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Is adrenaline life-saving or deadly? Should it be the standard of care treatment for cardiopulmonary resuscitation?

Abstract

Adrenaline is commonly used in the treatment of anaphylaxis and cardiopulmonary resuscitation (CPR). However, its use in CPR may cause adverse neurological effects. Moreover, adrenaline overdose and overexposure to adrenaline may both lead to fatality. This is a literature review on the mechanism of action of adrenaline, its uses, and its effects. Adrenaline is a life-saving medication when it is administered correctly, and most of its fatal effects are preventable. However, the PARAMEDIC2 trial in the United Kingdom provided concrete evidence that adrenaline in CPR is associated with poor neurological outcome. Whether adrenaline should be the standard of care treatment for cardiopulmonary resuscitation needs to be reviewed.

Introduction

Adrenaline is a hormone that is secreted by the chromaffin cells of the adrenal medulla when the cells are stimulated by the neurons of the sympathetic nervous system. Adrenaline is also known as epinephrine. It is a catecholamine, a monoamine neurotransmitter. It stimulates alpha- and beta-adrenergic receptors and can cause a variety of physiological effects, such as increased contractility of the heart, bronchodilation in the lungs, and vasodilation or constriction.

As a medication, adrenaline is often used in emergencies. For example, it is the first line of treatment for anaphylaxis. Anaphylaxis is a ‘life-threatening, systemic’ allergic reaction that can affect people of all ages, and the early administration of adrenaline is associated with physiological benefits in the treatment of anaphylaxis.[1] A study in the UK has identified 1.06 million children and young people who have been prescribed adrenaline auto-injectors, and there is evidence to support that the rate of prescription is increasing.[2] Adrenaline is also used in cardiopulmonary resuscitation and many other medical settings.

However, adrenaline can also be harmful or deadly. Some studies have shown that the use of adrenaline in cardiopulmonary resuscitation causes adverse neurological effects.[3] Furthermore, it is suspected that a surge of adrenaline after a traumatic event could cause Takotsubo syndrome, also known as broken heart syndrome, which is a form of acute heart failure.[4] The difficulty of the administration of adrenaline could also cause deadly overdoses as it is easily overlooked.[5]

An overview of the mechanism of action of adrenaline

Adrenaline is a ligand that binds to a class of G-protein-coupled receptors (GPCRs), also known as adrenergic receptors. A GPCR is a seven-pass transmembrane receptor with an associated G protein on the other side of the plasma membrane. When adrenaline binds to a GPCR, it induces a conformational change in the GPCR, causing the G protein on the other side of the membrane to be activated. The effects of activated G proteins vary between cells and induce different physiological responses.[6]

Figure 1: This illustrates a signalling pathway caused by the stimulation of a GPCR by adrenaline.[7]

Adrenaline as life-saving- the use of adrenaline in anaphylaxis

Anaphylaxis is a severe, systemic allergic reaction that occurs within minutes to hours of exposure to an allergen, such as certain foods, medications, and venom. In an anaphylactic reaction, pathophysiological changes develop- bronchial smooth muscle contraction, increased mucus secretion, and increased vascular permeability. These changes could lead to a constricted airway, laryngeal oedema, and decreased blood pressure. Without immediate treatment, an anaphylactic reaction can cause respiratory compromise, cardiovascular collapse, and death.[8] [9] Hence, treatment for anaphylaxis must be prompt.

In the treatment of anaphylaxis with adrenaline, α-, β1– and β2– adrenoreceptors are stimulated. When adrenaline binds to α-adrenoreceptors on vascular smooth muscle cells, it induces contraction of the muscle cells, causing vasoconstriction. This increases peripheral vascular resistance, which increases blood pressure and coronary perfusion, and reduces angioedema.[10] By reducing angioedema, such as that of the tongue, the airway will be less obstructed and will alleviate the patient’s shortness of breath.

