PRIVATE: THE ACUTE CARDIAC EFFECTS OF COCAINE

FEBRUARY 22, 2015 S1308150EDIT

Images licensed under Creative Commons Attribution-Share Alike 2.0 Generic license. Left “Matters of the Heart” by Denise Chan; right by Zxc.

This site was made by a group of University of Edinburgh medical students who studied this subject over 10 weeks as part of the SSC. This website has not been peer reviewed. We certify that this website is our own work and that we have authorisation to use all the content (e.g. figures / images) used in this website. With thanks to our tutor Dr Gareth Clegg, Clinical Senior Lecturer and Honorary Consultant in Emergency Medicine, Royal Infirmary of Edinburgh.

Despite the downward trend in cocaine use noted by the Scottish Crime and Justice Survey 1, cocaine remains a large problem. Of the illicit drug user population of 6.2% of adults in Scotland, 10.2% reported that cocaine was their most frequently used drug in the last month. Although the survey did as much as possible to reduce any stigma relating to self-reporting it is still likely that these statistics are underreported.

This represents a significant number of people at risk from the potentially fatal sequelae involved with cocaine use. Cocaine has now become more easily available and with that price has come down, broadening its potential market and putting a new demographic at risk of the negative health effects associated with its use.

In 2012 there were 2 cocaine related deaths, 2.4% of the drug-related deaths in the Lothian area 2, highlighting it as an important local issue worthy of research and for appropriate management to be identified.

Our aims for this SSC2b project are to cover the mainstays of the acute treatment of a typical cocaine abusers hospital presentation, and the science behind it. This will include:

The specific pathophysiology of acute problems involved with cocaine use, particularly arrhythmias and Acute Coronary Syndrome.

The routine management of arrhythmias and Acute Coronary Syndrome.

The management of both of those conditions in the setting of recent cocaine use

To produce an algorithm specifying the recommended treatment of arrhythmias and acute coronary syndrome following cocaine use.

Total Website Word count: 8,424

Word count minus Contributions page, References page, Information Search Report, Word Version appendix and other sections clearly marked as Appendices: 5992

PRIVATE: CARDIAC PATHOPHYSIOLOGY OF COCAINE USE

Pathophysiology of Acute Coronary Syndrome

Cocaine causes a high incidence of chest pain due to ischaemia and/or infarction. The sympathetic effects of the drug are to increase the myocardial oxygen demand and reduce the coronary artery blood supply, by inducing vasoconstriction. In addition, it enhances platelet aggregation which increases the likelihood of ischemia due to a thrombus occluding coronary arteries.

More

Pathophysiology of Arrhythmias

Cocaine is a cause of many abnormalities in function, but one of the principal cardiac emergencies caused by cocaine abuse is arrhythmia. Cocaine has been traditionally classified medically as a local anaesthetic as it is a non-specific voltage gated sodium channel blocker and, because of this, it can seriously alter the electrical conduction of an action potential within the heart. It can affect the heart adversely in a manner similar to both type I and type III antiarrhythmics , the effects typically including either a prolonged QT interval, corrected for heart rate, (QTc) or Torsades de Pointes (TdP), both of which are abnormalities observed through the use of an electrocardiogram (ECG).

More

PRIVATE: ACUTE CORONARY SYNDROME

Ischaemia and infarction due to cocaine administration is multifactorial, with several pathophysiological complications being induced: increased myocardial oxygen demand, decreased arterial supply and enhanced platelet activation leading to establishment of thrombi are all implicated 1.

Cocaine amplifies alpha-adrenergic stimulation, and hence raises heart rate whilst decreasing myocardial oxygen supply. By obstructing presynaptic reuptake of catecholamines, cocaine increases postsynaptic sympathetic stimulation2. In the coronary arteries, increased vascular tone causes vasoconstriction, due to the increased adrenergic stimulation. Moreover, cocaine results in endothelin-1 production, causing further vasoconstriction whilst inhibiting the production of the vasodilator nitric oxide by endothelial cells 3. Such vasoconstriction is termed inappropriate in combination with raised heart rate; as the combination of increased demand and tone causes supply to plummet. These physiological effects increase risk of myocardial infarction as a result of ischaemia.

Cocaine causes increased arterial blood pressure alongside enhancement of platelet aggregation and thrombus formation 4. Activation of platelets, their release of platelet alpha-granules which are essential for proper platelet function, fibrinogen levels and plasminogen activator inhibitor levels are all increased acutely after administration5. These changes predispose formation of thrombi which can lead to occlusion of already narrowed coronary arteries.

The presentation of angina pectoris or MI subsequent to cocaine administration does not necessarily correlate to the quantity of cocaine in blood plasma. Cocaine is rapidly absorbed into vascular circulation subsequent to intranasal administration; maximal plasma concentration occurs within approximately 30 minutes. Its elimination half-life sits between 45-90 minutes following administration1. Variation is observed in the time interval between administration and presentation of patients’ symptoms; onset of angina pectoralis and myocardial infarction may be within the outlined timeframe or later, when blood plasma concentration is significantly lowered or undetectable. A study which assessed the degree of coronary vasoconstriction against the concentration of plasma cocaine found that the diameters of the coronary arteries subsequent to administration were not proportional to the plasma cocaine levels 1. Instead, benzolyecgonine and ethyl methyl ecgonine – the major active metabolites of cocaine – have been implicated in the explanation of these findings 1.

The risk of a significant cardiac event is increased in individuals with pre-existent atherosclerotic coronary artery disease. Similarly to exercise, cigarette smoking and exposure to cold temperatures, cocaine’s effect on atherosclerotic vasculature is increased, in comparison to minimally damaged areas, causing augmented vasoconstriction in these areas1. Normal and minimally damaged portions of vessel may still produce adequate levels of endothelium-derived vascular muscle relaxants despite the cocaine. This production may help counteract the excessive alpha-adrenergic stimulation to avoid significant constriction and subsequent reduced oxygen supply. Conversely, individuals with atherosclerotic, damaged vessels have inhibited ability to compensate for increased muscle tone and therefore be at increased risk of an ischaemic cardiac event 1.

PRIVATE: ARRHYTHMIAS

Cocaine causes many functional abnormalities, including arrhythmia 1. Cocaine has been traditionally classified as a local anaesthetic, as it non-specifically blocks voltage gated sodium channels 2, and hence can seriously alter the conduction of cardiac action potentials. It can affect the heart adversely in a manner similar to both type I and type III antiarrhythmics 3, the effects including either a prolonged QT interval, corrected for heart rate, (QTc) or Torsades de Pointes (TdP)4, both of which are abnormalities observed on an electrocardiogram (ECG). These effects were noted4 in a small study conducted on 45 cocaine users with and without chest pain. Whilst this study is an interesting observation of the common ECG effects of cocaine and highlights common cocaine induced arrhythmias, it is underpowered for evaluating these arrhythmias thoroughly. However, it

should be noted that it is difficult to achieve a substantial sample size due to the low frequency of cocaine abusers hospital admission, and due to the stigma of cocaine.

