Flecainide Intoxication Research Articles

565 UNUSUAL LIFE-THREATENING FLECAINIDE TOXICITY: A CASE REPORT

Abstract Background Anti-arrhythmic drug therapy has often a narrow therapeutic index and could be responsible of toxic side effects including malignant arrhythmias and life-threatening hemodynamic deterioration. Flecainide toxicity can occur even at normal serum levels in the setting of electrolyte disturbances such as hyponatremia. We report a case of flecainide toxicity, likely due to dual mechanism: reduced excretion and potentiation of the toxic effects due to concomitant hyponatremia. Case description A 82-year-old woman was admitted to our hospital for syncope. The ECG at admission showed atrial fibrillation, complete atrio-ventricular (AV) block and a wide QRS escape rhythm. She has a history of hypertension, COPD and atrial fibrillation. She was currently taking flecainide at a dosage of 150 mg per die. Laboratory tests reported an elevated lactate concentration (4.6 mmol/L), hyponatremia (128 mmol/L), severe reduction of renal function (eGFR 19 ml/min), and NT-proB-type Natriuretic Peptide 17563 pg/ml, (ULN<450). Echocardiography showed a reduced left ventricular ejection fraction (EF=35%). Suspecting flecainide poisoning, we started intravenous sodium bicarbonate and temporary pacing for severe bradycardia and pauses. However, despite numerous attempts of lead reposition and the use of maximum output, we failed to document ventricular capture in the immediate post-operative. Half hour later, dopamine infusion was started for sustained severe hypotension. The day after we were able to obtain ventricular capture. At serial ECG examination, she also developed progressive QRS narrowing with concomitant clinical improvement. Discussion Flecainide toxicity is a rare but potentially life-threatening condition. The excess of sodium channel blockade causes in fact delayed conduction through the AV node, His-Purkinje system, and ventricles with possible AV block, ventricular tachycardia, ventricular fibrillation, and asystole. In addition, hemodynamic instability can develop rapidly in flecainide intoxication due to chronotropic and inotropic incompetence. The majority of flecainide intoxication reported cases are due to a drug overdose. However, flecainide toxicity can occur with serum levels within the range of normality. Particularly, this can occur in the setting of hyponatremia. The observed pacemaker malfunction was also due to flecainide intoxication. In our case, the patient was taking therapeutic doses of this drug. The toxic effect was probably due to the reduced excretion (secondary to kidney failure) and the simultaneous presence of hyponatremia. The main treatment for flecainide intoxication is sodium bicarbonate and supportive care. However, there is currently no recommended standardized protocol for flecainide toxicity. The inotropic agents could be helpful in case of cardiogenic shock, but their use may be limited by the rate-dependent effect of flecainide and the increased risk ventricular arrhythmias. Left ventricular assist devices have been also used to support hemodynamic through flecainide-induced cardiogenic shock.

The Case of Flecainide Toxicity: What to Look For and How to Treat

Introduction: Flecainide is a class Ic antiarrhythmic agent used to prevent and treat both ventricular and supraventricular tachycardias including atrial fibrillation, AV nodal re-entrant tachycardia (AVNRT), and Wolff- Parkinson-White syndrome (WPW). Flecainide can cause serious side effects include cardiac arrest, arrhythmias, and heart failure. Despite its growing use, the presenting signs and symptoms of flecainide toxicity are not familiar to most clinicians. Case description: This was a 58 year-old female who presented from her skilled nursing facility due to hypoxia and altered mental status. Past medical history was notable for paroxysmal atrial fibrillation for which she was on flecainide. At the nursing facility the patient was noted to be obtunded, whereas at baseline she was reportedly alert and oriented. On presentation to the Emergency Department EKG demonstrated wide-complex tachycardia. Subsequent lab results were notable for hypokalemia and an acute kidney injury (AKI). A repeat EKG was concerning for ischemia in leads II, III, aVF and cardiology was emergently consulted. They noted the EKG changes were consistent with flecainide toxicity, specifically a prolonged PR interval and QRS. She was eventually admitted to the medical intensive care unit. Her wide complex tachycardia on admission was ultimately attributed to flecainide toxicity in setting of AKI. Six days after presentation, it was found that her flecainide level was in the toxic range at 2.02 ug/mL (normal range: 0.20-1.00 ug/mL, toxic>1.50 ug/mL). Discussion: Flecainide intoxication is rare but serious due to the potential for cardiogenic shock. Its diagnosis can be difficult as the flecainide serum level may take days to result and there are no pathognomonic clinical signs. This case demonstrates the necessity of keeping flecainide toxicity on the physician’s differential for patients who are taking the drug, as well as what ECG and laboratory findings can suggest it as the etiology. A heightened suspicion is warranted in the patient with new renal impairment. Treatment can be lifesaving if initiated promptly.