Figure 2: This diagram illustrates the reaction pathway on a cellular level. α1-adrenoreceptors are coupled to Gq proteins in the cell membrane (shown as R and Gq at the top of the diagram). When adrenaline binds to an α1-adrenoreceptor (signified by the first arrow), a conformational change is induced, causing the associated Gq protein to be activated. This activates phospholipase-C (PLC), an enzyme that hydrolyses the phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3), a second messenger. IP3 is a water-soluble sugar-phosphate that then diffuses to an inositol trisphosphate receptor (IP3R). IP3R is a glycoprotein complex acting as a calcium ion channel, releasing calcium 2+ (Ca2+) ions from the sarcoplasmic reticulum of the smooth muscle cells.

The influx of Ca2+ ions binds to the protein calmodulin, which binds to the enzyme myosin light-chain kinase. This results in the phosphorylation of myosin light chain, which enables myosin to bind with actin and begin the cross-bridge cycle.[11] The cross-bridge cycle causes the sarcomere to shorten, resulting in contraction of the vascular smooth muscle. Contraction of the vascular smooth muscle causes vasoconstriction, which increases blood pressure and increases coronary perfusion. This reduces the risk of cardiovascular collapse in an anaphylactic patient.

Figure 3: The diagram shows the interaction between actin (red) and myosin (pink) during the cross-bridge  cycle.[12]In part A of the diagram, the myosin S1 region binds to actin. In part B, the myosin S1 region bends, causing the actin to shift to the right, whilst the myosin remains in the same place. The myosin will then dissociate from the actin and reach forwards to bind to a new actin molecule. This process will be repeated and is known as the cross-bridge cycle.

β1– adrenoreceptors are mainly located in the heart and are associated with the Gs protein. When adrenaline binds to a β1– adrenoreceptor, Gs is stimulated, which upregulates adenyl cyclase, turning adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). Protein kinase A (PK-A), which is dependent upon cAMP, then phosphorylates the calcium channels in cardiomyocytes, resulting in a series of changes: increased heart rate due to increased sinoatrial nodal and atrioventricular nodal firing (positive chronotropy), increased conduction velocity (positive dromotropy), increased contractility due to increased ventricular muscular firing (positive inotropy) and increased relaxation of myocytes (positive lusitropy).[13] The cardiac output equation can be applied here, where stroke volume multiplied by heart rate equals cardiac output. With increased stroke volume (due to positive inotropy) and increased heart rate (due to positive chronotropy), the cardiac output is increased, which will increase perfusion around the body.

β2– adrenoreceptors are predominantly located in the smooth muscle cells of the lungs. They are also associated with the Gs protein and follow a similar pathway- adenyl cyclase is upregulated, producing cAMP, which activates PK-A. This causes the myosin light chain kinase in the smooth muscle cells of the bronchi to be inhibited, which reduces phosphorylation of myosin light chain and inhibits the cross-bridge cycle between myosin and actin. Furthermore, myosin light chain phosphatase is activated, which dephosphorylates the myosin light chain. These changes result in the relaxation of the smooth muscle cells in the bronchi of the lungs and bronchodilation. β2– adrenoreceptors are also located in the mast cells and basophils of the lungs. By increasing the levels of intracellular cAMP, the secretion of bronchoconstrictor mediators from the mast cells and basophils in the bronchi is inhibited, reducing inflammation.[14]Both bronchodilation and reduced inflammation allow breathing to be less laboured in an anaphylactic patient.

Adrenaline is able to produce a rapid response within minutes of administration, which makes it suitable to be used in the emergency treatment of anaphylaxis. Its ability to act on various organ systems and relieve symptoms by increasing blood pressure, increasing perfusion, increasing bronchodilation, and reducing inflammation mediators proves why adrenaline is the medicine of choice in anaphylaxis. If adrenaline is not administered to an anaphylactic patient, the patient risks hypoperfusion and cardiovascular collapse, as well as a respiratory compromise due to laryngeal oedema and inflammation of the bronchi. Both of these outcomes are potentially fatal. Hence, if adrenaline is administered to a patient after the onset of anaphylaxis, it is certainly life-saving.