At a cellular level, cocaine acts on ion channels important for the conduction of cardiac action potential and normal electrical cardiac rhythm. Cocaine blocks sodium channels and inactivates them, binding and being recovered from the channels slowly 5. This was discovered5 in a well designed study investigating effects of cocaine on sodium channels in guinea pig myocytes. The authors account for many of the sources of error inherent in the patch clamp technique. Unfortunately, the animal cell nature of the study does leave room for further work. Again, it is understood that it would be very difficult to perform similar work outside of animal models.

The blocking of sodium channels leads to an increase in time taken for the membrane potential to reach its peak, thereby causing a reduction in the rate of conduction. This is in addition to the prolongation of the repolarising phase after an action potential. On top of this, cocaine blocks rapid phase potassium channels, and thus induces an increase in the length of the QT interval, as observed by O’Leary 7 in his study on HERG (rapid potassium) channels. Whilst this experimental study was conducted on cloned channels, this is the only way to examine the electrophysiology of the heart, and efforts were taken by the author to reduce the effects of instrument resistance and non-potassium ions on the result. These electrophysiological effects are due to leaky slow phase and rapid phase potassium channels being responsible for potassium efflux. (figure 1).

Action_potential_ventr_myocyte

Fig. 1 - Cardiac action potential generation. This image is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. The original author was Wikipedia user Quasar, and the work was modified by users Mnokel and Silvia3.

Cocaine is thought to have a biphasic effect on repolarisation: at low concentrations, it is thought that cocaine prolongs repolarisation through its effects on the rapid phase potassium channels 7. However, at higher concentrations, it is believed that the sodium blocking effects prevent normal influx of sodium (which ordinarily prolongs the action potential during the plateau phase) This counters the potassium channel block, leading to earlier repolarisation 3. Additionally, at high concentrations cocaine inhibits L-type calcium channels 7, which contribute to the plateau phase of the action potential. A reduction in the length of the plateau phase will lead to an earlier repolarisation. This was studied, along with window sodium currents and potassium currents in the work of Clarkson et al. 7, which expanded upon the work of Crumb and Clarkson by performing similar experiments with the additional objective of examining the other ion channels involved. This expands on our understanding of the mechanisms behind cocaine’s proarrhythmic pathologies, by

identifying the ions affected at various concentrations. This could be useful in predicting clinical disease course, related to cocaine dosage.

These cellular changes cause cocaine to produce abnormalities on an ECG. These include an increased QTc and TdP, a polymorphic ventricular tachycardia (VT). Cocaine is thought to block noradrenaline transporters, causing increased action of noradrenaline on β-adrenoceptors,8 and hence increased heart rate. This, in combination with the aforementioned effects of cocaine on repolarisation, causes an abnormally high QTc.9 In their study, Haigney et al studied the ECGs of 29 cocaine abusers who were administered differing concentrations of cocaine, and then administered a second dose one week later with 17 of their original 29. This study adds observations on cocaine’s effects on QT time, but the sample size means that it is underpowered, especially due to the drop out of 12 participants. However, it is clear that (similar to “Long QT Syndrome” (figure 2)) this poses a risk of spontaneous VT, including the TdP type. This risk is exacerbated further as cocaine increases the temporal heterogeneity of repolarisation, a key predisposing factor in TdP 10.

E315_(CardioNetworks_ECGpedia)

Fig. 2 - An ECG of a patient with long QT syndrome. This image is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. The author was Michael Rosengarten BEng, MD.

Torsades de Pointes is among the most serious arrhythmias arising from cocaine abuse. It is a polymorphic VT (figure 3) and may progress to ventricular fibrillation or sudden cardiac death 10. In TdP, an ectopic ventricular systole (inverse QRS complex on an ECG) leads to a compensatory post-ectopic pause, followed by a sinus beat with a prolonged QT and a pronounced U wave (which represents Purkinje and M cell repolarisation). If another ectopic ventricular systole occurs on top of the U wave, the rhythm degenerates into TdP10. In more detail, the block of potassium channels causes increased QT intervals - to which Purkinje Fibres and M cells are more receptive. This leads to increased heterogeneity of cardiac repolarisation, and a block due to an area of functional refractoriness. At the same time, the increase in repolarisation time leads to an inward depolarising current, called an early after-depolarisation, which triggers another action potential. This, combined with the unidirectional block, leads to a re-entry circuit, predisposing to TdP11. This arrhythmia may either continue (typically progressing dangerously) or resolve, in which case the likely presentation will be syncope.

112_(CardioNetworks_ECGpedia)

Fig. 3 - An ECG of a patient displaying Torsades de Pointes. This image is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. The author was Michael Rosengarten BEng, MD.

In summary, the principle consequences of cocaine abuse on cardiac rhythm are SVTs, VTs, including TdP, and VF and these are caused through sympathetic stimulation combined with the potent action of cocaine on cardiac ion channels.

PRIVATE: ROUTINE MANAGEMENT

In order to properly discuss the literature regarding the early management of the cardiac sequelae in the setting of cocaine, the normal management must be presented to highlight the differences.

This will be laid out in two separate sections:

Early Management of Acute Coronary Syndrome

And

Early Management of Arrhythmias

PRIVATE: ROUTINE TREATMENT OF ACUTE CORONARY SYNDROME

In order to understand differences in treatment protocol between patients with standard Acute Coronary Syndrome (ACS) and cocaine associated ACS, one must understand the policy for the standard situation.

This section covers UK recommendations (from the National Institute for Health and Care Excellence1) on treating patients presenting with ischaemic chest pain, ACS. These are tailored to specific causes of ACS: unstable angina, Non-ST elevated Myocardial Infarction (NSTEMI) and ST elevated Myocardial Infarction (STEMI). The treatment for unstable angina and NSTEMI are combined, and separated from STEMI by the ECG findings.

For a patient presenting with chest pain currently or within 12 hours a clear history is needed to identify suspicions of ACS and rule out other causes. The symptoms associated with ACS are: recent onset of angina, rapid deterioration of angina, or angina upon little exertion2. An integral part of the treatment is keeping the patient calm and informed, which is helpful in itself, and facilitates important communication to guide treatment.

After identifying that the clinical signs suggestive of ACS offer pain relief immediately, which may be a GTN, vasodilator, or IV opioids may be offered. A loading dose of Aspirin should also be offered for

its antiplatelet activity. Beta-antagonists are also offered here, for their effects on cardiac vasculature; including an improvement in progression rates from unstable angina to MI, and positive outcomes when treating MI3. Routine oxygen is not required although pulse oximetry monitoring should be commenced. One must promptly take a resting 12-lead ECG to monitor for further deterioration. Blood should also be taken for Troponin and other biomarkers.