Phospholipidosis in cardiomyocytes suffering flecainide intoxication.

Phospholipidosis in cardiomyocytes suffering flecainide intoxication.

Three Cases of Cardiac Arrest with Massive Flecainide Intoxication Treated with Extracorporeal Assistance

Flecainide acetate is a Vaughan Williams class 1C anti-arrhythmic agent. Overdose causes severe cardiac and neurologic disturbances and carries a risk of fatality. No antidote is currently available.We present three cases of massive flecainide intoxication in which the patients were kept alive by extracorporeal circulation. Extracorporeal support in cases of flecainide intoxication is the only approach that can alleviate acute cardiac dysfunction, preserve blood flow to vital organs, and maintain liver metabolism and renal excretion of the toxin, while waiting for the improvement of cardiac function. Furthermore, clinical practice highlights that age, duration of CPR, PH, and lactate levels should not be a hindrance to decision-making, and demonstrates the positive, long-term neurologic and cardiologic outcomes that can be achieved with the use of extracorporeal assistance in the setting of severe flecainide intoxication.

Temporary rapid pacing to prevent ventricular fibrillation recurrence in electrical storm refractory to medical therapy

Drug-refractory electrical storm due to VF or polymorphic VT is rare but has poor prognosis. Case reports have suggested temporary pacing could be useful to suppress recurrent arrhythmia. All consecutive patients admitted to the Cardiac Intensive Care Unit of our institution from 2009 to 2017 for VF electrical storm refractory to medical therapy in whom temporary pacing was used at the acute phase were included. Ten patients met inclusion criteria. Nine men and one woman mean age was 67 ± 21. Two patients were already equipped with an ICD in secondary prevention. Mean number of arrhythmic events during electrical storm was 28.7 ± 43.5. Electrical storm was related to a recent ischemic event (6 patients), Brugada syndrome with fever episode (1), or Flecainide intoxication (1). Cause remained unknown in 2 patients. Mean LVEF was 36 ± 15%. Medical therapy using Amiodarone (6), B-blockers (4), and Lidocaine (5) for ischemic patients or Isoproterenol for Brugada syndrome had failed in all patients. Rapid pacing (99.0 ± 20.8 bpm) at the atrial (4), ventricular (5), or both (1) levels was initiated at this stage. Pacing therapy was ineffective with the Flecainide intoxication and the idiopathic VF patient, reduced the number of VF episodes with the Brugada syndrome patient and completely suppressed arrhythmias in all other patients. Atrial and ventricular pacing were equally effective. Patients with effective temporary pacing underwent ablation (2), or were managed medically (3). There was no serious pacing-related complication. Temporary pacing seems to be a quick and safe therapeutic option in VF electrical storm. It's particularly effective in patients with recent ischemic events in which it can be used as a bridge to ablation or to await medical therapy optimization.

Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice.