Adrenaline as life-saving- the use of adrenaline in cardiac arrest or cardiopulmonary resuscitation (CPR)

Cardiac arrest occurs when the heart fails to pump blood to the organs in the body. It can be fatal within minutes if it is not treated. Causes of cardiac arrest include arrhythmias, structural changes to the heart, ischemic heart disease, previous heart attacks, and medications. Arrhythmias are caused by a malfunctioning intrinsic conduction system of the heart. The intrinsic conduction system consists of the sinoatrial (SA) node in the right atrium, the atrioventricular (AV) node, the bundle of His, and the Purkinje fibres in the ventricular walls. Contractions of the heart are controlled by this conduction system. An impulse is spread through the atria from the SA node to the AV node, which causes the atria to contract. Afterwards, the impulse spreads to the bundle of His, the bundle branches, and the Purkinje fibres, causing the ventricles to contract. However, if one of the nodes is damaged, or if the bundles are blocked, arrhythmias may occur. Other factors may also cause arrhythmias: changes in the structure of the heart such as a thickened heart muscle (cardiomyopathy) or scarring of the heart tissue due to a previous heart attack may both cause electrical signals to conduct abnormally throughout the heart.[15] Patients with ischemic heart disease may have an inadequate blood supply to the myocardium due to the build-up of plaque in the coronary arteries. If an area of plaque ruptures and causes a blood clot to form, that will also cause reduced blood supply. The lack of blood supply to the myocardium may cause arrhythmias. Diuretic medications also increase the risk of arrhythmias due to the fluctuation in levels of potassium and magnesium in the blood. A common type of arrhythmia that causes cardiac arrest is ventricular fibrillation when the ventricles quiver in a disorganized manner. When this occurs, the heart is unable to pump blood to the organs, and this may be fatal.

The emergency treatments of a cardiac arrest are cardiopulmonary resuscitation and defibrillation in order to restore a regular heartbeat and breathing. Adrenaline has been in resuscitation guidelines worldwide since the 1960s.[16] In both CPR and anaphylaxis, adrenaline causes the same response in the vascular smooth muscle cells. Adrenaline stimulates the α1-adrenoreceptors, inducing a conformational change and activates the associated Gq protein. This activates PLC, hydrolyzing PIP2 to IP3, which then causes an influx of Ca2+ ions. This influx indirectly induces the cross-bridge cycle, which causes contraction of the vascular smooth muscle cells- vasoconstriction. The result of peripheral vasoconstriction is increased aortic diastolic pressure, which leads to an increase in coronary perfusion pressure (CPP) and coronary blood flow. The increase in CPP may lead to a return of spontaneous circulation (ROSC), meaning that perfusing cardiac activity is restored. Patients without ROSC will not survive a cardiac arrest. A study on the relationship between CPP and ROSC has been conducted on 100 patients with cardiac arrest. In patients without ROSC, the mean initial CPP value was 1.6 ± 8.5 mmHg, whereas, for patients with ROSC, the mean initial CPP value was 13.4 ± 8.5 mmHg.[17] The data indicate that a high CPP value is associated with a higher likelihood of ROSC, and hence a greater chance of survival.

Adrenaline has also shown to be able to stabilize ventricular fibrillation by reducing the duration of the action potential as well as by reducing the cellular refractory period. This makes reentrant arrhythmogenesis less likely when a re-entry wavefront coincides with the refractory period of a cell.[18] Although the mechanism of action of adrenaline in stabilizing ventricular fibrillation is unclear. A study has shown that the reduction in duration of the action potential is reversed by propranolol, which is a beta-blocker. This indicates that adrenaline stabilizes ventricular fibrillation by stimulating beta-adrenoreceptors, suggesting that on a cellular level, the change in the action potential duration could be caused by the increased levels of cyclic adenosine monophosphate and protein kinase A. [19]

Since the use of adrenaline in CPR can stabilize ventricular fibrillation and increase the chance of a return of spontaneous circulation, the likelihood of restoring a regular pulse and breathing in a patient with cardiac arrest is increased. Given that a cardiac arrest can cause death within minutes, the administration of adrenaline alongside CPR points towards an increase in the prospect of survival due to the ability of adrenaline to cause physiological responses rapidly (within two to three minutes). If both CPR and defibrillation are unsuccessful, adrenaline is potentially life-saving medication to reverse the cessation of breathing and circulation in a patient with cardiac arrest.