At this point in the treatment pathway the diagnostic criteria for an MI should be evaluated. These are the detection of the rise or fall of a biomarker (ideally Troponin) with at least one of the following:

Symptoms of ischaemia

ECG changes indicative of new ischaemia

Development of pathological Q wave on ECG or

Imaging evidence of new loss of healthy myocardium or wall motion abnormalities.

The management from this point separates into the two areas mentioned; unstable angina and NSTEMI being represented as one pathway and STEMI the other.

Unstable angina and NSTEMI

It is important to inform the patient about treatment options, to help maintain autonomy. Patients should already have received aspirin, with clopidogrel offered for hypersensitive patients. Formal cardiovascular risk assessments should be carried out at this stage: Individuals at high or intermediate risk should be referred to cardiology, with those at low risk being treated conservatively with various regimens of antiplatelet and antithrombotics. If patients are at a low risk of bleeding, fondaparinux should also be offered as antithrombotic therapy unless coronary angiography is imminent, in which case unfractionated heparin is advised. Before discharge, low risk patients must undergo ischaemia testing, and if positive then they should be referred to cardiology1.

STEMI

Those presenting with STEMI should be immediately assessed for coronary reperfusion therapy, either Percutaneous Coronary Intervention (PCI) or fibrinolysis. PCI should be commissioned quickly as there are positive outcomes related to immediate treatment. This should be preceded by coronary angiography in order to identify the target artery. This further treatment would be carried out under the care of the cardiology department1.

PRIVATE: ROUTINE TREATMENT OF ARRHYTHMIA

As with the section on Acute Coronary Syndrome, one must first understand standard diagnosis and management of arrhythmias, in order to understand the nuances of managing cocaine-associated arrhythmias.

Diagnostically, a thorough clinical history alongside a 12-lead ECG trace should be sufficient to diagnose the type, and presence of an arrhythmia. Clinicians should be aware that generally patients with paroxysmal arrhythmias will be asymptomatic during the consultation, so a detailed history is crucial for arrhythmia recognition. Indicative features include palpitations, fatigue, lightheadedness, chest discomfort, dyspnea, presyncope or, rarely, syncope.1 Tachyarrhythmias experience palpitations more often than bradyarrhythmias, and details of the context, onset, duration and frequency should be established, as these can indicate the arrhythmia2. Patients presenting with syncope or dyspnea with palpitations should be referred to arrhythmia specialists promptly1. Any potential causative factors such as congestive heart failure, cardiomyopathy, coronary artery disease; stress, anxiety, infection or drugs1, should be established early, as this can guide treatment plans.

A resting 12-lead ECG should be recorded immediately on identification of indicative symptoms, and evaluated for signs of abnormal rhythm, pre-excitation, prolonged QT interval, sinus tachycardia, segment abnormalities, and evidence of underlying heart disease1. However, a normal ECG does not exclude arrhythmia, but warrants investigation. Patients with suspected paroxysmal arrhythmia that produce an inconclusive ECG may need invasive electrophysiological study or catheter ablation, to make a diagnosis1 .

Establishing the type of arrhythmia, and identification of precipitating factors is crucial in guidance of treatment. Regardless of the arrhythmia type, the causative factors should be dealt with, alongside appropriate symptomatic treatment1,3. Following this, the specific arrhythmia should be confronted. Supraventricular arrhythmias should first be met with vagal manoeuvres if there are no signs of shock or acute pulmonary oedema, and, if unsuccessful, adenosine should follow. If adenosine does not work, a senior doctor should be consulted, to consider giving metoprolol, esmolol or verapamil, considering direct cardioversion if this fails.

If there are signs of shock or acute pulmonary oedema, synchronised direct current cardioversion should be initiated, with referral to a Cardiologist if unsuccessful3. Ventricular tachycardia should be controlled with intravenous amiodarone, procainamide or sotalol if haemodynamically stable, otherwise electrical cardioversion is indicated. Torsades de pointes in particular is treated by withdrawing QT interval prolonging drugs, and starting IV magnesium4. Ventricular fibrillation is an emergency that should be treated using advanced life support interventions5.

PRIVATE: CARDIAC MANAGEMENT FOLLOWING COCAINE USE

This section will review the evidence surrounding the:

Management of Acute Coronary Syndrome

And

Management of Cocaine Induced Arrhythmias

With regards to the management of ACS in cocaine use, Benzodiazepenes are the mainstay of treatment, but standard treatments also apply.

Cocaine induced arrhythmias should be treated in different manners depending on the arrythmia present.

These will be discussed further in the relevant sections.

PRIVATE: FOR ACUTE CORONARY SYNDROME

Beta-Antagonists

Alpha-Antagonists

Benzodiazepines

PRIVATE: FOR ARRHYTHMIA

Sodium Bicarbonate

Lidocaine

Calcium Channel Blockers

Benzodiazepines

PRIVATE: BETA-ANTAGONISTS

Beta-blockers reduce heart rate and contractility by inhibiting beta-adrenergic stimulation at receptors on post-synaptic neuron membranes. They are currently administered as an effective treatment for myocardial infarction 1 and are also indicated in the treatment of some dysrrhythmias. However, guidelines produced in 2005 by the American Heart Association have stated that Beta-blockers should be avoided following cocaine use, 2 despite beta-adrenergic stimulation causing some of cocaine’s dangerous, physiological changes. This section evaluates the use of beta-blockers in the treatment of cocaine-associated chest pain.

Building upon previous work which determined the extent of coronary vasoconstriction induced by cocaine administration, Lange et al. performed a study in 1990 to assess the influence of beta-blocking agents on coronary vasculature following cocaine use 3. The study included 30 patients undergoing cardiac catheterisation, of which 10 received a dose of cocaine followed 15 minutes later by an intracoronary infusion of propranolol. Within this group, propranolol induced little effect on 5 of the patients. However, augmented vasoconstriction was observed in 4, whilst 1 patient had significantly worsened coronary vasoconstriction. Lange concluded that beta-blocker administration allowed unopposed alpha-adrenergic stimulation, causing increased coronary vasoconstriction. This propagates a higher incidence of ischaemia and possible infarction.

Further case reports concur with these findings; anecdotal tales outline exacerbated hypertension despite resolution of tachycardia following propranolol administration in patients suffering from acute, cocaine-induced toxicity 4. Although Lange’s study had a relatively small sample size, when coupled with sporadic case reports, the potentially detrimental effects of propranolol are appreciable. Thus, beta-blocker therapy became contraindicated in acute settings.

Naturally, soon after these publications, further studies were carried out to assess the influence of labetalol (both an alpha and beta-adrenergic inhibitor) on cocaine-induced coronary vasoconstriction: in 1993 a study almost identical to that performed by Lange was performed 5. Intravenously administered labetalol (0.25 mg/kg) was given to 9 patients undergoing cardiac catheterisation, whilst a control group of 6 patients were given a saline solution. Results showed that despite labetalol decreasing the augmented arterial pressure; it produced no positive effect on overcoming coronary-vasoconstriction. At this dose, labetalol’s beta-adrenergic blocking capacity takes precedence over its ability to inhibit alpha-adrenergic stimulation, although a larger dose has never been administered, and therefore its possible value never examined. In Boehrer’s study, the patient number was so small that any significant findings would have required review and repetition.

