Terapia de insulina y glucosa para el tratamiento de intoxicación grave con bloqueantes de canales de calcio en pediatría. Reporte de un caso / Insulin/glucose therapy for the treatment of severe calcium channel blocker poisoning in pediatrics. Case report

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of high-dose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution

[Insulin/glucose therapy for the treatment of severe calcium channel blocker poisoning in pediatrics. Case report]. / Terapia de insulina y glucosa para el tratamiento de intoxicación grave con bloqueantes de canales de calcio en pediatría. Reporte de un caso.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of highdose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution.

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Efficacy of methylene blue in a murine model of amlodipine overdose.

INTRODUCTION: Amlodipine overdoses have significant cardiac toxicity and are difficult to treat. Methylene blue has potential as a treatment for overdoses. METHODS: A randomized controlled study of methylene blue as a treatment for amlodipine toxicity was conducted in C57Bl/6 mice. A baseline echocardiography was followed by gavage administration of amlodipine (90 mg/kg). Five minutes after gavage, animals received either vehicle solution (controls) or methylene blue (20 mg/kg) by intra-peritoneal injection. Animals were continuously monitored, and cardiac parameters were acquired every 15 min up to two hours. RESULTS: Only 50% of control animals survived to the two-hour endpoint compared to 83% that received methylene blue. Amlodipine delivery induced significant reduction in left ventricular ejection fraction (EF), fractional shortening (FS), stroke volume (SV), and cardiac output (CO) in the vehicle treated animals relative to animals in the treatment group (p < 0.05 vehicle versus Methylene blue for EF, FS, SV, CO, and HR). DISCUSSION: The amlodipine dose induced cardiotoxicity that were effects were more pronounced in the untreated group. 50% vehicle controls quickly progressed into heart failure (within 90 min of exposure) and did not survive the two h observation endpoint. Distinctly, only one animal from the Methylene blue treatment group did not survive (83% survival) the study. Additionally, the surviving animals from the Methylene blue group displayed significantly higher ejection fraction, fractional shortening, stroke volume, and cardiac output compared to vehicle group, indicating that methylene blue preserved cardiac function. CONCLUSION: In this mouse model of amlodipine overdose, methylene blue decreased cardiac toxicity.

Postmortem fatal and non-fatal concentrations of amlodipine.

Amlodipine is a dihydropyridine calcium channel blocker widely used in the treatment of high blood pressure and coronary heart disease. Intoxication can lead to reflex tachycardia following massive hypotension and death. The objective of this work was to study the post-mortem concentrations of amlodipine in 62 patients in order to determine whether the use of the reference concentrations from the living patients was applicable in postmortem setting, and to define more precisely the fatal and non-fatal postmortem concentrations of amlodipine. The amlodipine concentrations were measured in femoral whole blood by LC-MS/MS validated method. When sufficient information was available, the data were classified into 2 different groups, based on the conclusions of the autopsy and toxicological results: G1: non-toxic death and G2: fatal poisoning involving amlodipine alone or as part of a multidrug poisoning. The median concentration of amlodipine [1st quartile - 3rd quartile] of the whole population (n = 62) was 81 [42-134] ng/mL. Twenty-two cases were classified as G1 and thirteen as G2. The observed median [1st quartile - 3rd quartile] concentration of amlodipine was 66 [40.5-79.5] ng/mL in G1 and 240 [170-404] ng/mL in G2. The median concentrations observed in "non-toxic" deaths (66 ng/mL) were three times higher than those usually observed in living patients. Amlodipine distribution ratio between plasma and whole blood concentrations seems insufficient to explain this difference and postmortem redistribution from organs should be considered, and could suggest the same redistribution pattern for other drugs belonging to the same family.

Persistent Hyperinsulinemia Following High-Dose Insulin Therapy: A Case Report.