Adverse effects of adrenaline- adrenaline in cardiac arrest

Although adrenaline has been used in treating cardiac arrests since the 1960s due to its ability to increase coronary perfusion pressure and increase the likelihood of a return of spontaneous circulation, there has been speculation that adrenaline causes worse neurological outcomes. Adrenaline can increase cerebral perfusion pressure and global cerebral blood flow by stimulating alpha adrenoreceptors and cause vasoconstriction, but vasoconstriction can reduce microcirculatory flow and cause microvascular ischemia in the brain. This will lead to a hypoxic brain injury, resulting in poor neurological outcomes. [20]

In a porcine study that investigated the effect of adrenaline during CPR, it was shown that although adrenaline increased cerebral perfusion pressure, there was a ‘significant decrease’ in microcirculatory blood flow and brain perfusion. [21] In the post-hoc analysis of a Norwegian clinical trial, there was evidence that the use of adrenaline improved short-term survival, but it also caused unfavourable neurologic outcomes and a lower rate of long-term survival. [22] Another study has also shown that there are less neurologically intact survivors among patients who received adrenaline during their treatment for cardiac arrest. [23] Although many studies have suggested that adrenaline has adverse effects on neurologic outcome, most of the studies are observational and are not supported by rigorous experimental trials and scientific data.

The first randomized, double-blind placebo-controlled trial to determine the effect of adrenaline on survival in out-of-hospital cardiac arrests was conducted in Australia. [24] However, ethical issues presented by the government and its ethics committees prevented four out of five ambulance services from participating in the trial. This is because adrenaline is a ‘standard of care’ medication for cardiac arrest patients, and it is unethical to withhold this medication from them. Although the results of the trial showed a trend towards increased rates of survival with the use of adrenaline, the results did not achieve statistical significance due to the inadequate sample size. However, the PARAMEDIC2 trial conducted later in the United Kingdom provided concrete evidence for the adverse effects of adrenaline. [25] This trial achieved statistical significance as it had a large sample size.

In the PARAMEDIC2 trial, 8014 patients with cardiac arrest were included. 4015 had adrenaline, and 3999 had a placebo saline injection. The use of adrenaline was associated with a higher likelihood of ROSC- 36.3% of patients in the adrenaline group had ROSC, whereas only 11.7% of patients in the placebo group did. The rate of survival at 30 days was also higher for the adrenaline group. However, severe neurological disabilities occurred in 31% of patients in the adrenaline group in comparison to 17.8% in the placebo group. In this trial, a modified Rankin score of 4-5 was categorized as a severe neurological disability. Score 4 on the modified Rankin scale represents ‘unable to walk and attend to own bodily needs without assistance’, and score 5 represents ‘bedridden, incontinent and requiring constant nursing care and attention’. [26] Such neurological disabilities compromise the patient’s quality of life and can impact them emotionally, financially, and socially. The patient’s disability will also affect their family or carer.

Although adrenaline increases the rate of survival in a cardiac arrest and can be life-saving, the use of adrenaline ought to be reviewed due to the poor neurological outcome associated with it. Perhaps a lower dose of adrenaline should be used to reduce its effects on the microcirculatory flow. It has been suggested that a delay in administering adrenaline is associated with worse outcomes, so perhaps adrenaline should be used earlier in the treatment of cardiac arrest. Furthermore, alternatives for adrenaline can be considered. For example, the use of vasopressin can also increase coronary perfusion pressure and increase the likelihood of a return of spontaneous circulation with more benign neurological effects. This is because some studies have correlated the use of vasopressin to an increase in cerebral blood flow and cerebral oxygenation.