However, recent studies suggest that beta blockers are not as harmful as previously suggested in treatment of cocaine-associated chest pain 6,7. One study by Fanari et al looked retrospectively at admissions in two hospitals to compare outcomes in patients treated with or without beta blockers over a seven year period 6. It was a reliable study as it was a large patient group of 376 and the study used multivariate analysis to minimise confounding factors. The study found that Beta-blockers were not associated with any significant differences in ECG presentation, troponin levels, ventricular arrhythmias or death. In addition to this a study by Rangel et al found similar outcomes with Beta-blockers not being associated with adverse events in patients with recent cocaine use.

Moreover, in 2008, Dattilo et al concluded that Beta blockers were beneficial for patients after cocaine use as they reduce the incidence of myocardial infarction (MI) 8. The results were statistically significant, eliminating the role of chance in producing these findings. The study subsequently stated that beta-blockers’ benefits of reducing the risk of MI could outweigh the previously stated coronary spasm caused by their use in cocaine users.

Beta-blockers as treatment for cocaine-associated chest pain are contraindicated due to the augmentation of coronary vasoconstriction, as outlined by the above studies. In recent times, however, studies have suggested that beta-blockers may be less harmful than previously believed. Despite these findings, protocol for treatment of cocaine-associated chest pain continues to disregard beta-blockers 9. The validation of such recent findings through further studies may cause alteration of these current guidelines in the future.

PRIVATE: ALPHA-ANTAGONISTS

Cardiovascular vasoconstriction, mediated by alpha-adrenergic stimulation, is a dangerous adverse effect that occurs in cocaine use1-4. Naturally, alpha-blockade has been suggested as an antidote1-4. Research has assessed phentolamine as treatment for cocaine-associated acute coronary syndrome (CAACS)1-4, it is unavailable in Britain at the moment, but knowledge of the evidence on alpha blockers is important, in case they become more available in clinical situations.

Adverse drug reactions from phentolamine stem from vasorelaxation, its indication. This may lead to dangerous hypotension and arrhythmias; for this reason (and its inavailability) other antihypertensive agents have displaced phentolamine3.

A 1989 clinical trial found that phentolamine reversed cocaine-induced alterations in arteriography and haemodynamics1. This suggested that α-antagonists could treat CAACS, as myocardial oxygen demand returned to normal, and perfusion improved. However, no one in this study had signs or symptoms of cardiac ischaemia, so it would be important to produce literature on the efficacy of alpha blockers on patients who are symptomatic. These results are, however, promising.

In 1992, Hollander published a case report on the use of phentolamine in treatment of cocaine induced myocardial ischaemia2: First line treatment (oxygen, diazepam, aspirin, nitroglycerin) did not relieve symptoms or ECG signs, so phentolamine was given. This resolved the pain, and later there were no signs of myocardial ischaemia. The author’s recommendation was further evaluation of phentolamine for cocaine-induced myocardial ischaemia.

More recently, a 2006 report described a similar situation3. Phentolamine was given after first line treatment of CAACS failed; which led to a positive outcome. Authors recommended that this report should give clinicians confidence that when standard CAACS therapy fails, phentolamine may be implemented. The authors recognised the potential adverse effects of phentolamine, and suggested that the dose should be titrated in small amounts, so that clinicians can stop using the drug when hypotension (the main ADR) starts, or symptomatic relief occurs, this to maintain clinical safety3.

Both of these case reports suggest that α-antagonists could be useful when dealing with CAACS. As they are clinical reports, not trials, limited information can be taken. These suggest that further research on alpha blockade should be done.

In conclusion, promising evidence is available on alpha blockers, and if phentolamine becomes available in the UK more powerful evidence could be produced. What little evidence we have is positive, but not nearly powerful enough to warrant the recommendation of alpha blockers as first line standard procedure in CAACS treatment. In the meantime, if phentolamine is available, the evidence suggests that clinicians should recognise it as a second line treatment of CAACS.

PRIVATE: BENZODIAZEPINES IN ACS

Indications: History of recent cocaine use and presentation with chest pain, particularly in a patient with anxiety and tachycardia.

Relevant Pharmacology: Benzodiazepines act selectively on GABAA receptors to mediate inhibitory neurotransmission within the Central Nervous System. By binding to a regulatory site, on the GABAA receptor they increase affinity of GABA for its receptor 1.

The net effect of benzodiazepines are to increase inhibitory neurotransmission in the central nervous system 2. This accounts for its anxiolytic actions, and as proven in animal models, produces calming effects, 2 hence reducing heart rate and blood pressure 3.

As well as central effects of enhancing GABA, the reduced anxiety levels should decrease sympathetic outflow. Hence, peripheral adverse effects of cocaine on the heart and coronary vessels are somewhat reversed; slowing the heart rate and causing coronary vasodilation.

Benzodiazepines would not usually be given for a patient with acute coronary syndrome. However in the setting of cocaine use it is an effective treatment 5.

Evidence Base: Given the relevant pharmacology outlined above, patients expected to respond well to benzodiazepines are anxious and sympathomimetic, due to cocaine’s effects 4. Benzodiazepines help alleviate tachycardia and reduce blood pressure, hence decreasing oxygen demand of the myocardium 4.

The ‘Advanced Cardiovascular Life Support’ (ACLS) Guidelines, from 2000, recommend benzodiazepines in a patient who presents with symptoms suggestive of acute coronary syndrome, when cocaine has been used. They suggest that benzodiazepines are effective for treating chest pain5.

The existing guidelines that recommend benzodiazepines as standard in treatment of cocaine associated chest pain are based largely on anecdotal evidence and animal models 6. However some recent studies have compared the use of benzodiazepines in combination with nitroglycerine versus treating with only nitroglycerine 6,7. One of the studies, by Hollander & Judd also assessed the efficacy of using only benzodiazepines, specifically ‘diazepam’.

One difficulty in our research was a lack of controlled trials of benzodiazepines in the clinical setting of cocaine associated chest pain. There are only two controlled trials that have investigated benzodiazepines, each obtaining different results.

Hollander & Judd’s controlled trial assessed 40 patients who presented to the emergency department with chest pain resultant from cocaine use. They measured the perceived chest pain by a visual analog scale, as well as heart rate and blood pressure over a 15 minute period. During this the patient could be administered a maximum of three doses of the chosen therapy every five minutes, at the physician’s discretion. The results obtained showed that although both Nitroglycerine and diazepam were effective treatment options, there was no actual benefit seen in the combined therapy.