The human cardiac action potential in atrial and ventricular cells is initiated by a fast-activating, fast-inactivating sodium current generated by the SCN5A/Nav1.5 channel in association with its β1/SCN1B subunit. The role of Nav1.5 in the etiology of many cardiac diseases strongly suggests that proper regulation of cell biology and function of the channel is critical for normal cardiac function. Hence, numerous recent studies have focused on the regulatory mechanisms of Nav1.5 biosynthetic and degradation processes as well as its subcellular localization. The purpose of this study was to investigate the role of microRNAs in the Scn5a/Nav1.5 posttranscriptional regulation. Quantitative polymerase chain reaction, immunohistochemical and electrophysiological measurements of distinct microRNA gain-of-function experiments in cardiomyocytes for the assessment of Scn5a expression. Functional studies of HL-1 cardiomyocytes and luciferase assays in fibroblasts demonstrate that Scn5a is directly (miR-98, miR-106, miR-200, and miR-219) and indirectly (miR-125 and miR-153) regulated by multiple microRNAs displaying distinct time-dependent profiles. Cotransfection experiments demonstrated that miR-219 and miR-200 have independent opposite effects on Scn5a expression modulation. Of all the microRNAs studied, only miR-219 increases Scn5a expression levels, leading to altered contraction rhythm of HL-1 cardiomyocytes. Electrophysiological analyses in HL-1 cells revealed that miR-219 increases the sodium current. In vivo administration of miR-219 does not alter normal cardiac rhythm, but abolishes some of the effects of flecainide intoxication in mice, particularly QRS prolongation. This study demonstrates the involvement of multiple microRNAs in the regulation of Scn5a. Particularly, miR-219 increases Scn5a/Nav1.5 transcript and protein expression. Our data suggest that microRNAs, such as miR-219, constitute a promising therapeutical tool to treat sodium cardiac arrhythmias.

救急外来におけるフレカイニド中毒の診断と治療

救急外来におけるフレカイニド中毒の診断と治療

外傷性ショックが疑われたフレカイニド中毒の1例

外傷性ショックとして搬送されたフレカイニド中毒の1症例を経験したので報告する。症例は89歳の男性，原付自転車乗車中に自損転倒し，救急搬送された。来院時意識清明であったが，収縮期血圧60 mmHg台，心拍数75 /minの非常に幅広いQRS波形の心室調律を認めた。血圧の低下は心室調律によるものと判断し，電気的除細動を試みたが奏効せず，アミオダロンの静脈内投与で洞調律へ復帰した。原因精査に冠動脈造影も行ったが，急性冠症候群を示唆する所見は認めなかった。検査終了後心室頻拍が出現したが，アミオダロンの持続静注を開始したところ再び洞調律へ復帰した。既往歴に心筋梗塞，心房細動を有し，フレカイニドを内服していたが，血中濃度高値でありフレカイニド中毒と診断した。抗不整脈薬の血中濃度上昇が致死的不整脈発現の誘因となっている場合もあり，既往歴の詳細な確認，薬物血中濃度の測定，治療法の熟知が肝要である。

Usefulness of postmortem biochemistry in forensic pathology: Illustrative case reports

The aim of this work is to present some practical, postmortem biochemistry applications to illustrate the usefulness of this discipline and reassert the importance of carrying out biochemical investigations as an integral part of the autopsy process. Five case reports are presented pertaining to diabetic ketoacidosis in an adult who was not known to suffer from diabetes and in presence of multiple psychotropic substances; fatal flecainide intoxication in a poor metabolizer also presenting an impaired renal function; diabetic ketoacidosis showing severe postmortem changes; primary aldosteronism presented with intracranial hemorrhage and hypothermia showing severe postmortem changes. The cases herein presented can be considered representative examples of the importance of postmortem biochemistry investigations, which may provide significant information useful in determining the cause of death in routine forensic casework or contribute to understanding the pathophysiological mechanisms involved in the death process.

Case Report II

Case Report II

Life-Threatening Flecainide Intoxication in a Young Child Secondary to Medication Error

