TOXICOLOGY/CASE REPORT

Extracorporeal Albumin Dialysis in Three Cases of Acute CalciumChannel Blocker Poisoning With Life-Threatening Refractory

Cardiogenic ShockNicolas Pichon, MD, Anthony Dugard, MD, Marc Clavel, MD, Jean Bernard Amiel, MD, Bruno François, MD,

Philippe Vignon, MD, PhD

From the Medical-Surgical Intensive Care Unit, Dupuytren Teaching Hospital, Limoges Cedex, France (Pichon, Dugard, Clavel, Amiel, François,Vignon); the CIC-P 0801 Inserm, Dupuytren Teaching Hospital, Limoges, France (Pichon, Dugard, Clavel, Amiel, François, Vignon); and the

University of Limoges, Limoges, France (Vignon).

We describe 3 patients admitted to the medical-surgical ICU in a university hospital with life-threatening cardiogenicshock after the ingestion of high doses of calcium channel blockers (8.4 g sustained-release diltiazem, 4.2 gsustained-release diltiazem, and 14.4 g slow-release verapamil). Cardiovascular failure and cardiac conductiondisturbances were unresponsive to the usual therapy (eg, intravenous injection of high doses of calcium, glucagon,hyperinsulinemia-euglycemia therapy, fluid resuscitation) and to increasing doses of simultaneous infusions ofadrenergic agonists. Albumin dialysis with Molecular Adsorbents Recirculating System (MARS) therapy wasperformed because of its unique ability to selectively remove from circulation protein-bound toxins (and potentiallydrugs) that are not cleared by conventional hemodialysis. A single procedure was successfully performed in eachpatient, which was followed by rapid weaning of adrenergic agonist agents and full recovery of the life-threateningcardiovascular failure. At 2-year follow-up, patients were asymptomatic. Albumin dialysis with MARS therapy may beeffective when used as a rescue procedure in patients presenting with sustained, life-threatening cardiogenic shockas a result of massive calcium channel blocker poisoning. [Ann Emerg Med. 2012;59:540-544.]

0196-0644/$-see front matterCopyright © 2011 by the American College of Emergency Physicians.doi:10.1016/j.annemergmed.2011.07.029

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INTRODUCTIONDrug-induced cardiovascular failure remains a leading

cause of death. Among 847,483 poisonings in adultsreported to the American Association of Poison ControlCenters Toxic Exposure Surveillance System, cardiovasculardrugs are involved in 5.8% of the cases and account fornearly 19% of the overall 1,261 poisoning fatalities.1

Calcium channel blockers are the most commoncardiovascular drugs involved in poison exposures reportedto the Toxic Exposure Surveillance System. Of the more than10,868 toxic exposures reported in 2009, 22% were treatedin a health care facility, 445 were intentional, and 62resulted in a major effect and 16 in a fatal outcome.2

Calcium channel blockers act with different degrees ofselectivity on cardiac myocytes, conductive cardiac tissue, andvascular smooth muscle. Accordingly, they variously alter thevascular tone, myocardial contractility, cardiac automaticity,and atrioventricular conduction. Predominant clinical findingsassociated with severe diltiazem and verapamil overdoses includesustained hypotension, bradycardia, sinus arrest, cardiacconduction disturbances, and life-threatening cardiovascularfailure.3 Survival from severe calcium channel blocker poisoninghas been reported with the use of aggressive conventional

therapy (eg, gastric lavage, administration of activated charcoal, a

540 Annals of Emergency Medicine

uid loading, infusion of high doses of calcium salts and oflucagon, hyperinsulinemia-euglycemia therapy, fat emulsionherapy, administration of adrenergic agonist agents).4-6 Theeported fatalities have been attributed to shock unresponsive toonventional pharmacologic agents with refractory cardiacrrest, accounting for a 10% mortality rate.7 Circulatoryssistance techniques such as intra-aortic balloonounterpulsation or extracorporeal life support may beifesaving, but their indications remain a matter of debate.8-10