The second study that our literature search identified, by Honderick & Williams, proposes a benefit to treating with sublingual nitroglycerine(NTG) and benzodiazepines- specifically lorazepam. Given that this study does not asses the treatment outcomes of using just lorazepam, one cannot state how beneficial they are when used as monotherapy. However, the study assessed perceived chest pain slightly differently to Hollander’s, by an ordinal scale from 1-10. The results showed that the reduction of chest pain was significantly greater in the patients treated with both sub-lingual NTG and lorazepam, evidence that this method is safe and effective. The only variable in the study was giving 1mg lorazepam to 12 of the 27 patients, which caused a greater reduction of chest pain, hence suggesting that lorazepam should be first line therapy for cocaine induced chest pain.

Conclusion: Further studies could identify the most effective benzodiazepine. The current comparison of the two above studies may suggest that lorazepam is more effective in alleviating chest pain, however due to the small sample size, this is inconclusive. A prospective study to compare several benzodiazepines and their effects on chest pain could identify the best treatment.

PRIVATE: SODIUM BICARBONATE

Sodium bicarbonate has long been used in treatment of type 1a antiarrhythmics and tricyclic antidepressant overdose 1. These drugs act on cardiac sodium channels, as does cocaine, hence sodium bicarbonate has traditionally been used to treat arrhythmias in cocaine abuse. More recently, further work has been done to confirm the benefits of this treatment, primarily through animal models and case reports (due to ethical issues surrounding clinical trials in overdose presentations).

One of the more common rhythm abnormalities in cocaine abuse, ventricular tachycardia (VT), is characterised by broad QRS complexes. In experiments performed in dogs2, 3 cocaine was administered intravenously, and followed by sodium bicarbonate. There studies show noticeable decreases in QRS breadth, suggesting a curative role for sodium bicarbonate in VT.

Sodium chloride has also been suggested as an antidote in cocaine-associated arrhythmias. This is based on the hypothesis that the curative effects of sodium bicarbonate are related to the higher concentrations of sodium overwhelming the sodium block affected by cocaine. However, Parker et al. 4 showed through experiments in that sodium chloride was not a suitable alternative treatment and lacked the efficacy of sodium bicarbonate.

Instead, this experiment appears to validate another hypothesis supported in case reports published by Wang 5 and Kerns et al 1. This hypothesis posits that acidaemia, commonly found in cocaine overdose as a consequence of hypoxia and the metabolism of the drug, leads to the effect of cocaine on cardiac function. First, changes in pH interfere with myocyte calcium channels, causing a depolarising current and delayed action potential conduction. Secondly, cocaine favours its ionic

fraction when in low pH and this has a slower dissociation time, causing a more prolonged sodium block. Thus, increasing pH through sodium bicarbonate administration leads to the normalisation of calcium balance, and reduces the length of time cocaine blocks sodium channels.

In a study by Winecoff et al., 6 sodium bicarbonate was observed to be as efficacious as lidocaine at reversing the ECG effects of cocaine in guinea pig hearts. It is suggested that lidocaine at the levels required for effectiveness are outside its therapeutic range, which leads clinicians to favour sodium bicarbonate. With sodium bicarbonate, blood pH must be monitored to avoid alkalaemia, and therapy is should be discontinued at pH 7.5. In comparing the use of sodium bicarbonate against lidocaine, the recommendation of the National Poisons Information Service through their TOXBASE® online database favours sodium bicarbonate as a first line treatment 7, with lidocaine as reserve treatment. This position seems well supported by clinical experience and animal research.

PRIVATE: LIDOCAINE

Lidocaine is an antidote to cocaine-induced arrhythmias. It acts as a class 1b antiarrhythmic; acting on sodium channels blocked by cocaine1. This has been verified in many studies, although mainly in animal models and retrospective reviews, due to the ethical problems of trialling the effects in patients.

The blockage of Na+ channels by cocaine causes a prolonged QRS complex in Ventricular Tachycardia1. Lidocaine antagonises cocaine through competitive binding in papillary muscle, thus preventing the slowing of ventricular conduction2 in dog myocardium. However, in arrhythmias due to sodium channel blockade, Lidocaine has been surpassed by administration of Sodium Bicarbonate as a first line treatment. Nonetheless, Lidocaine remains a back-up treatment, to be used if Bicarbonate fails, or causes alkalaemia1. On presentation to ED the patient should be examined: if acutely toxic from cocaine, then they should be started on Sodium Bicarbonate. However, if they are not, and still in arrhythmia, Lidocaine should be initiated1, as the arrhythmia is due to an MI caused by cocaine2, with a higher likelihood of it being true VT, rather than due to sodium channel conduction1.

However, the use of Lidocaine in cocaine-associated cardiac pathology is controversial as it can exacerbate the convulsions associated with cocaine toxicity, by competitively inhibiting sodium channels3. The evidence is unclear and these issues have not been found in humans, for example, Shih et al found no serious exacerbation of cocaine toxicity through Lidocaine3.

It is therefore clear that the drug lidocaine remains a useful backup to Sodium Bicarbonate in the treatment of cocaine associated VT.

PRIVATE: CALCIUM CHANNEL BLOCKERS

In the heart, a massive increase in calcium concentration triggers spontaneous action potentials, with shorter refractory periods 1. Therefore, in order to prevent lethal arrhythmias a control of the intracellular calcium must be exercised. Verapamil, a calcium channel blocker, may help regain control of the calcium channels and prevent progression to lethal arrhythmias such as VF.

The underlying mechanism causing VF is not entirely clear, but it is suggested to be due to calcium influx into the myocardium 2. This is hypothesised to be due to cocaine associated catecholamines, which increases calcium influx, thus changes the rate of depolarisation 2.

A study by Billman et al (1988), on dogs, found that verapamil was protective against VF following injection with cocaine 2. This was thought to be both due to its direct effect on calcium channels and, potentially, verapamil’s blockage of alpha-adrenergic receptors 2.

Billman expanded on this; hypothesising that the causative effect of calcium was due to its secondary adrenergic messenger 3. Cocaine’s sympathomimetic activity causes calcium mobilisation, and increased calcium entry into myocardium, a synergistic effect leading to increased effect of calcium 3. This canine study found that calcium channel antagonists not only prevented and reversed the arrhythmias due to increased calcium, but also helped reduce cocaine associated hypertension and tachycardia 3. This effect on heart rate was thought to be significant, as it is a major factor in VF development.

It is therefore clear that calcium antagonists have a major role to play in preventing cocaine induced arrhythmias, especially VF.

PRIVATE: BENZODIAZEPINES IN ARRHYTHMIA

In cocaine-associated arrhythmia, benzodiazepines are indicated 1, for much the same reasons that they are indicated in acute coronary syndrome. Their action as anxiolytics 2 is useful in the management of the stress with which these patients typically present. Additionally, they act to lower heart rate 3, which is beneficial in leading arrhythmias to resolve. For more information on the use of benzodiazepines in the treatment of the cardiac complications section, see the section on their use in acute coronary syndrome.

