Pharmacological and mechanical management of calcium channel blocker toxicity

Abstract

Cardiovascular instability associated with calcium channel blocker toxicity comprises a small percentage of overdose presentations, yet they are associated with a high mortality rate. We detail the management of a 64-year-old man who took an intentional overdose of 840 mg nimodipine. We include the treatment he received and highlight the scarcity of evidence behind the use of gastric decontamination, calcium, glucagon, intravenous lipid emulsion, high-dose insulin therapy, sodium bicarbonate, vasopressors and methylene blue in calcium channel blocker toxicity. Additionally, the article explores the use of electrical pacing and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Following successful weaning of VA-ECMO, the patient was successfully extubated but remained neurologically impaired due to hypoxic-ischaemic brain injury, critical care polyneuropathy and renal failure requiring dialysis. He has cerebral performance category 3; he has mild cognitive impairment but able to perform some activities of daily living independently and communicate his thoughts and needs. He requires no respiratory or cardiovascular support.

Background

The management of calcium channel blocker toxicity often requires a multitude of pharmacological agents with scarce evidence for their use. Patients can deteriorate quickly, and prompt administration of medications is vital to achieve cardiovascular stability and a good neurological outcome. Patients who fail pharmacological treatment may benefit from escalation to venoarterial extracorporeal membrane oxygenation (VA-ECMO).

Case presentation

A 64-year-old man presented to a district hospital following an intentional overdose of nimodipine 840 mg, metformin 42 g, risperidone 88 mg, pravastatin 840 mg and ranitidine 9 g. He had been involved in an altercation with a neighbour prior to the overdose. He called the ambulance himself; however, we could not verify how soon after the overdose this occurred. On arrival, he had a patent airway and conversing but was in extreme cardiogenic shock with sustained sinus bradycardia at 50 beats per minute (figure 1) and systolic blood pressure of 45 mm Hg. His Glasgow Coma Scale was 15/15; he had a rectal temperature of 32.4°C and a glucose level of 11.9 mmol/L.

Figure 1.

ECG showing sinus bradycardia (standard 25 mm/s and 10 mm/mV calibration).

His medical history included hypertension, type 2 diabetes mellitus, depression, psychosis and gastro-oesophageal reflux disease. He lived by himself and was independent of daily activities, and he had no family members.

Investigations

His initial arterial blood gas showed pH 7.01, paO₂47.6 kPa, p_aCO₂3.3 kPa, base excess −24.8 mmol/L and lactate 17 mmol/L. His osmol gap, calculated from serum osmolality − calculated osmolality [2(Na⁺ + K⁺)+glucose + urea] was 10.5 mOsm/kg H₂O. He had an undetectable plasma alcohol level, <10 mg/L paracetamol level and <50 mg/dL salicylate level.

Treatment

Initial resuscitation started with peripheral ephedrine, four 500 µg boluses of atropine and two 1000 mL of warmed normal saline, while a central venous catheter and an arterial line were sited. This was escalated to aliquots of epinephrine (100 µg) before epinephrine and dobutamine infusions were started (at 0.10 µg/kg/min and 3.13 µg/kg/min, respectively). Contact was made with the National Poisons Information Service and the intensive care team. Concurrently, he was receiving 30 mL of 10% calcium gluconate, glucagon 10 mg intravenous bolus followed by a 2 mg/hour infusion, intravenous lipid emulsion (ILE) 100 mL bolus followed by 1200 mL/hour infusion and three 100 mL boluses of 8.4% sodium bicarbonate. He remained persistently hypotensive and bradycardic; the decision was made to start him on hyperinsulinaemia/euglycaemia therapy. Fifty millilitres of 50% intravenous dextrose was followed by a loading dose (1 unit/kg) of intravenous short-acting insulin and an insulin maintenance infusion at 0.5 units/kg/hour. When repeated sampling showed that blood gas values were not improving (pH 6.93, p_aO₂42.9 kPa, p₂CO₂5.4 kPA, base excess −23.8 mmol/L) and lactic acidosis of >20 mmol/L, he was intubated with 10 mg propofol and 20 mg atracurium. VA-ECMO was performed bedside in the emergency department 4 hours into the resuscitative effort, and the patient was transferred out to our nearest ECMO centre. An intravenous infusion of methylene blue was started at 1 mg/kg/hour.