nlike some toxins, calcium channel blockers are poorandidates for removal by hemodialysis.11 One case report hashown that specific extracorporeal albumin dialysis with the

olecular Adsorbents Recirculating System (MARS therapy)as the potential to efficiently remove protein-bound drugs,uch as diltiazem, from the circulation.12 The MARS system isn extracorporeal device that uses the principles of albuminialysis to selectively remove toxins, normally degraded in the

iver, that otherwise would not be removed by standardemodialysis. It combines the efficacy of sorbents to removelbumin-bound toxins by using a double-sided, albumin-mpregnated, hollow-fiber dialysis membrane with theelectivity of highly biocompatible dialysis membranes.13 Weeport 3 cases of refractory life-threatening cardiogenic shock as

result of acute calcium channel blocker poisoning in which

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albumin dialysis with MARS therapy was followed by weaningof adrenergic agonist agents and full recovery.

CASE REPORTCase 1

A 55-year-old woman (patient 1) was admitted to theemergency department (ED) for shock 4 hours after theingestion of 8.4 g sustained-release diltiazem in a suicideattempt. The patient presented with severe hypotension (bloodpressure 45/24 mm Hg) and oliguria. The patient promptlyreceived tracheal intubation and mechanical ventilation. Gastriclavage was performed and activated charcoal (50 g) wasadministered. An ECG recorded sinus bradycardia (pulse rate56 beats/min) associated with first-degree atrioventricular block.Despite aggressive fluid resuscitation (7,000 mL) and repeatedintravenous injections of calcium gluconate (10 g) and glucagon(9 mg), hypotension persisted and rapidly became refractory toincreasing doses of adrenergic agonist agents up to 0.72 �g/kgper minute of norepinephrine and 0.62 �g/kg per minute ofepinephrine. Transesophageal echocardiography depicted aglobal left ventricular systolic dysfunction (ejection fraction35%) without findings consistent with a cardiac preloaddependence. Eight hours after admission, biologicalabnormalities indicated metabolic acidosis (pH 7.03;bicarbonate level 7 mmol/L; base excess �22 mmol/L) withhigh lactate level (20.1 mmol/L) and acute renal failure(creatinine level 164 �mol/L). Serum diltiazem anddesacetyldiltiazem concentrations measured with liquidchromatography–diode array detection (not available onadmission to the ICU and tested before the medical decision ofperforming MARS therapy) were 2,658 �g/L (therapeutic range70 to 200 �g/L) and 500 �g/L (therapeutic range 10% to 30%of serum diltiazem concentrations), respectively.

Case 2A 13-year-old girl with a medical history of anorexia (body

mass index 14) and compulsive obsessional disorders wasadmitted to the ED 3 hours after the intentional ingestion of4.2 g sustained-release diltiazem. The onset of a generalizedclonic convulsion required tracheal intubation and mechanicalventilation. Gastric lavage and oral administration of activatedcharcoal (25 g) were performed. Five hours after toxic ingestion,the child exhibited anuria and severe hypotension (bloodpressure 40/26 mm Hg) associated with sinus bradycardia (pulserate 45 beats/min). An ECG recorded sinus bradycardia withoutconductive disorders. Transthoracic echocardiography showed amild left-sided ventricular systolic dysfunction (ejection fraction45%) but no cardiac preload dependence. Despite initial fluidresuscitation (4,000 mL), repeated intravenous injections ofcalcium (6 g) and glucagon (2 mg), and hyperinsulinemia-euglycemia therapy, the marked hypotension became refractoryto the rapid increase in doses of adrenergic agonists up to 2.33�g/kg per minute of norepinephrine and 0.97 �g/kg perminute of epinephrine. Nine hours after admission, biological

abnormalities indicated metabolic acidosis (pH 7.15; t

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icarbonate level 9 mmol/L; base excess �19 mmol/L)ssociated with a high lactate level (14.2 mmol/L), and acuteenal failure (creatinine level 196 �mol/L). Serum diltiazem andesacetyldiltiazem concentrations measured in the ICU after theedical decision to use albumin dialysis were 8,580 �g/L and