PRIVATE: CONCLUSIONS

The treatment of cocaine-associated chest pain and arrhythmia is similar in many ways to the standard treatment of these cardiac problems. For more information on this, see the pages on arrhythmia and acute coronary syndrome. However, there are some key differences, as we have outlined in this project.

The evidence base within toxicology is sparse. This is due largely to the ethical issues surrounding clinical trials in overdose situations. However, through a combining recorded clinical experience and animal models it is possible to obtain a picture of the proper way to treat these patients.

From our review of the literature, the suggested treatment plan for a patient presenting with cocaine-associated chest pain would look like so:

Copy of Conclusion

And if a patient presents with a cocaine-associated arrhythmia, the treatment plan would look like so:

Copy of Copy of Conclusion (1)

FLOWCHART TEXT:

Patient under the age of 60 presents with symptoms of arrhythmia

Take history which addresses cocaine use and other differentials

Carry out 12-lead ECG as soon as possible.

Offer pain relief

Cocaine associated arrhythmia

Follow routine management for arrhythmia

with some exceptions

Use benzodiazepines and avoid beta-blockers

Sustained VT or SVT

Treat with sodium bicarbonateIf blood pH rises above 7.5 and treatment has proven ineffective, treat with lidocaine

VF

Defibrillate

Considered Calcium Channel Blocker

Symptoms

Take history which addresses cocaine use. If not reported consider urine sample.

Patient under the age of 60 presents with cardiac symptoms.

Carry out 12-lead ECG as soon as possible.

Offer pain relief

Cocaine associated chest pain identified

Follow routine management for acute coronary syndrome

with some exceptions

Possible role of alpha-antagonists in the future

PRIVATE: CONTRIBUTIONS

Alex Wade played a crucial role in organising the project and liaising with the tutor. He also wrote the section on routine management of acute coronary syndrome. In addition, Alex wrote a section covering cocaine and smoking which was later removed.

Calum McDonald wrote the sections on lidocaine and calcium channel blockers. He also created a section on pregnancy and cocaine but this was later removed due to the word constraints.

Colin Irving played a significant role in formatting the website, as well as writing sections on pathophysiology of arrhythmias and the use of sodium bicarbonate and benzodiazepines in management.

Mark McBrien contributed to the section on the use of beta antagonists and created a section on cocaine and ethanol which was removed.

Neil Rowan wrote about alpha antagonists and created the search report. He had also written about the long term effects of cocaine which was deleted. He met with Sheila Fisken to help direct the search report, and he played an essential role in editing the wordpress and referencing.

Rob Gilhespy contributed to the section on the use of beta antagonists as well as writing the section covering the pathophysiology behind cocaine and acute coronary syndrome.

Stewart Rodney wrote the section on benzodiazepines in the treatment of acute coronary syndrome. He also played a large role in background research of treatment which lead to guiding and directing our project.

Valerie Patterson wrote the section on routine management of arrhythmias which was crucial in guiding the rest of our project. She also met with Sheila Fisken to help direct the search report.

Dr Euan Sandilands met with Neil, Alex, Rob and Colin to help interpret our findings and to guide the direction of our project.

PRIVATE: INFORMATION SEARCH REPORT

First we performed preliminary searches and read relevant reviews, to gain a basic understanding of the topic, including an important review by Phillips et al on Cocaine Cardiotoxicity. Then we had a meeting with Dr Gareth Clegg, our tutor, who helped guide us towards the areas of controversy in current literature, which we would have to address.

We then met Sheila Fisken to help formulate a sensitive literature search. Upon this meeting we used the following search terms on the medline database:

cocaine / OR cocaine-related disorders / OR cocaine. ti,ab

AND

chest pain / OR exp Arrhythmias, Cardiac / OR (chest adj2 pain*)

limit to ‘all adult (19 plus years)

limit to clinical trial, all

From the results we excluded those that did not fit our inclusion criteria, and split the papers into separate topics, for respective members of the group to explore. We consulted each of these papers’ references to identify any further relevant literature.

After preliminary research we met toxicology consultant Dr Sandilands in order to ensure that our research topic was relevant, and novel, and that our findings were in concordance with the evidence.

PRIVATE: REFERENCES

HOMEPAGE:

Laura Robertson (2014) Scottish Crime and Justice Survey 2012/13: Drug use. Available at: http://www.gov.scot/Resource/0045/00455131.pdf(Accessed: 3/03/2015).

A large-scale survey measuring peoples’ experience and perceptions of crime in Scotland, specifically relating to drug use in this case

Edinburgh and Lothians Drug-related Deaths Case Review Group (2013). Drug-related Deaths 2012, Edinburgh and Lothians. Edinburgh: Edinburgh Alcohol and Drug Partnership, Midlothian and East Lothian Drugs and Alcohol Partnership, West Lothian Tobacco, Alcohol and Drug Partnership, NHS Lothian.

A summary of all the drug related deaths in Lothian in 2012. A basic report on the epidemiology

PATHOPHYSIOLOGY OF ACUTE CORONARY SYNDROME:

Pitts WR, Lange RA, Cigarroa JE, Hillis LD. July 1997. Cocaine-Induced Myocardial Ischaemia and Infarction: Pathophysiology, Recognition and Management. Progress in Cardiovascular Diseases. 40(1):65-76

Rump AFE, Theisohn M, Klaus W. January 1995. The pathphysiology of cocaine cardiotoxicity. Forensic Science International. 71(2):103-11

Boghdadi MS, Henning RJ. November 1997. Cocaine: Pathophysiology and clinical toxicology. Heart Lung. 26(6):466-483

Kloner RA, Hale S, Alker K, Rezkalla S. February 1992. The Effects of Acute and Chronic Cocaine Use on the Heart. Circulation. 85(2):407-419

Rinder HM, Ault KA, Jatlow PI, Kosten TR, Smith BR. September 1994. Platelet alpha-granule release in cocaine users. Circulation. 90(3):1162-1167

PATHOPHYSIOLOGY OF ARRHYTHMIAS:

Pilgrim JL, Woodford N, Drummer OH. Cocaine in sudden and unexpected death: A review of 49 post-mortem cases. Forensic Sci. Int. 2013 Apr 10. 227(1-3). 52-59.

Due to the post-mortem nature of the study, the relevance of this to arrhythmias presenting in patients may be limited. However, this study was useful in examining some of the more severe cocaine-associated arrhythmia.

Lange RA, Cigarroa RG, Yancy CW, Willard JE, Popma JJ, Sills MN, McBride W et al. Cocaine-Induced Coronary-Artery Vasoconstriction. NEMJ. 1989 Dec 7. 321. 1557-1562.

Bauman JL, DiDomenico RJ. Cocaine-Induced Channelopathies: Emerging Evidence on the Multiple Mechanisms of Sudden Death. J. Cardiovasc. Pharmacol. Ther. 2002. 7(3). 195-202.