INTRODUCTION: Overdoses of beta-adrenergic antagonists and calcium channel antagonists represent an uncommonly encountered but highly morbid clinical presentation. Potential therapies include fluids, calcium salts, vasopressors, intravenous lipid emulsion, methylene blue, and high-dose insulin. Although high-dose insulin is commonly used, the kinetics of insulin under these conditions are unknown. CASE REPORT: We present a case of a 51-year-old male who sustained a life-threatening overdose after ingesting approximately 40 tablets of a mixture of amlodipine 5 mg and metoprolol tartrate 25 mg. Due to severe bradycardia and hypotension, he was started on high-dose insulin (HDI) therapy; this was augmented with epinephrine. Despite the degree of his initial shock state, he ultimately recovered, and HDI was discontinued. Insulin was infused for a total of approximately 37 hours, most of which was dosed at 10 U/kg/hour; following discontinuation, serial serum insulin levels were drawn and remained at supraphysiologic levels for at least 24 hours and well above reference range for multiple days thereafter. CONCLUSION: The kinetics of insulin following discontinuation of high-dose insulin therapy are largely unknown, but supraphysiologic insulin levels persist for some time following therapy; this may allow for simple discontinuation rather than titration of insulin at the end of therapy. Dextrose replacement is frequently needed; although the duration is often difficult to predict, prolonged infusions may not be necessary.

The unknown known: non-cardiogenic pulmonary edema in amlodipine poisoning, a cohort study.

Context: Amlodipine is the most common calcium channel blocker (CCB) on the Swedish market, and poison center (PC) consultations for amlodipine overdoses are increasing. The clinical picture is dominated by vasodilation with relative preservation of cardiac function. CCBs selectively dilate vessels on the afferent side of the capillary network which, in states of preserved or increased blood flow may lead to edema formation, including non-cardiogenic pulmonary edema (NCPE). This complication has been considered rare in CCB poisoning. In this cohort study of nineteen amlodipine poisonings with high amlodipine blood levels, the incidence and clinical significance of NCPE in severe amlodipine poisoning are explored.Methods: During 2017-2018 the Swedish PC prospectively encouraged the gathering of blood samples in amlodipine poisonings with symptoms requiring treatment with inotropes or vasopressors. Samples were sent by mail to the Forensic Toxicology Division at the Swedish National Board of Forensic Medicine for screening and quantification of relevant toxicants. Patients with blood amlodipine levels >0.25 µg/mL were included in a cohort whose case details were gathered from medical records and PC-case notes with a special focus on signs of NCPE.Results: Nineteen patients met the blood amlodipine inclusion criteria. Four (21%) died and one patient was treated with VA-ECMO. Nine patients developed NCPE defined as a need for positive pressure ventilation (PPV) while having an echocardiographically normal left ventricular function.Conclusion: In this prospective cohort study of consecutive and analytically confirmed significant amlodipine poisonings NCPE was a common finding occurring in 47% of the whole cohort and in 64% of patients who did not go on to develop complete hemodynamic collapse.

Extracorporeal therapy for amlodipine poisoning.

A young male presented in refractory shock from amlodipine poisoning despite vasopressors, insulin-normoglycemia therapy, calcium gluconate and glucagon. He needed venoarterial ECMO for hemodynamic support and TPE to remove protein-bound amlodipine. The use of extracorporeal membrane oxygenation (ECMO) for cardiotoxic poisoning and Total Plasma Exchange (TPE) in removing drugs has been described in the literature. We report a rare case where both lifesaving extracorporeal therapies were used in a patient with a severe drug overdose. Stabilizing hemodynamics with ECMO combined with TPE for drug removal is a feasible strategy in unstable patients with amlodipine overdose.

Outcomes following calcium channel blocker exposures reported to a poison information center.

BACKGROUND: Calcium channel blockers (CCBs) are widely used drugs that have a narrow therapeutic index. Even minor overdoses must be treated in-hospital due to the risk of severe hypotension and bradycardia. We aimed to describe trends in CCB use and overdoses in Denmark. METHODS: Data on enquiries concerning CCBs reported to the Danish Poisons Information Center (DPIC) from January 2009 to January 2015 was coupled with data on hospitalization and mortality obtained from Danish National Registers. We obtained data on the general use of CCBs in Denmark and retrieved medical charts on fatal cases. RESULTS: From a total of 126,987 enquiries to the DPIC in 2009-2014 we identified 339 CCB unique exposures (3‰ of all). Children < 5 years accounted for 20% all exposures and these were classified as 'intake during playing' (61%) and 'medication errors' (39%). Among adults 'suicidal poisonings' (58%), and 'medication errors' (34%) were most frequent. A majority (81%) of exposures led to hospital admission. Seven patients (2%) died from the CCB exposure and all were adults with 'suicidal poisoning'. Amlodipine accounted for 95% of all CCB prescriptions, was involved in 71% of enquiries and in 29% of fatalities. Verapamil accounted for 3% of prescriptions, was involved in 13% of enquiries and 57% of fatalities. CONCLUSION: Four fifths of enquiries to the DPIC result in hospitalization and one fifth concern small children. Mortality were infrequent and occurred only in adults with suicidal exposures and with and an overrepresentation of verapamil exposures.

