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Art & science | hypertension drugs

AbstractThe management of patients who have overdosed with calcium channel blockers (CCBs), which are commonly prescribed for hypertension, arrhythmia and angina, can be difficult but early initiation of the correct treatment increases the likelihood of good outcomes. This article refers to a case study to illustrate the unpredictable nature of overdose with CCBs and describes the treatment needed to reverse their effects.

KeywordsOverdose, calcium antagonist, hypotension, euglycemia

Serena Mann discusses treatment for people who have taken potentially lethal doses of drugs intended for arrhythmia, angina and hypertension

Management of calcium channel blocker overdose

Correspondenceserena.mann@UHBristol.nhs.uk

Serena Mann is a staff nurse in the emergency department at University Hospitals Bristol NHS Foundation Trust

Date submittedJanuary 23 2014

Date accepted February 11 2014

Peer reviewThis article has been subject to double-blind review and has been checked using antiplagiarism software

Author guidelinesen.rcnpublishing.com REGULARLY PRESCRIBED for the management

of hypertension, arrhythmia and angina, calcium channel blockers (CCBs), also known as calcium channel antagonists, are increasingly being taken to overdose (Abeysinghe et al 2010).

Such overdoses can cause hypotension, bradycardia, lethargy and syncope (Pohler 2006), as well as hyperglycaemia, lactic acidosis, seizures and non‑cardiogenic pulmonary oedema (Patel et al 2007, Whyte et al 2012). Death has been reported after accidental ingestion of 2.16g of one type of CCB, diltiazem (Cantrell and Williams 2005), although a girl survived after ingestion of 12g of the same drug (Durward et al 2003).

The 2011 annual report of the American Association of Poison Control Centres national poison data system shows that CCBs account for more than 60% of all deaths from cardiovascular medications, and high doses of CCBs are associated with morbidity and mortality (Levine et al 2007, Bronstein et al 2012).

It is important, therefore, that emergency department (ED) clinicians can identify the

signs of CCB overdose early to ensure that the patients concerned are managed appropriately, and to reduce the associated risks of morbidity and mortality.

Physiologically, CCBs decrease cardiac inotropy, dromotropy, chronotropy and vascular tone by blockading the L‑type calcium channels in myocardial and vascular smooth muscle (Lheureux et al 2006).

There are three classes of commonly used CCB: phenylalkylamines, such as verapamil; benzothiazepines, such as diltiazem; and dihydropyridines, such as amlodipine, felodipine and nifedipine (Whyte et al 2012).

Although all classes of CCB can cause bradycardia and hypotension (Cumpston et al 2010), each affects the cardiovascular system in a different way. Benzothiazepines, for example, are associated with high morbidity rates because, although they have moderate vasodilatory properties, they also decrease myocardial contractility and slow conduction through the sinoatrial and atrioventricular nodes (Anderson 2005).

Some CCBs are administered in a sustained‑ release form, which can lead to unpredictable absorption and delayed onset of toxicity when they are taken in overdoses (Cumpston et al 2010). For this reason the primary clinical toxicology database of the National Poisons Information Service (Toxbase 2009) recommends that, while patients who have taken normal‑release preparations in overdose should be observed for at least 12 hours, those who have taken modified‑release CCB preparations should be monitored for at least 24 hours.

A case study involving a woman who had deliberately taken an overdose of CCBs is presented and discussed opposite.

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Case studyA 48-year-old woman presented at the emergency department (ED) after taking a polypharmacy overdose, including a high dose of diltiazem. On arrival, she appeared to be haemodynamically stable. She was hypotensive, at 90mmHg systolic, but asymptomatic, alert and oriented. Cardiovascular, respiratory and neurological examinations produced normal results.

The patient’s initial treatment involved administration of 2L of crystalloid solution but over the next hour, her condition deteriorated. Her blood pressure (BP) decreased to 60mmHg systolic and she became bradycardic, with a pulse of 40 beats per minute (bpm). In addition, she became less responsive.

The National Poisons Information Service was contacted and, following its suggestions, the patient was given atropine, calcium chloride and glucagon.

Eventually, the patient’s systolic BP increased to 90mmHg and her heart rate to 60bpm, but she remained critically ill with persistent hypotension and an altered mental status. She was intubated for airway protection and had an arterial line inserted for continuous BP monitoring before her case was reviewed and she was transferred to an intensive care unit (ICU) for further management.

Eight days after her initial presentation and against medical advice she discharged herself from the ICU.