Gamouras GA, Monir G, Plunkitt K, Gursoy S, Dreifus LS. Cocaine Abuse: Repolarization Abnormalities and Ventricular Arrhythmias. Am. J. Med. Sci. 2000 Jul. 320(1). 9-12.

This was a good study, and one of the best methodologies among the studies reviewed. It was a randomised controlled trial. However, the small sample size combined with the attrition rate in the study does limit it’s power and its significance in the field.

Crumb WJ, Clarkson CW. Characterization of cocaine-induced block of cardiac sodium channels. Biophys. J. 1990 Mar. 57. 589-599.

This was a study in an animal model. Whilst this limits its implications for clinical practice, it provides useful insight into the cellular mechanisms of cocaine’s action and and is well designed to reduce equipment error.

O’Leary ME. Inhibition of Human Ether-A-Go-Go Potassium Channels by Cocaine. Mol. Pharmacol. 2001. 59(2). 269-277.

Clarkson WC, Xu YQ, Chang C, Follmer CH. Analysis of the Ionic Basis for Cocaine’s Biphasic Effect on Action Potential Duration in Guinea-pig Ventricular Myocytes. J. Mol. Cell. Cardiol. 1996. 28. 667-678.

Schurr JW, Gitman B, Belchikov Y. Controversial Therapeutics: The β-Adrenergic Antagonist and Cocaine-Associated Cardiovascular Complications Dilemma. Pharmacotherapy. 2014. 34(12). 1269-1281.

Haigney MCP, Alam S, Tebo S, Marhefka G, Elkashef A, Kahn R, et al. Intravenous Cocaine and QT Variability. J. Cardiovasc. Electrophysiol. 2006 Jun. 17. 610-616.

Yap YG, Camm AJ. Drug Induced QT Prolongation and Torsades de Pointes. Heart. 2003. 89. 1363-1372.

Antzelevitch C, Sicouri S. Clinical Relevance of Cardiac Arrhythmias Generated by Afterdepolarizations. J. Am. Coll. Cardiol. 1994 Jan. 23(1). 259-277.

ROUTINE TREATMENT OF ACUTE CORONARY SYNDROME:

NICE. Acute coronary syndromes overview. [Internet]. 2014 [cited 2015 Mar 10]; [3 pages]. Available from: http://pathways.nice.org.uk/pathways/acute-coronary-syndromes#content=view-info-category%3Aview-about-menu.

Grubb N., Newby D., Bradbury A., Cardiovascular disease. In Walker, B., Colledge, N., Ralston, S. and Penman, I., editors. Davidson’s Principles & Practice of Medicine. London:Elsevier; 2014. p. 589-99.

Scottish Intercollegiate Guidelines Network (SIGN). Acute coronary syndromes. Edinburgh: SIGN; 2013. (SIGN publication no. 93). [February 2013]. Available from URL: http://www.sign.ac.uk (Accessed: 7/03/2015).

ROUTINE TREATMENT OF ARRHYTHMIAS:

Blomström-Lundqvist C,© 2003 by the American College of Cardiology Foundation, the American Heart Association, Inc., and the European Society of Cardiology Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias. 2003. American College of Cardiology Web Site. [cited 1 March 2015] Available at: http://www.acc.org/clinical/guidelines/arrhythmias/sva_index.pdf

American Heart Association guidelines for the management of patients with SVT, as recommended by the European Society of Cardiology

Raviele A, Giada F, Bergfeldt L, Blanc J, Blomstrom-Lundqvist C, Mont L et al. Management of patients with palpitations: a position paper from the European Heart Rhythm Association [Internet]. 1st ed. European Society of Cardiology; 2011 [cited 1 March 2015]. Available from: http://europace.oxfordjournals.org/content/13/7/920.full

Barts Health NHS Trust. SVT. NHS; 2014. [cited 5 March 2015]. Available from: https://secure.collemergencymed.ac.uk/Shop-Floor/Clinical%20Guidelines/Local%20Guidelines/Default.asp?f=edit#Adult

Cardiac arrhythmias in coronary heart disease [Internet]. 1st ed. NHS Scotland; 2007 [cited 5 March 2015]. Available from: http://www.sign.ac.uk/pdf/sign94.pdf

2010 Resuscitation Guidelines [Internet]. 1st ed. 2010 [cited 9 March 2015]. Available from: https://www.resus.org.uk/pages/als.pdf

MANAGEMENT OF ACUTE CORONARY SYNDROME FOLLOWING COCAINE:

BETA ANTAGONISTS:

Rang HP, Dale MM. Rang & Dale’s Pharmacology. 7th ed. Edinburgh: Churchill Livingstone; 2012.

McCord J, Jneid H, Hollander JE, de Lemos JA, Cercek B, Hsue P, et al. Management of Cocaine-Associated Chest Pain and Myocardial Infarction: A Scientific Statement From the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation 2008 Apr 8; 117(14):1897–907.

Lange RA, Cigarroa RG, Flores ED, McBride W, Kim AS, Wells PJ et al. June 1990. Potentiation of Cocaine-Induced Coronary Vasoconstriction by Beta-Adrenergic Blockade. Annals of Internal Medicine. 12:897-903.

Ramoska E, Sacchetti AD. November 1985. Propranolol-Induced Hypertension in Treatment of Cocaine Intoxication. Annals of Emergency Medicine. 14(11):1112-1113.

Boehrer JD, Moliterno DJ, Willard JE, Hillis LD, Lange RA. June 1993. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. The American Journal of Medicine. 94(6):608-610

Fanari Z, Kennedy KK, Lim MJ, Laddu AA, Stolker JM. Comparison of in-hospital outcomes for beta-blocker use versus non-beta blocker use in patients presenting with cocaine-associated chest pain. Am J Cardiol 2014 Jun 1; 113(11):1802–6.

A reliable and useful study as it involved a large study of 376 patients and it also used multivariate analysis to eliminate confounding factors.

Rangel C, Shu RG, Lazar LD, Vittinghoff E, Hsue PY, Marcus GM. Beta-blockers for chest pain associated with recent cocaine use. Arch Intern Med 2010 May 24; 170(10):874–9.

Dattilo PB, Hailpern SM, Fearon K, Sohal D, Nordin C. β-Blockers Are Associated With Reduced Risk of Myocardial Infarction After Cocaine Use. Ann Emerg Med. 2008 Feb; 51(2):117–25.

UK National Poisons Information Service. TOXBASE®. [internet]. 2009 [cited 2015 Mar 12]; [9 screens]. Available from: http://www.toxbase.org/Poisons-Index-A-Z/C Products/Cocaine/

ALPHA ANTAGONISTS:

Lange, RA., Cigarroa, RG., Yancy, CW., Willard, JE., Popma, JJ., Sills, MN., et al. Cocaine-Induced Coronary-Artery Vasoconstriction, NEJM, 1989 Dec. 7; 321: 1557-1562.