,043 �g/L, respectively.

ase 3A 43-year-old man with a history of psychiatric disorders,

hronic alcoholism, and ischemic cardiopathy (ejection fraction0%) was admitted to the ED 6 hours after the intentionalngestion of 14.4 g slow-release verapamil and bisoprolol. Onrrival, the Glasgow Coma Scale score was 8 and the patientresented severe hypotension (blood pressure 65/44 mm Hg).n ECG recorded sinus bradycardia (pulse rate 43 beats/min),ith significant QTc prolongation. The patient received

racheal intubation and mechanical ventilation. Despiteemporary intravenous pacing (pulse rate 75 beats/min) andedical management (eg, gastric lavage, administration of

ctivated charcoal, fluid resuscitation [5,000 mL], continuousnfusion of supratherapeutic doses of calcium salts [8 g] andlucagon [4 mg], hyperinsulinemia-euglycemia therapy),ypotension became refractory to a maximal dose oforepinephrine and epinephrine of 1.45 �g/kg per minute and.93 �g/kg per minute, respectively. Transesophagealchocardiography depicted a mild left-sided ventricular systolicysfunction (ejection fraction 45%) without predicted fluidesponsiveness. Ten hours after admission, the patient exhibitedevere metabolic acidosis (pH 7.08; bicarbonate level 13.4 mmol/L;ase excess �14.6 mmol/L) with high lactate level (10.54 mmol/L)nd acute renal failure (creatinine level 319 �mol/L). The serumerapamil concentration measured in the ICU and after theedical decision to perform albumin dialysis was 2,200 �g/L

therapeutic range 30 to 170 �g/L). The serum bisoprololoncentration was 53 �g/L (therapeutic range 45 to 80 �g/L).

lbumin Dialysis TherapyConsidering the severity of shock unresponsive to

onventional therapy, the life-threatening multiorgan failureespite aggressive resuscitation for our 3 patients, and areviously reported case treated with albumin dialysis,12 bloodetoxification based on albumin dialysis and Gambro’s MARSherapy (Meyzieu Cedex, France) with a Fresenius Medical CareSavigny Cedex, France) hemodialysis system 4008S wasubsequently performed for 6 hours for patient 1 and 4 hoursor patients 2 and 3. Albumin dialysis was initiated 10 hoursnd 11 hours after hospital admission for the 2 diltiazemoisonings and the verapamil poisoning, respectively. Theetrospective results of circulating drugs levels were not availablen the ED and therefore failed to alter the acute management ofatients, including the duration of individual albumin dialysis.o complications related to the procedure were encountered.During the procedures and throughout the next 2 days, the

erum concentrations of diltiazem and its metabolite, as well as

he serum concentration of verapamil, decreased significantly

Annals of Emergency Medicine 541

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Extracorporeal Albumin Dialysis in calcium channel Blocker Poisoning Pichon et al

(Figure 1). The blood lactate level decreased for all 3 patients(Figure 2), whereas the mean arterial pressure increasedsignificantly (Figure 2). The doses of epinephrine andnorepinephrine were rapidly tapered (Figure 2), and adrenergicagonist agents were withdrawn 24 hours, 3 days, and 28 hoursafter hospital admission for patients 1, 2, and 3, respectively.

Figure 1. Serum concentrations course of diltiazem and itsmetabolite for patient 1 (A) and patient 2 (B), as well asserum concentration of verapamil for patient 3 (C) beforeand after albumin dialysis.