Adrenaline as deadly- adrenaline in Takotsubo syndrome and chronic stress

Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy or broken-heart syndrome, was first identified in Japan in the 1990s. It is a sudden weakening and apical ballooning of the left ventricle. The shape of the ballooning resembles a Tako-tsubo, a pot used to trap octopuses; hence this syndrome is named Takotsubo cardiomyopathy. Symptoms of Takotsubo cardiomyopathy are similar to that of a heart attack, and an electrocardiogram of a patient with Takotsubo syndrome will show a similar ST-segment elevation to that found in a heart attack. [27]

electrocardiogram
Figure 4: This is an example of an electrocardiogram showing ST-segment elevation (indicated by the blue arrow). This segment is usually a plateau, but in the diagram, it is elevated.

However, an angiogram of a patient with this syndrome will not show stenosis of the coronary arteries, and an echocardiogram will show ballooning of the apex. [28] Although abnormalities to the left ventricle are reversible and may naturally resolve over time, the weakening of the ventricle could also lead to acute heart failure, ventricular arrhythmias, and ventricular rupture. On rare occasions, this condition may lead to death. The condition is usually triggered by a stressful event, such as receiving bad news, a fight, an intense argument, or fear. Although the cause of this condition is unknown, experts believe that it could be due to a surge in stress hormones, for example, adrenaline. As a result, doctors have been prescribing beta-blockers to patients with Takotsubo syndrome to control the effect of stress hormones.

Some experts suspect that Takotsubo syndrome is caused by adrenaline reaching lethal levels after a traumatic event, causing adverse effects on the muscle of the heart. A study was carried out on rats to investigate transient left ventricular apical ballooning, and the results showed that experiences of emotional stress-induced apical ballooning in rats that did not receive pretreatment with an adrenoreceptor blocker. [29] This animal model suggests that Takotsubo syndrome could be caused by the over-stimulation of the adrenoreceptors. When a high concentration of adrenaline is released, beta-1 adrenoreceptors are rapidly stimulated. The binding of adrenaline to a β1– adrenoreceptor increases the intracellular level of cAMP. PK-A, which is dependent upon cAMP, then phosphorylates the calcium channels in cardiomyocytes, causing an influx of calcium ions. The overload of calcium ions in cardiocytes has shown to induce a toxic effect leading to a decrease in cell viability. [30] The apex is particularly prone to ballooning due to its structural limitations- it has limited elasticity and quickly becomes ischemic due to limited coronary perfusion. [31] The apex has also shown to be more responsive to stimulation by adrenaline in comparison to other regions of the heart, such as the basal region. This could suggest that the apex has a higher density of beta-adrenoreceptors. [32]

Other investigators have suggested that apical ballooning is due to an ‘aborted myocardial infarction’. The sudden surge of adrenaline can stimulate the alpha adrenoreceptors in the vascular smooth muscle cells, which causes rapid vasoconstriction. Vasoconstriction leads to an increase in coronary perfusion pressure, which may cause temporary occlusions to occur in the coronary arteries. Investigators believe that it is these occlusions alongside spontaneous thrombus lysis that affect the left anterior descending coronary arteries, causing the apical abnormality. [33] This apical abnormality can cause the intrinsic conduction system to malfunction and lead to arrhythmias, or even heart failure and death.

Takotsubo syndrome is an acute condition due to a sudden surge of adrenaline. However, chronic conditions can also cause overexposure to adrenaline, such as chronic stress. Overexposure can have adverse effects on the body, for example, hypertension and other types of cardiomyopathy. Prolonged exposure to adrenaline means that the alpha and beta adrenoreceptors are stimulated continuously.

Stimulation of alpha adrenoreceptors causes an increase in calcium ions in smooth muscle cells, which leads to vasoconstriction, and therefore hypertension. The constant high blood pressure can damage the endothelial cells of arteries and lead to atherosclerosis and coronary thrombosis. Not only can hypertension cause atherosclerosis, but it can also cause aneurysms. An aneurysm is the weakening of the artery wall, causing a bulge that can rupture and cause severe internal bleeding. Both atherosclerosis and aneurysms can cause an inadequate supply of blood to the heart and the brain. Inadequate supply to the heart can lead to arrhythmias and myocardial infarctions, whereas inadequate supply to the brain can cause transient ischaemic attacks and stroke. Other organs can also be affected by hypertension.