This clinical trial was double-blind and placebo controlled, with a good method. The relevant findings only included 13 patients, so had low power. This did not involve treatment of cardiac ischaemia, as the patients were asymptomatic, so the conclusions may not be relevant.

Hollander, JE., Carter, WA., Hoffman, RS. Use of Phentolamine for Cocaine-Induced Myocardial Ischemia [letter] NEJM, 1992 Jul 30; 327: 361.

Chan, GM., Sharma, R., Price, D., Hoffman, RS, Nelson, LS. Phentolamine Therapy for Cocaine-Associated Acute Coronary Syndrome (CAACS), J Med. Toxicol. 2006 Sep; 2(3): 108-111.

Reference 2 and 3 are case reports, so all-encompassing conclusions cannot be drawn.

Lange, RA., Hillis, LD. Cardiovascular complications of cocaine use. N Engl J Med, 2001 Aug 2; 345(5): 351-8.

BENZODIAZEPINES:

Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. The Nervous System. In: Rang and Dale’s Pharmacology. 7th ed. London: Churchill Livingstone; 2007. p. 353-5.

Griffin CE, Kaye AM, Kaye AD. Benzodiazepine Pharmacology and Central Nervous System- Mediated Effects. Ochsner J 2013; 13 (2): 214-223.

Baumann BM, Perrone J, Hornig SE, Shofer FS, Hollander JE. Randomized, Double-blind, Placebo-controlled Trial of Diazepam, Nitroglycerin, or Both for Treatment of Patients with Potential Cocaine-associated Acute Coronary Syndromes. Acad Emerg Med 2008; 7 (8): 878-885.

Hollander JE. The Management of Cocaine-Associated Myocardial Ischeamia. N Engl J Med 1995; 333 (19): 1267-72.

American Heart Association. Introduction to ACLS 2000: Overview of Recommended Changes in ACLS From the Guidelines 2000 Conference- Part 6: Advanced Cardiovascular Life Support. Circulation 2000; 46 (1): 103-7.

Unfortunately, this advice may be dated as they are 15 years old, however in our search we could not find any more recent advice.

Honderick T, Williams D, Seaberg D, Wears R. A prospective, randomized, controlled trial of benzodiazepines and nitroglycerine or nitroglycerine alone in the treatment of cocaine-associated acute coronary syndromes. Acad Emerg Med 2003; 21 (1): 39-42.

The patient cohort was relatively small- only assesing 27 patients, which may lead to it being underpowered, and not reflecting the entire populations response to drug treatments.

MANAGEMENT OF ARRHYTHMIAS FOLLOWING COCAINE:

SODIUM BICARBONATE:

Kerns W, Garvey L, Owens J. Cocaine-Induced Wide Complex Dysrhythmia. J Emerg Med. 1997; 15(3):321-329.

Beckman KJ, Parker RB, Hariman RJ, Gallastegui JL, Javaid JI, Bauman JL. Hemodynamic and Electrophysiological Actions of Cocaine: Effects of Sodium Bicarbonate as an Antidote in Dogs. Circulation. 1991 May; 83(5):1799-1807.

Wilson LD, Shelat C. Electrophysiologic and Hemodynamic Effects of Sodium Bicarbonate in a Canine Model of Severe Cocaine Intoxication. Clin Toxicol. 2003; 41(6):777-788.

Parker RB, Perry GY, Horan LG, Flowers NC. Comparative Effects of Sodium Bicarbonate and Sodium Chloride on Reversing Cocaine Induced Changes in the Electrocardiogram. J Cardiovasc Pharmacol. ‐1999 Dec: 34(6);864-869.

Wang RY. pH-Dependent Cocaine-Induced Cardiotoxicity. Am J Emerg Med. 1999 Jul; 17(4):364-369.

A useful set of case reports. Whilst limited in its implications due to the lack of control and the small sample size, it is a useful insight into the clinical experience on the topic

Winecoff AP, Hariman RJ, Grawe JJ, Wang Y, Bauman JL. Reversal of the Electrocardiographic Effects of Cocaine by Lidocaine. Part 1. Comparison With Sodium Bicarbonate and Quinidine. Pharmacotherapy. 1994; 14(6):698-703.

UK National Poisons Information Service. TOXBASE®. [internet]. 2009 [cited 2015 Mar 12]; [9 screens]. Available from: http://www.toxbase.org/Poisons-Index-A-Z/C-Products/Cocaine/

LIDOCAINE:

Hoffman R. Treatment of patients with cocaine-induced arrhythmias: bringing the bench to the bedside. British Journal of Clinical Pharmacology. 2010;69(5):448-457.

Good paper, as it provided an easy to understand overview of the issue, without being too simplistic

Albertson T, Dawson A, de Latorre F, Hoffman R, Hollander J, Jaeger A et al. TOX-ACLS: Toxicologic-oriented advanced cardiac life support. Annals of Emergency Medicine. 2001;37(4):S78-S90.

Shih R, Hollander J, Burstein J, Nelson L, Hoffmann R, Quick A. Clinical Safety of Lidocaine in Patients With Cocaine-Associated Myocardial Infarction. Annals of Emergency Medicine. 1995;26(6):702-706.

CALCIUM CHANNEL ANTAGONISTS:

Billman G, Hamlin R. The Effects of Mibefradil, a Novel Calcium Channel Antagonist on Ventricular Arrhythmias Induced by Myocardial Ischemia and Programmed Electrical Stimulation. The Journal of Pharmacology and Experimental Theraputics. 1996;277:1517-1526.

Billman G, Hoskins R. Cocaine-induced ventricular fibrillation: the protection afforded by the calcium antagonist Verapamil. FASEB. 1988;2:2990-2995.Gave a good insight into how calcium may lead to VF, but as it was an animal study, it may not be as clinically adaptable

Gave a good insight into how calcium may lead to VF, but as it was an animal study, it may not be as clinically adaptable

Billman G. Effect of Calcium Channel Antagonists on Cocaine-Induced Malignant Arrhythmias: Protection against Ventricular Fibrillation. The Journal of Pharmacology and Experimental Therapeutics. 1993;266:407-416.

Was a good comprehensive overview, but as it was a canine study, it may be of limited clinical application

BENZODIAZEPINES:

UK National Poisons Information Service. TOXBASE®. [internet]. 2009 [cited 2015 Mar 12]; [9 screens]. Available from: http://www.toxbase.org/Poisons-Index-A-Z/C-Products/Cocaine/

Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects. Ochsner J. 2013; 13(2):214-223.

Baumann BM, Perrone J, Hornig SE, Shofer FS, Hollander JE. Randomized, Double-blind, Placebo-controlled Trial of Diazepam, Nitroglycerin, or Both for Treatment of Patients with Potential Cocaine-associated Acute Coronary Syndromes. Acad Emerg Med. 2000 Aug; 7(5):878-885

PRIVATE: WORD VERSION

The cardiac effects of cocaine