Outcome and follow-up

Five days after his initial presentation, the patient was decannulated following ECMO weaning, and he was extubated 11 days later. He sustained hypoxic-ischaemic brain injury with multiple white matter infarcts on CT imaging of the brain, critical care polyneuropathy and renal failure requiring dialysis. Four months following the overdose, he remains an inpatient on a medical ward. He has cerebral performance category 3; he has mild cognitive impairment but is able to perform some activities of daily living independently and communicate his thoughts and needs. He has no respiratory or cardiovascular support, is undergoing physical rehabilitation and is awaiting placement.

Discussion

We detail the management of a patient who presented following an intentional overdose of medications. The resultant clinical picture was one of cardiovascular instabilities and a hyperlactataemia state, with diminished responses to common antidotes and vasopressors. It is important to maintain a broad differential of potential ingestions in this case. Medications known to result in elevated lactate include alcohol, cocaine, carbon monoxide, cyanide, linezolid, nucleoside reverse transcriptase inhibitors, metformin, epinephrine, acetaminophen, propofol, beta₂-agonists and aminophylline.¹

This review focuses on the management of calcium channel blocker toxicity. Despite calcium channel blocker toxicity comprising a small percentage of all overdose presentations, they can deteriorate quickly and are associated with a high mortality rate.² Calcium channel blockers have direct inhibitory action on voltage-gated L-type calcium channel receptors and control the influx of calcium into myocardial and vascular smooth muscle cells. This initiates sinoatrial node depolarisation and smooth muscle tone maintenance of vascular and gastrointestinal cells. L-type calcium channels are also present in pancreatic islet cells and are responsible for regulating cardiac glucose consumption. The resultant negative inotropic and chronotropic effects and peripheral vasodilatation result in persistent hypotension and bradycardia.³

Gastric decontamination

In a retrospective review of ingestions involving a mix of substances (including calcium channel blockers) within the paediatric population, Loe et al⁴ found that whole bowel irrigation with polyethylene glycol electrolyte lavage solution in 57 patients resulted in no major adverse effects. Cumpston et al,⁵ however, reported two cases of hyperemesis resulting in abdominal distension and aspiration pneumonia and persistent hypotension. While one had haemodynamic instability throughout (and ultimately went into asystole), the other patient became hypotensive 3.5 hours into his bowel irrigation. Both had taken sustained release preparations and complications rose following episode of vomiting. In a case series, one patient survived to discharge after receiving polyethylene glycol, while another died following haemodynamic fluctuation.⁶

In another retrospective review of paediatric patients, 174 patients received gastric decontamination in the form of activated charcoal, gastric lavage, whole bowel irrigation or a mixture of them. There were no major effects or deaths.⁷ Similar experiences were also reported by other studies.^8–10 Cardiac arrest was reported following gastric lavage in one case report.¹¹ In all of these cases, neither improvement nor deterioration was attributable to gastric decontamination.

Lapatto-Reiniluoto et al¹² performed a randomised crossover study measuring plasma and urine concentrations of various drugs including verapamil following treatment with either 25 g activated charcoal or gastric lavage. The authors showed a mean AUC (area under the plasma concentration-time curve from 0 to 24 hours) reduction of 92.8% (p<0.01) in the charcoal group but only 4.0% in the gastric lavage group, compared with control. Activated charcoal is administered within 1–2 hours of ingestion at a dose of 1 g/kg. They are effective up to 4 hours after ingestion of sustained release preparations.¹³

The American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists published a position paper in 2013, highlighting the limited evidence to support gastric lavage and the flawed methodology of studies that do show clinical benefit. They concluded that gastric lavage should not be routinely performed, if at all, and that activated charcoal or observation and supportive care should take precedence over gastric lavage.¹⁴

Calcium

In theory, an increase in extracellular calcium should maximise calcium entry through unblocked channels. Animal studies show improvements in cardiac output and blood pressure following administration of intravenous calcium with little effect on heart rate. These are, however, short lived to around 60 min even in cases where an infusion was given.^15–21 Observational human studies are more inconsistent, with no clear dose–response relationship.^22–24 Although affording some survivability, it appears that administration of calcium should only be a temporising inotropic measure. Doses differ, but in general, adverse effects of hypercalcaemia are rarely seen; one patient recorded a serum value of 5.9 mmol/L following 30 g of calcium administered with no observed complications. Some advocate that the aim of calcium treatment would be to overcome competitive blockade of the conducting system; the degree of hypercalcaemia would thus be dependent on the level of calcium channel blocker and its relative effects on these tissues.²⁵ Kerns II²⁶ provides a reasonable dosing regime; 0.6 mL/kg bolus of 10% calcium gluconate (or equivalent of calcium chloride) should be given intravenously followed by an infusion at 0.6–1.5 mL/kg/hour. The exact endpoint is less clear, either observed improvement in blood pressure or contractility (if measured) or serum calcium levels at double the normal value.