Stimulation of beta-adrenoreceptors increases cellular levels of cAMP, which activates PK-A and leads to an increase in the concentration of calcium ions. This causes positive chronotropy and positive inotropy and may lead to tachycardia. When a person is tachycardic, the heart is not able to efficiently supply blood around the body, which can cause symptoms such as syncope. If the heart does not have an adequate blood supply, it may cause myocardial infarction. Moreover, the constantly elevated heart rate and contractility may cause cardiomyopathy, which is the thickening or stiffening of the myocardium. A common type of cardiomyopathy is hypertrophic cardiomyopathy, which can be caused by hypertension. The structural changes to the heart may lead to heart valve disease, arrhythmias, and heart failure. [34]

It is clear that sudden surges of adrenaline and constantly elevated levels of adrenaline can both be deadly. Although Takotsubo cardiomyopathy is hard to prevent due to its sudden and acute nature, chronic stress causing hypertension or tachycardia can be controlled by medication. Beta-blockers such as propranolol are competitive antagonists that block adrenaline from binding to a GPCR. By reducing the stimulation of adrenoreceptors by adrenaline, blood pressure and heart rate can be maintained under control. In addition, by reducing or removing factors causing stress in daily life, the deadly effects of adrenaline can be prevented.

Adrenaline as deadly- adrenaline overdose

Due to the ability of adrenaline to act on multiple organ systems, it has many uses, from treating anaphylaxis to being used with local anaesthetics in surgeries. However, the appropriate administration of adrenaline appears to be challenging, with multiple cases of adrenaline overdose.

A survey was conducted at two UK hospitals on the use of adrenaline in anaphylaxis by junior doctors. [35] All junior doctors were given the same questionnaire (see appendix 1). Out of 95 junior doctors surveyed, only 16 (16.8%) were able to correctly respond with the appropriate dose and route to administer adrenaline in anaphylaxis as recommended by the UK Resuscitation Council Guidelines. Out of the 28.4% who would administer adrenaline intravenously, 29.6% would administer a dose, which is higher than the recommended dosage. 7.4% were unsure of the dosage and route of administration. Inappropriate choices of dosage and route of administration can lead to fatal consequences. However, from the survey, it is clear that most junior doctors do not know the recommended treatment for anaphylaxis, even though they could be the first responders to an anaphylactic patient. This shows that education on the treatment of anaphylaxis requires reviewing, and perhaps resuscitation carts in hospitals should include clear guidance on the use of adrenaline in anaphylaxis.

A case of adrenaline overdose was reported in a pediatric patient with anaphylaxis. [36] A 9-year-old boy had developed anaphylaxis after ingesting a dairy product at school. He was administered intramuscular adrenaline before ambulance arrival. Upon the arrival of the ambulance, the boy was still presenting with elevated heart rate and elevated respiratory rate, but no blood pressure measurements were taken. Another dose of intramuscular adrenaline was administered, with intravenous adrenaline administered later due to no improvement of symptoms. It was upon arrival at the hospital when adrenaline toxicity was suspected because no oxygen saturation measurements could be taken despite the boy’s high blood pressure (207/187 mmHg) and high heart rate (160 bpm). The blood pressure measurement of 207/187 mmHg can be deemed a hypertensive crisis. An electrocardiogram taken later also showed sinus tachycardia.