DiscussionManagement As the case study shows, patients who have taken CCB overdoses can deteriorate rapidly. On her arrival, the patient concerned exhibited possible symptoms of vasodilation, namely her hypotension, which became more evident as she developed refractory hypotension and as her BP failed to improve with fluid challenges.

According to Shepherd (2006), CCB poisoning usually results in hypotension that can be refractory to standard resuscitation measures, which makes hypotension management challenging (Kanagarajan et al 2007).

Although emergency practitioners should initiate the appropriate forms of management early, some management techniques are time dependent. Activated charcoal and orogastric lavage, for example, are recommended for use only up to one hour after ingestion of toxins (Givens 2012).

Comprehensive histories should be obtained quickly, therefore, to determine the dosages, routes and types of drug thought to have been ingested or administered (Costello and Syring 2008), and to help assess, plan and manage patients’ care.

The goals of CCB toxicity management are to remove the drug from the system, thereby improving cardiac contractibility and increasing vascular tone, and to maintain tissue oxygenation to provide metabolic support (Watling et al 1992).

Initial treatment should focus on airway, breathing and circulation, and intravenous (IV) access should be obtained, and normal saline solution administered, immediately (Pohler 2006).

Fluid resuscitation can improve patients’ BP or can indicate that more aggressive forms of management, such as inotropic support, are needed.

Decontamination Preventing the absorption of potentially toxic substances is a fundamental principle in the treatment of patients who have overdosed (Tenenbein 2000), and gastrointestinal decontamination techniques include administration of activated charcoal through nasogastric or orogastric tubes (Givens 2012).

Activated charcoal is most effective if it is administered no more than one hour after the drug was ingested (Anderson 2005). However, because patients who have taken intentional overdose often delay presentation, or because the time of ingestion cannot be ascertained, the usefulness of decontamination may be limited (Patel et al 2007).

Another treatment for CCB poisoning is administration of calcium to reverse the calcium‑channel blockade (Patel et al 2007).

Calcium is also indicated in patients who present with heart blocks after CCB overdose, especially if they have taken benzothiazepines (Whyte et al 2012). Patients who do not present with heart block can also be given calcium when there is evidence of haemodynamic compromise, as with the patient in the case study. Calcium is an easily accessible drug in EDs and emergency practitioners are familiar with its administration (Anderson 2005).

The recommended initial treatment dose of calcium chloride for CCB toxicity in adults is 10mL IV 10% solution, and a continuous calcium chloride infusion is required to sustain an increase in BP (Zimmerman 2003).

The calcium concentration levels of these patients should be monitored every two hours and serial electrocardiography should be undertaken to avoid clinically significant hypercalcaemia (Kambali et al 2013).

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Art & science | hypertension drugs

High‑dose calcium infusions are reported to be beneficial in the management of CCB toxicity (Lam et al 2001, Isbister 2002). However, Anderson (2005) suggests that, because even large doses of calcium can prompt only transient or minimal responses, other forms of management, such as administration of glucagon, atropine and lipid emulsion, and hyperinsulinaemia euglycaemia therapy (HIET), could be required. If CCB toxicity is substantial, patients who become symptomatically bradycardic may require atropine to increase their heart rates. Although atropine can be used in these circumstances, its effects are variable and short lived (Engebretsen et al 2011).

Glucagon Increasing the intracellular concentration of cyclic adenosine monophosphate with glucagon can have a positive effect on cardiac contractility (Bailey 2003), by activating protein kinase C and increasing cellular calcium flux across cell membranes (Proano et al 1995).

A systematic review of CCB poisoning in animals suggests that glucagon increases heart rate and cardiac output, and reverses second‑ and third‑degree atrioventricular blocks, although it seems to have no effect on mean arterial pressure (Bailey 2003). Further studies conducted on animals suggest that the administration of glucagon does not result in better survival rates (Bailey 2003).

Hyperglycaemia and hypokalaemia are adverse effects of glucagon administration so patients’ blood glucose and potassium levels should be monitored regularly, and treatments to reverse hyperglycaemia and hypokalaemia should be initiated when necessary.

Vasoactive agents Several catecholamines and sympathomimetic agents can be used to counteract the hypotensive effects of CCB toxicity, but the results of their use are mixed (Proano et al 1995). Vasoactive agents, such as dopamine, dobutamine, adrenaline (epinephrine) and noradrenaline (norepinephrine), directly affect cardiac performance because they act on receptors, ion channels and enzymes located in the heart and in smooth muscle (Priebe 2004).