Glucagon

Glucagon has direct inotropic and chronotropic actions on cardiac muscles mediated through cyclic adenosine monophosphate (cAMP) production.²⁷ It has a rapid onset of action, peaking at 5–7 min and persisting for up to 15 min.²⁸In vivo preparations have demonstrated a direct reversal of myocardial depression induced by nifedipine, verapamil and diltiazem.²⁹ Experimental animal studies showed improvements in both heart rate and cardiac output^{30 31}; however, its efficacy is not consistently replicated in human studies. Walter et al³² reported an improvement in blood pressure following a 0.5 mg bolus of glucagon, Ramoska et al²² documented an improvement in blood pressure but not heart rate following 17 mg of glucagon, Love et al³³ reported five cases of blood pressure and heart rate corrections following a 3 mg bolus ±3 mg/hour infusion and Doyon et al³⁴ showed an improvement in blood pressure, although the heart was transvenously paced, and dopamine and dobutamine infusions were running concurrently at 16 µg/kg/min and 5 µg/kg/min. Glucagon failed to improve the haemodynamics of several patients as reported by three case series.^35–37 An experts consensus report looking into the treatment of calcium channel blocker toxicity does not recommend the routine use of glucagon due to reported variable effects.³⁸ In addition, glucagon reliably results in inhibition of gastric contractions, nausea and vomiting, which could further complicate the course of a patient with altered mental status who has yet to be intubated.³⁹

Intravenous lipid emulsion

The exact mechanism of action of ILE on drug concentration is unknown, although it is postulated that redistribution of a lipophilic drug is halted when given early in the treatment of an overdose. Paradoxically, serum concentrations of drugs have been shown to be increased following ILE, and whether ILE facilitates drug absorption from the gastrointestinal tract remains unclear.⁴⁰ The majority of cases reporting positive haemodynamic response used ILE as a rescue therapy,^41–45 although West et al⁴⁶ reported a case with no detectable improvement. What instead transpired was an interference in biochemical assays and blood gas oxygenation status. Pancreatitis and acute respiratory distress syndrome are documented adverse effects following ILE administration,⁴⁷ as is asystole as reported by Cole et al.⁴⁸ The Lipid Emulsion Therapy in Clinical Toxicology Workgroup concluded that the effects of ILE are heterogeneous, and the evidence for their use remains of low quality. Controlled studies were all performed on animals, while human publications were exclusively from case reports. They all showed variable response to ILE therapy.⁴⁹

High-dose insulin (euglycaemic) therapy

Long-chain free fatty acids are the preferred metabolic source of myocardium under aerobic conditions. In haemodynamic shock, glucose becomes the preferred substrate and facilitation of glucose transport into myocardial cells improves oxygenation and hence activity.⁵⁰ It is postulated that calcium channel blocker toxicity results in the uptake of glucose in a concentration-dependent manner rather than insulin mediated, explaining the need for high doses of glucose.⁵¹ It is hypothesised that insulin also exhibits calcium-dependent and independent positive inotropic effects through phosphatidylinositol-3-kinase in the failing myocardium and improves perfusion via vasodilatation of terminal arterioles.^{52 53} Its exact inotropic properties remain unproven.

Two observational studies,^{54 55} five human case series^56–60 and four animal studies^{51 61–63} document improvements in cardiovascular status and a potential increase in survival with high-insulin therapy. Blood pressure and cardiac output improves within 15–60 min of initiation of therapy.⁶⁰ There are reports (two patients) of restoration to normal sinus rhythm from complete heart block, although these are not reported elsewhere.²⁶ The typical starting dose is 1 U/kg followed by an infusion of 1 U/kg/hour with euglycaemia maintained with a dextrose infusion.³⁸ Titration of up to 10 U/kg/hour is only supported by case series, thus should be reserved for those who do not respond to alternative therapies. Monitoring involves continuous serum measurements of glucose and potassium and fluid balance to prevent volume overload. Bedside echocardiography (if available) is a rapid and non-invasive method of measuring myocardial response.