An overdose of adrenaline would cause overstimulation of the alpha and beta-adrenoreceptors, causing hypertension and a high heart rate. If adrenaline toxicity was not suspected, the overdose could progress further, causing stroke, arrhythmias, and potentially death. In this case, adrenaline toxicity was mistaken for an anaphylactic shock because the two conditions have similar symptoms. For a patient in anaphylactic shock, symptoms include hyperventilation, confusion or anxiety, cyanotic skin, and, most importantly, hypotension. A patient with adrenaline overdose can also present with similar symptoms, except that they would have hypertension instead of hypotension. Hence, blood pressure is an essential factor in distinguishing between the two. In the guidelines for the assessment and management of anaphylaxis by the World Allergy Organisation, reduced blood pressure is one of the three clinical criteria for diagnosing anaphylaxis. [37] Since blood pressure measurements were not taken before admission to the hospital, adrenaline toxicity was not suspected. Hence, it is crucial to take into account all the vital signs of the patient, especially blood pressure measurements. Furthermore, adrenaline should be administered via the intramuscular route. It has lower risks of overdose because the speed of absorption via the intramuscular route (within minutes) is slower in comparison to the intravenous route (within seconds). Intramuscular injections are, in fact, more effective in most cases as it does not require cannulation, which may cause a delay in administering adrenaline. Also, skeletal muscles have an adequate supply of blood vessels to allow the safe and rapid absorption of adrenaline. Hence, the UK Resuscitation Council Guidelines recommend intramuscular adrenaline as the initial treatment for adrenaline. However, if the patient is not responsive to multiple doses of adrenaline and is presenting severe hypotension, cardiac arrest or respiratory arrest, intravenous adrenaline may be used.

Not only is adrenaline used in anaphylaxis, but it is also used in surgery alongside local and general anaesthetics. Adrenaline is a good vasoconstrictor due to its ability to stimulate alpha adrenoreceptors in the vascular smooth muscle cells. Hence, when it is used alongside local anaesthetics, it is able to reverse the vasodilation effect of the anaesthetic and constrict surrounding blood vessels. This is to reduce the rate of absorption and spread of the anaesthetic around the body and prolong the effect of the anaesthetic. When adrenaline is used with general anaesthetics, the ability of adrenaline to stimulate alpha adrenoreceptors in the vascular smooth muscle cells and beta adrenoreceptors in cardiomyocytes can reverse hypotension caused by the anaesthetics.

Another case of adrenaline overdose was reported in a 23-year-old woman during a tympanoplasty under general anaesthesia. [38] A 1:200,000 dilution of adrenaline was thought to be administered, but soon after, the patient’s heart rate and blood pressure were both unrecordable. It was then realized that a 1:1000 solution was used. Within five minutes, the patient was in a state similar to acute peripheral circulatory failure. The high concentration of adrenaline administered had caused severe vasoconstriction in the peripheral arteries and veins, which could have led to organ failure due to inadequate blood flow to tissues. Systolic blood pressure levels rose to over 300 mmHg whilst pulse rate was still too high to be measured. Medications were administered to reverse the effects of adrenaline, but there were difficulties administering the medications intravenously due to the high blood pressure. A pressure pump was required to maintain the infusion of medications into the saphenous vein. It was fortunate that the patient survived and discharged after eight days. This case sheds light on how an adrenaline overdose could be deadly as the patient could have developed fatal arrhythmias and organ failure. The case also shows that it is vital for anaesthetists to check the dilution ratio of the medication being administered.

Although most adrenaline overdoses are due to medical errors, there has also been a case of suicide involving adrenaline.[39] As part of a suicide plan, a 34-year-old woman injected herself with an adrenaline auto-injector. In the autopsy, it was concluded that her death was caused by cardiac dysrhythmia and cardiac arrest as a result of an adrenaline overdose. Although adrenaline auto-injectors are life-saving in anaphylaxis, misuse of these auto-injectors have proved to be deadly. Hence, it is important that these auto-injectors are kept out of the reach of children and people at risk of self-harm. It is also essential for doctors to explain to their patients when they should and when they should not use their auto-injectors.

All three cases underline the dangers of adrenaline overdose and the potential for it to be deadly. It is crucial that the correct dosage of adrenaline is administered via the correct route under appropriate circumstances.