Depending on which cardiac cellular structure and activity is being stimulated or inhibited, this action produces different inotropic effects and can alter heart rate, BP and systemic vascular resistance (Priebe 2004).

Patients with CCB toxicity may require high doses of vasoactive drugs, which can cause arrhythmias (Kambali et al 2013), so cardiac pacing must be considered when significant bradycardia and

conductional blocks are being managed (DeRoos 2006). Pacing can increase heart rate, which in turn can increase cardiac output (Patel et al 2007). Cardiac pacing for patients with CCB overdose has produced successful and unsuccessful outcomes (Salhanick and Shannon 2003).

Intra‑aortic balloon pump or cardiopulmonary bypass can be considered in patients who have taken a CCB overdose, are hypotensive and do not respond to other interventions (Holzer et al 1999).

Intravenous lipid emulsion The administration of IV lipid emulsion (ILE) has emerged as a promising measure in emergency care despite being intended originally for parenteral nutrition (Forster et al 2012).

The mechanism that underpins ILE can be explained partially by the ‘lipid sink’ theory, whereby fat emulsion provides an additional vascular compartment by which to draw toxins into plasma so that they are trapped within the transient lipid phase (Forster et al 2012). A suggested treatment dose is 1.5mL/kg of 20% ILE as a bolus, followed by between 0.25 and 0.5mL/kg/min of 20% ILE for between 30 and 60 minutes to an initial maximum of 500mL (Jamaty et al 2010). Cooper et al (2010) report haemodynamic improvement as a result of ILE.

Hyperinsulinaemia euglycaemia therapy Calcium channel blocker overdose can cause hyperglycaemia because of the blockage of pancreatic L‑type calcium channels and subsequent impaired secretion of insulin (Levine et al 2007). Calcium channel antagonism decreases free fatty acid uptake and this, together with decreased insulin secretion, can cause cardiac failure that requires insulin for recovery of myocardial function (Kline et al 1995).

Hyperinsulinaemia euglycaemia therapy (HIET) can overcome impaired insulin secretion through the administration of a high, regular dose of insulin alongside glucose to maintain euglycaemia. The dose of insulin is typically between 0.5 and 1.0 IU/kg/hour in addition to glucose, which can be between 15 and 30g/hour depending on blood glucose level (Lheureux et al 2006).

The positive effects of HIET include increased inotropy, increased intracellular glucose and vascular dilation (Engebretsen et al 2011). Yuan et al (1999) describe four case studies in which HIET was used successfully as an adjunctive treatment in the management of CCB toxicity.

Within one hour of insulin administration, three patients showed an increase in BP or heart rate, although calcium, activated charcoal and glucagon were also administered.

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Conflict of interestNone declared

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Meanwhile, Engebretsen et al’s (2011) work with animals indicates that high‑dose insulin produces higher survival rates after CCB overdose than calcium salts, glucagon, adrenaline and vasopressin. In one study conducted on dogs, insulin therapy was associated with a greater survival rate due to better myocardial contractility, which increased glucose uptake and oxygen delivery, compared to other treatments for verapamil toxicity (Kline et al 1995).

Such studies differ from those conducted on humans, in which insulin is used as an adjunctive therapy, for example with calcium and glucagon. Consequently, HIET may not improve hemodynamic status in humans (Patel et al 2007).

Adverse effects of insulin therapy include hypoglycaemia and hypokalaemia (Shepherd 2006) so blood glucose and potassium levels must be monitored regularly. Clinicians often titrate insulin from doses used to treat diabetic ketoacidosis, but this is too timid an approach in the management of CCB toxicity (Levine and Boyer 2006).

Further research and clinical trials would be beneficial in gaining a greater insight into the

best management for CCB overdoses. Conducting randomised controlled trials is unlikely because patients with significant CCB toxicity are critically ill (Varpula et al 2009). Another limitation to formulating evidence‑based data is the wide variety of drugs and doses that patients receive, which limits the ability to conduct clinical trials (Zimmerman 2003).

Decontamination, glucagon, calcium and vasoactive agents all have roles to play in the management of patients with CCB overdose. It is difficult to assess the effectiveness of individual treatments because they are often given as adjuncts to other forms of management, but high‑dose insulin therapy appears to be of significant benefit, although evidence is limited to case reports.

ConclusionSignificant CCB overdose can result in morbidity and mortality, but the literature and the case study presented in this article suggest that appropriate and timely management and monitoring are likely to produce good outcomes.

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