Amlodipine (150 mg) Poisoning: A Case Study.

BACKGROUND: Treatments of patients with amlodipine (a calcium channel blocker, CCB) overdose/poisoning remain challenging and death is certain if not intervened timely. Furthermore, for the society, the availability and common use of this drug can drive more vulnerable groups, especially children, towards an accidental/suicidal poisoning. CASE REPORT: Herein, we describe the case of an 18 year-old-adolescent girl who took 150 mg of amlodipine with the suicidal intentions and was admitted in our hospital approximately 4-hours after the ingestion. She developed circulatory failure and tachypnea. Decontamination, calcium, glucagon, and dual vasopressors were started, however, persistent hypotension led to the initiation of hyperinsulinemiceuglycemia therapy. She recovered fully and discharged without any complications in few days. This case educates not only about the successful use of variant drugs in the management of CCB overdose/poisoning, but also calls for the attention of the society for a safe storage of often used drugs, especially away from the children/adolescents.

A Fatal Case of Amlodipine Toxicity Following Iatrogenic Hypercalcemia.

Using calcium salts in management of amlodipine overdose is challenging. A 25-year-old male with known history of adult polycystic kidney disease presented with hypotension, tachycardia, and intact neurological status after ingestion of 450 mg of amlodipine. Immediately, normal saline infusion and norepinephrine were initiated. Two grams of calcium gluconate was injected, followed by intravenous infusion of 1.16 mg/kg/h. The patient was put on insulin-glucose protocol to maintain euglycemia and hyperinsulinemia. Electrocardiography demonstrated junctional rhythm. Serum creatinine was 2.5 mg/dL with metabolic acidosis. By the end of 24 h post-admission, his consciousness, blood pressure, and urine output were normal. Almost 32 h post-admission, he became disoriented and his oxygen saturation decreased and therefore was mechanically ventilated. Second chest X-ray showed pulmonary edema. Serum calcium level increased to 26.1 mg/dL. Calcium was discontinued, and furosemide infusion and calcitonin were intravenously administrated. Urine output increased and hemodialysis improved pulmonary edema and serum calcium level with no change in consciousness. Three days after admission, the patient became anuric and developed multi-organ failure and died 5 days post-admission. To avoid the consequences of excessive infusion of calcium in renal failure patients, the minimum calcium dose with close monitoring is recommended.

Two Fatal Cases Involving Cardiovascular Drugs Diltiazem and Amlodipine.

A liquid chromatographic tandem mass spectrometric method for the identification and quantification of 18 cardiovascular drugs was developed in order to evaluate two cases of fatal intoxication involving diltiazem and amlodipine respectively. Samples were simply diluted and centrifuged using a three-steps procedure with methanol, acetonitrile and mobile phase. The method proved to be selective and all the validation parameters fulfilled the acceptance criteria. In particular, linearity was studied in the range limits of quantitation (LOQ)-1,000 ng/mL (LOQ ranging from 0.8 to 33.3 ng/mL for urine and from 0.7 to 41.3 ng/mL for whole blood). The method was successfully applied to two real cases involving diltiazem and amlodipine fatal intoxications, respectively. Though the subject intoxicated by diltiazem did survive several hours after drug intake, central and peripheral blood levels at autopsy were extremely high (23.4 and 13.4 mg/L, respectively); the cause could be due to the formation of a pharmacobezoar that was found in the duodenum and that could have delayed the drug absorption. Moreover, diltiazem showed postmortem redistribution. On the contrary, the amlodipine peripheral blood level in the second case was relatively low (0.17 mg/L), thus confirming that even the uncontrolled intake of a less toxic calcium channel blocker can lead to death. Furthermore, blood samples were analyzed after 2 years of storage at -20°C: both diltiazem and amlodipine showed a significant degradation (70 and 99%, respectively).