Full recovery of myocardial function was confirmed by

542 Annals of Emergency Medicine

igure 2. Time course of plasma lactate concentrations,ean arterial pressures, and vasopressor infusion rates of

he patients with acute calcium channel blocker poisoningreated with albumin dialysis. A, Patient 1; B, patient 2;

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echocardiography in all patients. Organ failure fully recoveredand the 3 patients were discharged from the ICU on days 5, 6,and 4, respectively. The serum diltiazem concentrationmeasured in patient 2 (8,580 �g/L) before albumin dialysis wasthe highest concentration reported to date, to our knowledge, ina patient who survived after calcium channel blocker poisoning.

DISCUSSIONThe clinical presentation of severe calcium channel blocker

intoxication is dominated by cardiovascular collapse withbradycardia and atrioventricular block or by cardiogenic shock.There is no specific antidote management for calcium channelblocker poisoning. In our patients, the cardiogenic shock wasrefractory to well-conducted conventional medical treatment.Although acute heart failure resulting from an overdose ofcalcium channel blockers is generally reversible, cardiac toxicitymay be prolonged. Calcium channel blockers are rapidlymetabolized by the liver to inactive metabolites and possesswidely varying half-lives (from 1 to more than 50 hours). Theirhalf-life can be prolonged in patients with overdose because ofthe saturation of hepatic enzymes. Although information on thepharmacokinetic profiles of calcium channel blockers duringoverdose is sparse, their elimination appears not to be linear athigh concentrations.14 Conventional therapy has a limited effecton the clearance of calcium channel blockers, as evidenced byserial plasma concentrations previously reported in poisoningcase reports.15 Although we could not determine the clearanceof calcium channel blockers obtained by the MARS therapy, therapidly favorable outcome and the markedly shorter duration ofcardiovascular failure in our 3 patients provides indirectevidence that albumin dialysis did accelerate toxic drug removal.The monitoring of plasma levels of calcium channel blockersconstitutes a biological confirmation of this clinical hypothesis.

When medical treatment fails, circulatory assistance (intra-aorticballoon counterpulsation or even extracorporeal life support) mustbe considered and can be lifesaving.8 A recent review of theliterature showed that treatment of poisoned hearts withextracorporeal life support is feasible, but its indications and efficacyare yet not well defined or documented.9 The use of extracorporeallife support requires several prerequisites in an ICU (eg, continuousavailability of cardiac surgeons), is an invasive method, may resultin serious complications, and presents 2 substantial limitations inpatients with calcium channel blocker overdose: the failure tocapture toxins and increased blood pressure despite the increase inpulse rate.9

Calcium channel blockers, with large volumes of distribution,are metabolized by the liver into inactive metabolites and are highlybound to proteins, making them poor candidates for removal byhemodialysis.11,16,17 No blood detoxification system has yet beenshown to improve life-threatening circulatory failure as a result ofsevere calcium channel blocker poisoning. To our knowledge, only1 case report has shown the potential efficacy of albumin dialysiswith MARS therapy to remove diltiazem from the circulation.12

MARS therapy is approved for use of drug poisonings only in the

United States.

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The MARS system appeared to be clinically valuable in ouratients with a life-threatening hemodynamic compromise as aesult of an overdose of calcium channel blockers. This rescueherapy could be considered when conventional symptomaticreatment fails in the setting of overdose of protein-bound drugshat otherwise could not be efficiently removed from the body. Asuch, it may constitute an alternative treatment whenxtracorporeal life support is not rapidly available in life-threateninghock associated with massive protein-bound drug intoxications.

upervising editor: Richard C. Dart, MD, PhD

unding and support: By Annals policy, all authors are requiredo disclose any and all commercial, financial, and otherelationships in any way related to the subject of this articles per ICMJE conflict of interest guidelines (seeww.icmje.org). The authors have stated that no such

elationships exist.

ublication dates: Received for publication June 1, 2011.evisions received June 30, 2011, and July 20, 2011.ccepted for publication July 25, 2011. Available onlineugust 20, 2012.

ddress for correspondence: Nicolas Pichon, MD, E-mailicolas.pichon@chu-limoges.fr.

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