Sodium bicarbonate

An acidotic environment potentiates the affinity of calcium channel antagonists to L-type calcium channels, and thus correction of the acidosis would help improve cardiovascular status. In severe toxicity, calcium channel blockers also exhibit an inhibitory action on fast sodium channels resulting in a widening of the QRS complex, similar to tricyclic antidepressants.²⁶ There is, at present, limited evidence to fully support its use, with one animal study⁶⁴ and two case reports^{65 66} showing improved outcome. It may be useful as an adjunct when there is evidence of a prolonged QRS. Bicarbonate therapy can be instituted with 1–2 mEq/kg aliquots followed by an infusion.⁶⁷

Catecholamine adrenergic receptor agonists

There is no one catecholamine that is superior to another and selection should be based on the type of shock. Patients with depressed myocardial contractility and decreased peripheral resistance would benefit from the α-adrenergic and β-adrenergic properties of norepinephrine and epinephrine.17 19 21 63 In the presence of cardiac decompensation secondary to depressed contractility, dobutamine may be used for its predominantly β₁-agonist effects.⁶⁸ Isoprenaline showed benefits at improving haemodynamic status of three patients in one case series⁶⁹ and one case report.⁷⁰ However, similar to dobutamine and dopamine, isoprenaline can worsen peripheral resistance and cause hypotension.⁷¹ Experimental animal studies and observational human studies have produced conflicting results on the use of vasopressin, with the former reporting worsened survival,^{72 73}while the latter showed blood pressure improvement when coadministered with other vasopressors.^{74 75} High infusion rates are often required with all agents.⁶⁸ In situations of symptomatic bradycardia, atropine may be used but is unlikely to achieve a sustained response.²¹

Methylene blue

Calcium channel blockers such as amlodipine increases endothelial nitric oxide, which contributes to vasodilatory shock.⁷⁶ Methylene blue works by inhibiting the nitric oxide–cyclic guanosine monophosphate pathway, scavenging nitric oxide and inhibiting its synthesis.^{77 78} Two case studies report on the efficacy of methylene blue in refractory shock, showing improvements within 1 hour of administration and rapid weaning of vasopressors.^{79 80} A starting dose of 1–2 mg/kg is recommended.⁷⁶ Care should be taken at higher doses as it can precipitate haemolytic anaemia and serotonin toxicity when ingested together with serotonergic agents.⁸¹ Patients should additionally be monitored for paradoxical methaemoglobinaemia due to direct oxidative effects on haemoglobin, especially patients with glucose-6-phosphate dehydrogenase deficiency as they do not produce sufficient nicotinamide adenine dinucleotide phosphate to reduce methylene blue to leukomethylene blue.⁸² The workgroup on calcium channel blocker toxicity currently do not recommend methylene blue as first-line therapy due to limited experience of its use.³⁸

Non-pharmacological management

Electrical pacing

Transvenous or transthoracic electrical pacing may be used to achieve a sustained heart rate, although in practice, electrical capture is either not achieved or it does not translate to an improvement in the blood pressure.²² This is due to the lack of intracellular calcium preventing adequate contractility of the heart.

Extracorporeal life support

Extracorporeal life support has shown a good survival outcome in at least one case report of verapamil toxicity⁸³ and three observational studies that also involve other cardiotoxic drugs.^84–86 Unfortunately, such an invasive procedure is not without side effects. VA-ECMO causes vascular (bleeding diathesis, thrombosis and limb ischaemia) and neurological complications (stroke, intracranial bleed and seizures), increases the risk of infection and can lead to multiorgan failure.⁸⁷ There are suggestions that concomitant infusion of ILE with VA-ECMO could result in fat emulsion agglutination, malfunction of the membrane oxygenator and increased risk of blood clot formation.⁸⁸ These complications were seen in at least one in vitro study⁸⁹ and one observational study,⁹⁰ although two case reports reported no such problems.^{91 92} An additional seven case reports made no specific comments of any complications.^93–99 This represents a growing area of research as clinicians gain more experience with using both modalities.

Learning points.

• The management of calcium channel blocker toxicity often requires a multitude of pharmacological agents with scarce evidence for their use.

• Patients can deteriorate quickly, and prompt administration of medications is vital to achieve cardiovascular stability and a good neurological outcome.

• Clinical toxicologists should be involved in the early management of any ingestion.

• In cases where pharmacological management has failed, consideration should be given to emergency extracorporeal life support as a resuscitative tool.