A Case of Severe, Refractory Hypotension After Amlodipine Overdose.

Calcium channel blockers (CCBs) are responsible for a substantial portion of the mortality associated with cardiovascular medication overdose cases. Amlodipine, a dihydropyridine CCB, can cause prolonged hypotension in overdose. This report describes a severe amlodipine overdose case that was refractory to multiple therapeutic approaches. A 53-year-old male presented after ingesting eighty 10 mg amlodipine tablets in a suicide attempt. The patient was initially managed with calcium boluses, glucagon, multiple vasoactive agents, lipid emulsion infusions and hyperinsulinemic euglycemic therapy. Methylene blue boluses were initiated when hypotension persisted despite conventional treatments. Refractory hypotension prompted the use of plasmapheresis in an attempt to lower serum amlodipine levels. Finally, the patient was placed on extracorporeal membrane oxygenation (ECMO) to maintain perfusion while the effects of the amlodipine ingestion dissipated. Following an episode of asystole and pulseless electrical activity prior to the start of ECMO, the patient suffered an anoxic brain injury and suspected herniation prompting the family to withdraw medical care. There is limited evidence in the literature describing the refractory treatment modalities utilized in this patient. This report is unique as it describes the clinical course of a patient when a multitude of unique treatments were combined.

Bilateral blindness secondary to optic nerve ischemia from severe amlodipine overdose: a case report.

BACKGROUND: Calcium channel blockers are commonly prescribed medications; calcium channel blocker overdose is becoming increasingly prevalent. The typical presentation of a calcium channel blocker overdose is hypotension and decreased level of consciousness. We describe a case of a calcium channel blocker overdose that led to bilateral cortical blindness, a presentation that has not previously been reported. CASE PRESENTATION: A 49-year-old white woman with known bilateral early optic atrophy presented to our hospital with hypotension and obtundation following a known ingestion of 150 mg of amlodipine. She was transferred to our intensive care unit where she was intubated, mechanically ventilated, and required maximal vasopressor support (norepinephrine 40 mcg/minute, epinephrine 40 mcg/minute, and vasopressin 2.4 units/hour) along with intravenously administered crystalloid boluses. Despite these measures, she continued to deteriorate with persistent hypotension and tachycardia, as well as anuria. Intralipid emulsion therapy was subsequently administered to which no initial response was observed. A chest X-ray revealed diffuse pulmonary edema; intravenous diuresis as well as continuous renal replacement therapy was initiated. Following the initiation of continuous renal replacement therapy, her oxygen requirements as well as urine output began to improve, and 3 days later she was liberated from mechanical ventilation. Following extubation, she complained of new onset visual impairment, specifically seeing only red-green colors, but no objects. An ophthalmologic examination revealed that this was due to bilateral optic atrophy from prolonged hypotension during the first 24 hours after the overdose. CONCLUSION: Persistent hypotension in the setting of a calcium channel blocker overdose can lead to worsening optic atrophy resulting in bilateral cortical blindness.

[The distribution of amlodipine in the organism of the warm-blooded animals]. / Raspredelenie amlodipina v organizme teplokrovnykh zhivotnykh.

The objective of the present study was to elucidate the specific features of amlodipine distribution in the organism of the warm-blooded animals (rats) following a single intragastric administration of the poisonous substance at a dose of 686 mg/kg b/w/ (LD50). Amlodipine was isolated from the blood and various organs of the animals by means of acetone extraction and purified on the silica gel column (100/160 mcm) with the elution by an ethanol-hexane (7:3) mixture. The identification and the quantitative measurement of amlodipine were performed with the use of the TLC, GC-M, and UV-spectrophotometry. The study has shown that unmetabolized amlodipine was present in large amounts in the internal organs and blood of the poisoned animals. The principal organs of its accumulation were the stomach, kidneys, and blood.

Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine.

Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, the available treatments fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs involved in death due to overdose. Importantly, in all cases reported until now in the literature, CCB intoxication was known at the time of patients' presentation and the medical challenge solely consisted of the therapeutic approach. In this case report, we describe our experience in treating a 72-year-old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor infusions. Prolonged pharmacologic support and intermittent sessions of hemofiltration induced stabilization and recovery. The results of an extensive diagnostic workup to elucidate the cause were unfruitful. The recurrent and paroxysmal nature of the clinical presentation along with its incidence after the patient left the protected setting of the hospital led the diagnostic approach to search for a possible external factor, which was shown to be, after toxicological investigation, unintentional amlodipine intoxication.