Conclusion

Adrenaline is very useful as a medication as it is able to act on multiple organ systems, in particular the cardiovascular, respiratory, and muscular systems. Adrenaline is life-saving for anaphylactic patients as it is able to prevent cardiovascular collapse and respiratory compromise by stimulating both alpha and beta-adrenoreceptors and produces a rapid response. Without adrenaline, anaphylaxis can be fatal within minutes. Given that adrenaline is crucial in the treatment of anaphylaxis, members of the community should be educated on the use of adrenaline auto-injectors.

Adrenaline is also life-saving in the treatment of cardiac arrest due to its ability to increase the likelihood of a return of spontaneous circulation and survival. Its ability to increase coronary perfusion and stabilize ventricular fibrillation is essential in the treatment of cardiac arrest. At the moment, the use of adrenaline in CPR is a standard of care treatment. However, since the PARAMEDIC2 trial has shown that adrenaline can cause severe neurological disabilities, the use of adrenaline in cardiac arrest ought to be reviewed. Given the results from the trial, it could be against non-maleficence to continue following the same guidelines on the use of adrenaline in CPR. Although adrenaline is associated with adverse effects, the idea of using adrenaline in CPR should not only be discarded. Instead, more rigorous clinical trials should be done to determine the appropriate dosage and route of administration of adrenaline, and perhaps adrenaline can be used alongside vasopressin for the most beneficial outcome.

Overexposure to adrenaline due to stress or overdoses because of medical errors can both be fatal due to the possibility of complications such as arrhythmias and organ failure. However, overexposure to adrenaline can be controlled, whether it is by using beta-blockers to reduce the stimulation of adrenoreceptors or by making lifestyle changes to reduce stress levels. Furthermore, overdosing of adrenaline due to medical errors can definitely be avoided, and this is the same for any other medication. For example, additional checks on the dilution ratio should be done before administering adrenaline; medical staff should be educated on the correct administration of adrenaline, as well as how to distinguish between anaphylactic shock and adrenaline overdose. Due to technological advancements, medical staff can now easily and quickly access flowcharts and datasheets for information on dosage and route of administration. Hence, the use of adrenaline is not entirely undermined by the cases of overdoses.

Not all uses of adrenaline and their effects have been explored in this investigation, but the fundamental mechanism of action of adrenaline remains the same. Although adrenaline can be deadly, its fatal effects can be prevented to a certain extent. Its life-saving abilities outweigh its deadly effects, and it is a vital and useful medication.

Appendix

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Glossary

(Definitions are from the Medical Dictionary of Health Terms- Harvard Health Publishing. https://www.health.harvard.edu/medical-dictionary-of-health-terms/a-through-c#C-terms)

Term Definition
Arrhythmia An abnormal heart rhythm caused by a disturbance in the heart’s electrical system.
Atrioventricular node Also known as the AV node. A major part of the electrical system in the heart that acts as a gateway between the atria and the ventricles. An electrical signal generated by the sinoatrial node (the heart’s natural pacemaker) moves through the heart until it reaches the atrioventricular node, a cluster of cells at the bottom of the right atrium.
Cardiopulmonary Resuscitation A combination of chest compressions and mouth-to-mouth breathing that keep oxygenated blood circulating to the brain and tissues. Commonly known as CPR.
Cardiac arrest The sudden cessation of contractions capable of circulating blood to the body and brain. Also called sudden cardiac arrest.
Ischaemic heart disease The most common form of heart disease, in which narrowed or blocked coronary arteries have difficulty supplying sections of the heart muscle with the blood they need (ischemia).
Myocardium The middle layer of heart tissue. The muscular myocardium is located between the outer layer (epicardium) and the inner layer (endocardium).
Sinoatrial node The natural pacemaker of the heart. Located in the right atrium, the sinoatrial node, sometimes called the sinus node, initiates the heart’s electrical activity.

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About The Author

profile picture Nicola is a Year 12 student at Guildford High School, currently studying sciences and maths. She has been awarded a Gold CREST award and aspires to study medicine at university. In her free time, Nicola enjoys playing music and volunteering. Her experiences of volunteering as a first aider sparked her interest in anaphylaxis and adrenaline, inspiring her to complete this investigation.

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