To describe a case of life-threatening flecainide intoxication in a toddler, secondary to accidental reversal of syringes used for oral administration. A 2-year-old male with a history of a persistent junctional reciprocating tachycardia had been receiving flecainide 4.8 mg/kg/day (1 mL 3 times daily) and nadolol 2 mg/kg/day (5 mL once daily) for 10 months. One morning, 3 hours after the drugs were administered, he became bradycardic (heart rate 50 beats/min) and then presented to the emergency department with vital signs absent. After initial cardiopulmonary resuscitation and epinephrine, he was bradycardic; this was followed by wide-complex tachycardia that converted rapidly to narrow-complex tachycardia after bolus administration of intravenous sodium bicarbonate for suspected flecainide intoxication. Following resuscitation, he remained hemodynamically stable and was discharged in normal sinus rhythm without neurologic sequelae. Drug concentrations obtained at the time of presentation showed a serum concentration of flecainide of 0.668 microg/mL. Drug formulations were also analyzed and found to contain the expected concentration of flecainide. Literature regarding adverse drug events in the pediatric outpatient population is reviewed, as well as how these risks apply to flecainide, a medication with a low margin of safety. Pediatric experience with flecainide intoxication and sodium bicarbonate administration as an antidote is reviewed. Analysis of the serum drug concentrations demonstrated blood concentrations consistent with syringe reversal, which would have produced a 5-fold flecainide overdose. The Naranjo probability scale indicated a highly probable relationship between flecainide ingestion and the life-threatening event in this case. This case of life-threatening flecainide intoxication in a young child, secondary to accidental reversal of medication syringes, underscores the importance of providing parents with accurate dispensing information and labeling medication bottles and syringes in an unambiguous manner.

Auto-intoxication with flecainide and quinapril: ECG-changes, symptoms and treatment.

Flecainide acetate is a sodium channel blocker and a class Ic antiarrhythmic agent with potential lifethreatening proarrhythmic and cardioinhibitory properties when taken in overdose. Quinapril is an angiotensin-converting enzyme inhibitor (ACE-inhibitor) and overdose can lead to prolonged hypotension and, less frequently, transient renal impairment.We describe the first published case of intoxication with both drugs. The patient developed a broad-QRS-tachycardia and severe hypotension. Treatment with volume expansion, hypertonic sodium bicarbonate, inotropic support with norepinephrine and insertion of an intra-aortic balloon pump led to complete recovery after 72 hours.We assume that the clinical picture was mainly dictated by flecainide intoxication. Relevant literature data are discussed.

Review on Flecainide Poisoning

Flecainide acetate is a Vaughn-Williams class IC antiarrhythmic. It is used mainly for treatment of supraventricular arrhythmias due to reentry and is highly effective in suppressing frequent premature ventricular depolarization and nonsustained ventricular tachycardia (VT). Although less than 1% of drug overdoses are fatal, severe intoxication with Vaughn-Williams class IC antiarrhythmics is associated with average mortality of 22.5% and the rate of mortality after flecainide overdose is approximately 10%. Severe flecainide overdose is frequently fatal because of the rapid onset of hypotension and ventricular arrhythmias. Its cardiotoxicity is mainly due to its sodium and potassium channels blocking effects. Commonly recommended therapies like haemolysis or haemoperfusion is not helpful because of its large volume of distribution. As a result, the treatment goals are to decrease the amount of blockade; correct aggravating conditions for arrhythmias, such as electrolytes disturbances or hypoxia; avoid drugs with sodium channels blocking effects. Recently, there are some successful data on using peripheral cardiopulmonary bypass technique in the treatment of severe flecainide intoxication. This may be a promising treatment option in this type of drug overdose.

Primary and secondary detoxification in severe flecainide intoxication

Since experience with primary and secondary detoxification in severe flecainide intoxications is limited, 2 different cases of flecainide intoxications are reported. In the first case, with plasma concentrations of 6500 ng/ml (therapeutic range: 200-980 ng/ml), the patient survived with a pacemaker and catecholamine support. In the second case, hemoperfusion terminated the need for emergency resuscitation during the initial phase, but was unsuccessful 3 h later. Even with a lower plasma concentration the patient died. Both patients had rapid onset of symptoms due to the very good bioavailability of the drug. Although it may be a rare intoxication, it is dangerous because of its quick onset and its efficiency in altering the cardiac stability. We recommend the prophylactic use of a pacemaker and gastric suction. The usefulness of hemoperfusion has not yet been proven.

Transient giant inverted T waves during flecainide intoxication

Transient giant inverted T waves during flecainide intoxication