the development of local thrombophlebitis and she was then weaned off vasopressors, not due to the complication. She did not require any intervention and was subsequently discharged. In the second case, a 57 YOM who presented with septic shock received an infusion of norepinephrine 8 mg in 250 mL D5W in his left hand over 11 h with a maximum rate of 7 μg/min. His infusion was discontinued 1.9 h into therapy due to the extravasation of his left hand leading to skin pallor. He was then weaned off vasopressors, not due to the complication. He did not require any intervention and was subsequently discharged. Lastly, the third patient was a 42-year-old female who presented with septic shock received an infusion of norepinephrine 8 mg in 250 mL D5W in her right hand over 28 h with a maximum rate of 19 μg/min. Her infusion was discontinued 2.5 h into therapy due to the extravasation of her right antecubital area leading to blanching skin erythema and she was then weaned off vasopressors, although not due to the complication. She did not require any intervention, was transferred to the ICU and subsequently expired during hospitalization (cause of death not specified) [39c]. Norepinephrine is the most well tolerated commonly used vasopressor in many conditions including septic shock. This study emphasize that while norepinephrine is notably safe, extravasation may occur and discontinuation of therapy appears to resolve presentation.

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[36] Vinson DR, Lugovskaya N, Warton EM, et al. Ibutilide effectiveness and safety in the cardioversion of atrial fibrillation and flutter in the community emergency department. Ann Emerg Med. 2018;71(1):96–108. e2. [C]. [37] Ntoskas T, Ahmad F, Woodmansey P. Safety and efficacy of physiologist-led dobutamine stress echocardiography: experience from a tertiary cardiac centre. Echo Res Pract. 2018;5(3): 105–12 [C]. [38] Chandraprakasam S, Alla VM, Mooss AN, et al. Dobutamine stress testing induced transient cardiomyopathy: a systematic review. Int J Cardiol Heart Vessel. 2014;4:221–2 [c]. [39] Medlej K, Kazzi AA, El Hajj Chehade A, et al. Complications from administration of vasopressors through peripheral venous catheters: an observational study. J Emerg Med. 2018;54(1): 47–53 [c].