Survival After Cardiac Arrest: ECMO Rescue Therapy After Amlodipine and Metoprolol Overdose.

Extracorporeal membrane oxygenation (ECMO) use in poisoned patients is increasing, but is rare post cardiac arrest. We report a case of ECMO use with complete recovery in a patient who arrested twice after a cardiotoxicant overdose. A 17-year-old male presented after an unknown overdose. He rapidly became hypotensive and bradycardic and received aggressive supportive care without improvement. He was transferred to our institution and suffered a cardiac arrest shortly after arrival. Six minutes of advanced cardiac life support resulted in return of spontaneous circulation. High-dose insulin, lipid emulsion, and ECMO were initiated. While awaiting ECMO deployment, he again became pulseless. Compressions resumed, and after 30 min, ROSC was achieved, and he was cannulated for veno-arterial ECMO. Within 48 h, he was decannulated, and then weaned off epinephrine 2 days later. Upon extubation, he was neurologically intact. Amlodipine and metoprolol were later confirmed in serum. Adolescent poisoned patients represent an ideal population for ECMO due to lack of comorbidities. As experience with ECMO in overdose increases, additional research is needed to determine appropriate indications and timing for its use. ECMO is an option for patients poisoned with a cardiotoxicant drug, even following witnessed cardiac arrest.

Conventional and Unconventional Lifesaving Therapies in an Adolescent With Amlodipine Ingestion.

Amlodipine, a dihydropyridine calcium channel blocker, is commonly prescribed for the treatment of hypertension. Ingestion of an overdose leads to severe hypotension; if the hypotension is not treated, death may be imminent. Conventional and unconventional interventions were used to treat an adolescent who ingested a life-threatening dose of amlodipine. Severe hypotension resistant to conventional treatment with intralipids and hyperinsulinemia-euglycemia therapy led to the use of plasmapheresis and a pneumatic antishock garment as lifesaving measures. Plasmapheresis has been described in only one other case of severe amlodipine overdose, and the use of a pneumatic antishock garment has never been described in the management of a calcium channel blocker overdose. Because short-term use of a pneumatic antishock garment has associated risks, the critical care nurse's anticipation of side effects and promotion of safe use of the garment were instrumental in the patient's care and outcome. (Critical Care Nurse 2016; 36[4]:64-69).

Failure of intravenous lipid emulsion in treatment of cardiotoxicity caused by mixed overdose including dihydropyridine calcium channel blockers.

INTRODUCTION: Calcium channel blockers and beta-blockers are among the most frequently ingested cardiovascular drugs in self-poisoning causing significant mortality. Intravenous lipid emulsion (ILE) is reported as a potentially novel antidote for treatment of acute poisoning caused by some of these drugs. CASE REPORT: We presented two cases of poisoning with these drugs. The case 1, a 24-year-old woman ingested amplodipine, metformin and gliclazide for self-poisoning. She presented with tachycardia and hypotension. Laboratory analyses revealed hyperglycaemia and metabolic acidosis. Despite the treatment which included fluid resuscitation, vasopressors, intravenous calcium, glucagon and ILE, circulatory shock occurred. The patient died 10 hours after admission due to cardiac arrest refractory to cardiopulmonary resuscitation. The case 2, a 41-year-old man, was found in a coma with empty packages of nifedipine, metoprolol and diazepam tablets. On admission vital signs included Glasgow Coma Scale (GCS) of 3, weak palpable pulses, undetectable blood pressure, and irregular breathing with oxygen saturation of 60%. An electrocardiography showed AV block (Mobitz II) with ventricular rate of 44/min with progression to third degree of AV block. In attempt to increase heart rate and blood pressure the following agents were administered: atropine boluses, normal saline with dopamine, glucagon, calcium chloride and ILE. Temporary transvenous pacemaker was placed, electrical capture was recorded, but without improvement in haemodynamics. Three hours after admission cardiac arrest happened and cardiopulmonary resuscitation was unsuccessful. CONCLUSION: Intravenous lipid emulsion may be ineffective in acute poisonings with amlodipine, nifedipine or metoprolol.